Neurogenetic Disorders

Pyruvate and acetyl-CoA are the substrate and product, respectively for pyruvate dehydrogenase complex (PDC). E3 binding protein (E3BP) – the product of PDHX and specific to PDC, is not depicted. E3, dihydrolipoamide dehydrogenase – the product of DLD, is not unique to PDC but shared by other NAD-dependent alpha-ketoacid dehydrogenase complexes, such as the branched-chain alpha-ketoacid dehydrogenase complex (BCKDC) and alpha-ketoglutarate dehydrogenase complex (KGDC), among others. Lipoate modification of E2 component is noted, which is crucial for the acyltransferase reaction. Pyruvate dehydrogenase phosphatase and kinase, such as those encoded by PDP1 and PDK3, respectively, are specific regulators to PDC, with other phosphatases and kinases unique to the other alpha-ketoacid dehydrogenase complexes. (Contributed by Dr. Jirair K Bedoyan.)

Abbreviations: CoA, coenzyme A; FAD, flavin adenine dinucleotide; NAD, nicotinamide adenine dinucleotide; R, methyl group for pyruvate as the PDC substrate; and TPP, thiamine pyrophosphate, aka thiamine diphosphate (TDP).

T2 FLAIR sequence shows white matter hyperintensities in the parietal-occipital lobes and basal ganglia in a patient with Fabry disease. (Source: Zhao Y, Zhu Y, Li F, et al. Brain MRI correlations with disease burden and biomarkers in Fabry disease. J Neurol 2023;270[10]:4939-48. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

A DWI sequence shows recent cerebral infarctions in the cerebellum in a patient with Fabry disease. (Source: Zhao Y, Zhu Y, Li F, et al. Brain MRI correlations with disease burden and biomarkers in Fabry disease. J Neurol 2023;270[10]:4939-48. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

MRI of a 27-year-old woman with Fabry disease showing discrete pathological MRI involvement. Axial FLAIR shows two small lesions in the periventricular white matter (a, b). (Source: Rekova P, Kovarova I, Uher T, et al. Missed diagnosis of Fabry disease: should we screen patients with multiple sclerosis? Neurol Sci 2024;45[1]:231-9. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Axial FLAIR of a 29-year-old woman with Fabry disease shows multiple typical laterodorsal hyperintense lesions in the cervical spinal cord. (Source: Rekova P, Kovarova I, Uher T, et al. Missed diagnosis of Fabry disease: should we screen patients with multiple sclerosis? Neurol Sci 2024;45[1]:231-9. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

MRI of a 44-year-old woman with Fabry disease showing discrete pathological MRI involvement fulfilling MRI criteria with a typical lesion distribution for multiple sclerosis. Axial FLAIR shows small lesions in the frontal lobe (a, b) in the typical subcortical region (b) and in the pons (c). (Source: Rekova P, Kovarova I, Uher T, et al. Missed diagnosis of Fabry disease: should we screen patients with multiple sclerosis? Neurol Sci 2024;45[1]:231-9. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Axial FLAIR of a 29-year-old woman with Fabry disease shows a small lesion. (Source: Rekova P, Kovarova I, Uher T, et al. Missed diagnosis of Fabry disease: should we screen patients with multiple sclerosis? Neurol Sci 2024;45[1]:231-9. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Sagittal T2-weighted MRI of 49-year-old woman with Fabry disease shows a typical intramedullary lesion. (Source: Rekova P, Kovarova I, Uher T, et al. Missed diagnosis of Fabry disease: should we screen patients with multiple sclerosis? Neurol Sci 2024;45[1]:231-9. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Sagittal FLAIR of a 49-year-old woman with Fabry disease shows callososeptal hyperintensities radiating from the lateral ventricles with a typical perpendicular orientation. (Source: Rekova P, Kovarova I, Uher T, et al. Missed diagnosis of Fabry disease: should we screen patients with multiple sclerosis? Neurol Sci 2024;45[1]:231-9. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Clinical features of Fabry disease in 20 children (13 boys and 7 girls). Abbreviation: LVH, left ventricular hypertrophy.

(Source: Savostyanov K, Pushkov A, Zhanin I, et al. Genotype-phenotype correlations in 293 Russian patients with causal Fabry disease variants. Genes [Basel] 2023;14[11]:2016. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(Source: Izhar R, Borriello M, La Russa A, et al. Fabry disease in women: genetic basis, available biomarkers, and clinical manifestations. Genes [Basel] 2023;15[1]:37. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Abbreviations: ALGLA, alpha-galactosidase A; FD, Fabry disease; GB3, globotriaosylceramide.

(Source: Izhar R, Borriello M, La Russa A, et al. Fabry disease in women: genetic basis, available biomarkers, and clinical manifestations. Genes [Basel] 2023;15[1]:37. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

A mother with a GLA variant on one of her two X chromosomes has a 50% probability of passing the Fabry disease gene to each of her offspring, regardless of their gender. Under normal circumstances with an x-linked recessive disorder, her sons with the abnormal gene will have Fabry disease, whereas her daughters with the abnormal gene will be carriers. However, although Fabry disease was initially considered to predominantly affect males, studies have uncovered that heterozygous Fabry women, carrying a single mutated GLA gene, can manifest a wide array of clinical symptoms, challenging the notion of asymptomatic carriers and instead suggesting that Fabry disease could be considered X-linked dominant with reduced penetrance. As with many other X chromosome disorders, it has also been argued that Fabry disease should be characterized as inherited in an X-linked manner, without distinction as to being recessive or dominant. (Source: Izhar R, Borriello M, La Russa A, et al. Fabry disease in women: genetic basis, available biomarkers, and clinical manifestations. Genes [Basel] 2023;15[1]:37. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Exosomes can carry anti- and pro-inflammatory cytokines both on their lumens and associated with their membranes. Several cytokines have been shown to be preferentially enriched within exosomes, including interleukin-2, -4, -10, -18, and -33; tumor necrosis factor-alpha; transforming growth factor-beta; and macrophage-colony-stimulating factor. Thus, an immune cell can communicate with another through exosomes, namely by activating or inhibiting the production of cytokines in the target cell. Also, exosomes can stimulate endothelial cells.

Abbreviations: ECAs, exosome-associated cytokines; IL, interleukin; M-CSF, macrophage-colony-stimulating factor; TLR4, Toll-like receptor 4; TNF, tumor necrosis factor.

(Source: Coelho-Ribeiro B, Silva HG, Sampaio-Marques B, et al. Inflammation and exosomes in Fabry disease pathogenesis. Cells 2024;13[8]:654. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Globotriaosylceramide and globotriaosylsphingosine influence the levels of soluble factors and signaling receptors and the inflammatory-cell profile in Fabry disease. Different immune responses may be triggered in Fabry disease patients of different genders or distinct disease manifestations. Fabry disease treatment, specifically enzyme replacement treatment, also influences the immune response.

Abbreviations: BNP, B-type natriuretic peptide; CCR2, monocyte chemoattractant protein-1 receptor; CD, cluster of differentiation; DCs, dendritic cells; DD, diastolic dysfunction; DN iNKT, double-negative invariant natural killer T cells; ERT, enzyme replacement treatment; FGF2, fibroblast growth factor 2; Gb-3, globotriaosylceramide; GM-CSF, granulocyte-macrophage-colony-stimulating factor; IL, interleukin; INF-γ, interferon-gamma; iNKT, invariant natural killer T cells; LGE, late gadolinium enhancement; LVH: left-ventricular hypertrophy; Lyso-Gb3, globotriaosylsphingosine; MCP-1, Monocyte Chemoattractant Protein-1; MHC, major histocompatibility complex; MMP: metalloproteinase; MR-proANP, midregional pro-atrial natriuretic peptide; No ≠: no differences; TGF, transforming growth factor; TLR, Toll-like receptor; TNF, tumor necrosis factor; TNFR, tumor necrosis factor receptor.

(Source: Coelho-Ribeiro B, Silva HG, Sampaio-Marques B, et al. Inflammation and exosomes in Fabry disease pathogenesis. Cells 2024;13[8]:654. Adapted from: Carnicer-Cáceres C, Arranz-Amo JA, Cea-Arestin C, et al. Biomarkers in Fabry disease. Implications for clinical diagnosis and follow-up. J Clin Med 2021;10[8]:1664. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

The autophagic process can be divided into mechanistically different phases: initiation, vesicle formation (elongation and closure), autophagosome-lysosome fusion, and breakdown of the cargo. (Source: Coelho-Ribeiro B, Silva HG, Sampaio-Marques B, et al. Inflammation and exosomes in Fabry disease pathogenesis. Cells 2024;13[8]:654. Adapted from: Chiramel AI, Brady NR, Bartenschlager R. Divergent roles of autophagy in virus infection. Cells 2013;2[1]:83-104. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(Left side) Functional alpha-gal-A activity in a person with no mutation in GLA gene or absent activity. As a result, there is no accumulation of unwanted substrate in the lysosome. Also, the enzyme is responsible for removing the terminal galactose sugar from Gb-3, which leads to the formation of lactosylceramide (LacCer). (Right side) The function of alpha-gal-A is altered due to the presence of a mutation in the GLA gene. The latter leads to a buildup of Gb-3. Thus, an accumulation of dysfunctional lysosomes occurs within the cell.

Abbreviations: alpha-gal-A, alpha-galactosidase A; Cer, ceramide; Gal, galactose; Gb-3, globotriaosylceramide; Glu, glucose; LacSer, lactosylceramide; Lysoo-Gb3, globotriaosulsphingosine.

(Source: Coelho-Ribeiro B, Silva HG, Sampaio-Marques B, et al. Inflammation and exosomes in Fabry disease pathogenesis. Cells 2024;13[8]:654. Adapted from: Rocchetti MT, Spadaccino F, Catalano V, et al. Metabolic fingerprinting of Fabry disease: diagnostic and prognostic aspects. Metabolites 2022;12[8]:703. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

The index patient (propositus) is marked with a black arrow. Affected males are indicated by solid black squares; female carriers are indicated by a round black circle within the larger circle denoting a woman. Numbers within symbols denote the number of male or female relatives; a question mark denotes subjects unavailable for biochemical and genetic evaluation due to refusal or death. (Source: Cianci V, Pascarella A, Manzo L, et al. Late-onset Fabry disease due to the p.Phe113Leu variant: the first Italian cluster of five families. Metab Brain Dis 2023;38[6]:1905-12. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

The index patient (propositus) is marked with a black arrow. Affected males are indicated by solid black squares; female carriers are indicated by a round black circle within the larger circle denoting a woman. Numbers within symbols denote the number of male or female relatives; a question mark denotes subjects unavailable for biochemical and genetic evaluation due to refusal or death. (Source: Cianci V, Pascarella A, Manzo L, et al. Late-onset Fabry disease due to the p.Phe113Leu variant: the first Italian cluster of five families. Metab Brain Dis 2023;38[6]:1905-12. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

The index patient (propositus) is marked with a black arrow. Affected males are indicated by solid black squares; female carriers are indicated by a round black circle within the larger circle denoting a woman. Numbers within symbols denote the number of male or female relatives; a question mark denotes subjects unavailable for biochemical and genetic evaluation due to refusal or death. Note how the disease appears to "skip" a generation in which both children were girls. (Source: Cianci V, Pascarella A, Manzo L, et al. Late-onset Fabry disease due to the p.Phe113Leu variant: the first Italian cluster of five families. Metab Brain Dis 2023;38[6]:1905-12. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

The index patient (propositus) is marked with a black arrow. Affected males are indicated by solid black squares; female carriers are indicated by a round black circle within the larger circle denoting a woman. Numbers within symbols denote the number of male or female relatives; a question mark denotes subjects unavailable for biochemical and genetic evaluation due to refusal or death. Note how the disease appears to "skip" a generation. (Source: Cianci V, Pascarella A, Manzo L, et al. Late-onset Fabry disease due to the p.Phe113Leu variant: the first Italian cluster of five families. Metab Brain Dis 2023;38[6]:1905-12. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

The index patient (propositus) is marked with a black arrow. Affected males are indicated by solid black squares; female carriers are indicated by a round black circle within the larger circle denoting a woman. Numbers within symbols denote the number of male or female relatives; a question mark denotes subjects unavailable for biochemical and genetic evaluation due to refusal or death. (Source: Cianci V, Pascarella A, Manzo L, et al. Late-onset Fabry disease due to the p.Phe113Leu variant: the first Italian cluster of five families. Metab Brain Dis 2023;38[6]:1905-12. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

MR angiography showing intracranial tortuous arteries characteristic of Menkes disease in a female infant with Menkes disease due to unfavorable switching of skewed X chromosome inactivation. (Source: Matsumoto A, Kano S, Kobayashi N, et al. Unfavorable switching of skewed X chromosome inactivation leads to Menkes disease in a female infant. Sci Rep 2024;14[1]:440. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

T2-weighted MR imaging shows diffuse atrophy of the cerebrum and delayed myelination in the splenium of the corpus callosum in a female infant with Menkes disease due to unfavorable switching of skewed X chromosome inactivation. (Source: Matsumoto A, Kano S, Kobayashi N, et al. Unfavorable switching of skewed X chromosome inactivation leads to Menkes disease in a female infant. Sci Rep 2024;14[1]:440. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Samples from individuals I-5, I-6, II-2, II-3, and III-1 were collected. (Source: Matsumoto A, Kano S, Kobayashi N, et al. Unfavorable switching of skewed X chromosome inactivation leads to Menkes disease in a female infant. Sci Rep 2024;14[1]:440. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Abbreviations: CCL18: chemokine ligand 18; ERT: enzyme replacement therapy; GauSS-I: Gaucher Severity Score Index for type I patients; GD-DS3: Gaucher disease type I severity scoring system; IV: intravenous; Lyso-Gb1/Lyso-GL1: glucosylsphingosine; MDT: multidisciplinary team; NSAIDS: non-steroidal anti-inflammatory drugs; PARC: pulmonary and activation-regulated chemokine; SRT: substrate reduction therapy; SSI: severity score index; TDS: three times daily; Tx: treatment.

(Adapted from: Torralba-Cabeza MÁ, Olivera-González S, Sierra-Monzón JL. The importance of a multidisciplinary approach in the management of a patient with type I Gaucher disease. Diseases 2018;6[3]:69.)

(Source: Louw VJ, Fraser I, Giraldo P. Management goals of type 1 Gaucher disease in South Africa: an expert Delphi consensus document on good clinical practice. PLoS One 2023;18[8]:e0290401. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Treatments are shown at the top. Neurologic findings and laboratory data are depicted in the middle and lower schemes, respectively. Abbreviations: ACE, angiotensin-converting enzyme; TRACP-5b, tartrate-resistant acid phosphatase 5b. (Source: Higashi K, Sonoda Y, Kaku N, et al. Rapid and long-lasting efficacy of high-dose ambroxol therapy for neuronopathic Gaucher disease: a case report and literature review. Mol Genet Genomic Med 2024;12[4]:e2427. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Sagittal T1-weighted (left) and axial fluid-attenuated inversion recovery (FLAIR, middle) image on day 24 of admission. No parenchymal lesion was detected in the FLAIR image at 3 months after discharge (right). (Source: Higashi K, Sonoda Y, Kaku N, et al. Rapid and long-lasting efficacy of high-dose ambroxol therapy for neuronopathic Gaucher disease: a case report and literature review. Mol Genet Genomic Med 2024;12[4]:e2427. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

May-Grunwald-Giemsa staining for Gaucher cells (arrows) in the bone-marrow smear. Scale, 10 μm. (Source: Higashi K, Sonoda Y, Kaku N, et al. Rapid and long-lasting efficacy of high-dose ambroxol therapy for neuronopathic Gaucher disease: a case report and literature review. Mol Genet Genomic Med 2024;12[4]:e2427. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(Left) When self-amplifying RNA (saRNA) is injected and delivered into cells, the translation of replicase takes place. The replicase uses the saRNA as a template and makes a negative saRNA strand, which in turn serves as a template for self-amplification by the replicase. Replicase recognizes sub-genomic promoter in the negative strand, so sgRNA is synthesized. Consequently, high levels of glucocerebrosidase are produced. (Right) When the mRNA is injected and delivered into the cells, it is translated into glucocerebrosidase protein. Ultimately, the glucocerebrosidase produced breaks down the GlcCer into glucose and ceramide leading to the normal condition.

Abbreviations: saRNA, self-amplifying RNA; mRNA, messenger RNA; sgPr, sub-genomic promoter; GD, Gaucher disease; GCase, glucocerebrosidase; GlcCer, glucosylceramide.

(Source: Feng S, Rcheulishvili N, Jiang X, et al. A review on Gaucher disease: therapeutic potential of β-glucocerebrosidase-targeted mRNA/saRNA approach. Int J Biol Sci 2024;20[6]:2111-29. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Normally, GBA1 is transcribed into mRNA, which is subsequently exported from the nucleus to the endoplasmic reticulum where glucocerebrosidase is synthesized. Glucocerebrosidase binds to LIMP-2, which is essential for the regulation of glucocerebrosidase transport from the endoplasmic reticulum through the Golgi apparatus (where the glucocerebrosidase protein undergoes maturation) to the lysosomes. The binding occurs at a neutral pH, and dissociation takes place within the acidic lysosomal environment. In the lysosome, with the support of its essential co-factor saposin C, glucocerebrosidase catalyzes the hydrolysis of GlcCer into glucose and ceramide. Due to a GBA1 mutation in Gaucher disease, the mutant glucocerebrosidase produced is a target for endoplasmic reticulum-associated degradation and proteasomal breakdown. Mutant glucocerebrosidase is unable to reach the lysosome, causing accumulation of GlcCer within the lysosomal compartment. The upregulated levels of intracellular GlcCer promote the formation of toxic soluble alpha-synuclein assemblies, exacerbating a pathogenic cycle by impairing the maturation of lysosomes and inhibiting the activity of functional glucocerebrosidase. This impairment results in further GlcCer accumulation and augmented alpha-synuclein formation due to its hampered degradation, leading to the release of inflammatory cytokines. The enzyme, known as GBA2 (the so-called second glucocerebrosidase), transforms GlcSph (also known as lyso-GlcCer) into sphingosine, which subsequently undergoes phosphorylation, resulting in the production of sphingosine-1-phosphate. Enhanced inflammatory response, along with the associated pathophysiology, contributes to bone fragility, lowering the erythrocyte and platelet levels and reducing lung function, and may also lead to neurodegeneration. Black arrows represent reactions that proceed normally. Broken red arrows indicate the normal reactions that do not occur. Solid red arrows denote the harmful reactions that do take place.

Abbreviations: GD, Gaucher disease; GCase, glucocerebrosidase; LIMP-2, lysosomal integral membrane protein 2; ER, endoplasmic reticulum; ERAD, endoplasmic reticulum-associated degradation; GlcCer, glucosylceramide; α-Syn, α-synuclein; GBA2, β-glucocerebrosidase 2; S1P, sphingosine-1-phosphate; lyso-GlcCer, lyso-glucosylceramide.

(Source: Feng S, Rcheulishvili N, Jiang X, et al. A review on Gaucher disease: therapeutic potential of β-glucocerebrosidase-targeted mRNA/saRNA approach. Int J Biol Sci 2024;20[6]:2111-29. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(A) FLAIR sequence shows bilateral subcortical white matter hyperintensities in frontal, parietal, and temporal lobes. (B) T2-weighted image shows bilateral hyperintensities in the dentate nuclei. (C) T2-weighted image shows bilateral hyperintensities in the basal ganglia. Note the sparing of both thalami in (A) and (C). (Source: Leal-Ortega R, Parra-Medina LE, González-Herrera LJ. L-2 hydroxyglutaric aciduria: report of a Mexican-Mayan patient with the mutation c.569C>T and response to vitamin supplements and levocarnitine. Tremor Other Hyperkinet Mov [N Y] 2024;14:12. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Cranial CT image in a male infant with mucolipidosis II (I-cell disease) caused by compound heterozygous GNPTAB mutations shows abnormal skull development and bilateral frontal atrophy with widened extracerebral spaces. (Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Cranial CT image in a male infant with mucolipidosis II (I-cell disease) caused by compound heterozygous GNPTAB mutations shows abnormal skull development and bilateral ventriculomegaly. There is also evident bilateral frontal atrophy with widened extracerebral spaces. (Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Transverse chest CT in a male infant with mucolipidosis II (I-cell disease) caused by compound heterozygous GNPTAB mutations shows a deformed chest and prominent interstitial changes in the lungs. (Source: He SJ, Li DJ, Lv WQ, et al. Outcomes after HSCT for mucolipidosis II (I-cell disease) caused by novel compound heterozygous GNPTAB mutations. Front Pediatr 2023;11:1199489. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Wrist x-ray in a male infant with mucolipidosis II (I-cell disease) caused by compound heterozygous GNPTAB mutations shows the cartilage development of the wrist joint was abnormal. (Source: He SJ, Li DJ, Lv WQ, et al. Outcomes after HSCT for mucolipidosis II (I-cell disease) caused by novel compound heterozygous GNPTAB mutations. Front Pediatr 2023;11:1199489. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Lateral spine x-ray in a male infant with mucolipidosis II (I-cell disease) caused by compound heterozygous GNPTAB mutations shows the spine has kyphosis at the junction of the thoracolumbar segment. (Source: He SJ, Li DJ, Lv WQ, et al. Outcomes after HSCT for mucolipidosis II (I-cell disease) caused by novel compound heterozygous GNPTAB mutations. Front Pediatr 2023;11:1199489. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Timeline of medical history in a male infant with mucolipidosis II (I-cell disease) caused by compound heterozygous GNPTAB mutations. Abbreviations: HSCT, hematopoietic stem cell transplantation; MLII, mucolipidosis II (I-cell disease); w, weeks. (Source: He SJ, Li DJ, Lv WQ, et al. Outcomes after HSCT for mucolipidosis II (I-cell disease) caused by novel compound heterozygous GNPTAB mutations. Front Pediatr 2023;11:1199489. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Joint contractures in a male infant with mucolipidosis II (I-cell disease) caused by compound heterozygous GNPTAB mutations. (Source: He SJ, Li DJ, Lv WQ, et al. Outcomes after HSCT for mucolipidosis II (I-cell disease) caused by novel compound heterozygous GNPTAB mutations. Front Pediatr 2023;11:1199489. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Abnormal facial features in a male infant with mucolipidosis II (I-cell disease) caused by compound heterozygous GNPTAB mutations include puffy eyelids, epicanthus, flat nasal bridge, anteverted nostrils, gingival hyperplasia, and macroglossia. (Source: He SJ, Li DJ, Lv WQ, et al. Outcomes after HSCT for mucolipidosis II (I-cell disease) caused by novel compound heterozygous GNPTAB mutations. Front Pediatr 2023;11:1199489. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Threshold perimetry in a 47-year-old man with mucolipidosis type III gamma shows a peripheral scotoma from the nasal site and well-preserved central sensibility. (Source: de Geer K, Mascianica K, Naess K, Sardh E, Lindstrand A, Björck E. Unraveling mucolipidosis type III gamma through whole genome sequencing in late-onset retinitis pigmentosa: a case report. BMC Ophthalmol 2023;23[1]:394. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

In this 47-year-old man with mucolipidosis type III gamma, the center is well bounded. There is pathological patchy hypoautofluorescence in the middle periphery and more homogenous hyperautofluorescence peripherally. (Source: de Geer K, Mascianica K, Naess K, Sardh E, Lindstrand A, Björck E. Unraveling mucolipidosis type III gamma through whole genome sequencing in late-onset retinitis pigmentosa: a case report. BMC Ophthalmol 2023;23[1]:394. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Extrafoveal scan of the right eye and foveal scan of the left eye in a 47-year-old man with mucolipidosis type III gamma show a mild epiretinal membrane with flattened foveal profile but without cystoid macular edema. (Source: de Geer K, Mascianica K, Naess K, Sardh E, Lindstrand A, Björck E. Unraveling mucolipidosis type III gamma through whole genome sequencing in late-onset retinitis pigmentosa: a case report. BMC Ophthalmol 2023;23[1]:394. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

In this 47-year-old man with mucolipidosis type III gamma, there is blunting of the foveal contour and scattered pigmentary changes in the middle periphery in the form of discrete bone spicules and pigment clumping. (Source: de Geer K, Mascianica K, Naess K, Sardh E, Lindstrand A, Björck E. Unraveling mucolipidosis type III gamma through whole genome sequencing in late-onset retinitis pigmentosa: a case report. BMC Ophthalmol 2023;23[1]:394. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Sagittal T2-weighted MRI sequence shows cervical spinal canal stenosis in a 3.3-year-old boy with mucolipidosis II. (Source: Ammer LS, Täuber K, Perez A, et al. CNS manifestations in mucolipidosis type II-A retrospective analysis of longitudinal data on neurocognitive development and neuroimaging in eleven patients. J Clin Med 2023;12[12]:4114. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Transverse T2-weighted MRI sequence shows cervical spinal canal stenosis in a 3.3-year-old boy with mucolipidosis II. (Source: Ammer LS, Täuber K, Perez A, et al. CNS manifestations in mucolipidosis type II-A retrospective analysis of longitudinal data on neurocognitive development and neuroimaging in eleven patients. J Clin Med 2023;12[12]:4114. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Sagittal T1-weighted MRI sequence shows cervical spinal canal stenosis in a 3.3-year-old boy with mucolipidosis II. (Source: Ammer LS, Täuber K, Perez A, et al. CNS manifestations in mucolipidosis type II-A retrospective analysis of longitudinal data on neurocognitive development and neuroimaging in eleven patients. J Clin Med 2023;12[12]:4114. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Sagittal FLAIR MRI sequence shows white matter signal changes in a 3.2-year-old boy with mucolipidosis II. (Source: Ammer LS, Täuber K, Perez A, et al. CNS manifestations in mucolipidosis type II-A retrospective analysis of longitudinal data on neurocognitive development and neuroimaging in eleven patients. J Clin Med 2023;12[12]:4114. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Transverse FLAIR MRI sequence shows white matter signal changes in a 2.4-year-old girl with mucolipidosis II. (Source: Ammer LS, Täuber K, Perez A, et al. CNS manifestations in mucolipidosis type II-A retrospective analysis of longitudinal data on neurocognitive development and neuroimaging in eleven patients. J Clin Med 2023;12[12]:4114. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Transverse T2-weighted MRI sequence shows white matter signal changes in a 2.4-year-old girl with mucolipidosis II. (Source: Ammer LS, Täuber K, Perez A, et al. CNS manifestations in mucolipidosis type II-A retrospective analysis of longitudinal data on neurocognitive development and neuroimaging in eleven patients. J Clin Med 2023;12[12]:4114. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Sagittal FLAIR MRI sequence shows white matter signal changes in an 11.2-year-old girl with mucolipidosis II (mucolipidosis intermediate). (Source: Ammer LS, Täuber K, Perez A, et al. CNS manifestations in mucolipidosis type II-A retrospective analysis of longitudinal data on neurocognitive development and neuroimaging in eleven patients. J Clin Med 2023;12[12]:4114. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Transverse T2-weighted MRI sequence shows white matter signal changes in an 11.2-year-old girl with mucolipidosis II (mucolipidosis intermediate). (Source: Ammer LS, Täuber K, Perez A, et al. CNS manifestations in mucolipidosis type II-A retrospective analysis of longitudinal data on neurocognitive development and neuroimaging in eleven patients. J Clin Med 2023;12[12]:4114. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Atrophy of the top part of the cerebellum and vermis and cervical spinal canal stenosis in an 11.2-year-old girl with mucolipidosis II (mucolipidosis intermediate). (Source: Ammer LS, Täuber K, Perez A, et al. CNS manifestations in mucolipidosis type II-A retrospective analysis of longitudinal data on neurocognitive development and neuroimaging in eleven patients. J Clin Med 2023;12[12]:4114. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Coronal T2-weighted MRI sequence shows white matter changes in an 11.2-year-old girl with mucolipidosis II (mucolipidosis intermediate). (Source: Ammer LS, Täuber K, Perez A, et al. CNS manifestations in mucolipidosis type II-A retrospective analysis of longitudinal data on neurocognitive development and neuroimaging in eleven patients. J Clin Med 2023;12[12]:4114. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Motor function and verbal abilities are presented based on the Bayley Scales of Infant and Toddler Development-III. The grey dashed line denotes the development of healthy children. Abbreviation: Aeqs, age-equivalent scores. (Source: Ammer LS, Täuber K, Perez A, et al. CNS manifestations in mucolipidosis type II-A retrospective analysis of longitudinal data on neurocognitive development and neuroimaging in eleven patients. J Clin Med 2023;12[12]:4114. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Adaptive behavior abilities are presented based on the Vineland Adaptive Behavior Scales-II. The grey dashed line denotes the development of healthy children. (Source: Ammer LS, Täuber K, Perez A, et al. CNS manifestations in mucolipidosis type II-A retrospective analysis of longitudinal data on neurocognitive development and neuroimaging in eleven patients. J Clin Med 2023;12[12]:4114. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Developmental curves are visualized as (A) cognitive age-equivalent scores (Aeqs) and (B) developmental quotients in relation to chronological ages. The grey dashed line denotes the development of healthy children. Abbreviations: Aeqs, age-equivalent scores; BSID, Bayley Scales of Infant and Toddler Development-II/III; GMDS, Griffith Scales of Child Development-III; KABC, Kaufman Assessment Battery for Children-II; SON, Snijders-Oomen Nonverbal Intelligence Test-2.5-7; VABS, Vineland Adaptive Behaviour Scales-II. (Source: Ammer LS, Täuber K, Perez A, et al. CNS manifestations in mucolipidosis type II-A retrospective analysis of longitudinal data on neurocognitive development and neuroimaging in eleven patients. J Clin Med 2023;12[12]:4114. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Handwriting and drawings of the dominant left upper extremity in a 42-year-old left-handed man with multiple cerebrotendinous xanthomatosis-related sequelae: motor examination pre-DBS placement and 6 months post-DBS VIM placement. The man's sequelae included developmental delay, cataracts, epilepsy, diabetes, chronic pancreatitis, anxiety, depression, parkinsonism, and postural or action tremor. His cerebrotendinous xanthomatosis-tremor was successfully treated with unilateral thalamic ventral intermediate nucleus (VIM) DBS (deep brain stimulation). (Source: Rich AM, Karakoleva EV, McInerney J, Farace E, De Jesus S. Cerebrotendinous xanthomatosis tremor successfully controlled post-ventral intermediate nucleus-deep brain stimulation: a case report. Front Neurol 2023;14:1243379. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Axial fat-saturated T2-weighted MRI of the left ankle shows diffuse enlargement of the Achilles tendon (arrows) with the characteristic speckled appearance (dotted arrows). (Source: Koroglu M, Karakaplan M, Gündüz E, et al. Cerebrotendinous xanthomatosis patients with late diagnosed in single orthopedic clinic: two novel variants in the CYP27A1 gene. Orphanet J Rare Dis 2024;19[1]:53. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Coronal T1-weighted MRI of the lower leg shows bilateral Achilles tendon xanthomas (long arrows) and multiple other tendon xanthomas around both ankles (short arrows). (Source: Koroglu M, Karakaplan M, Gündüz E, et al. Cerebrotendinous xanthomatosis patients with late diagnosed in single orthopedic clinic: two novel variants in the CYP27A1 gene. Orphanet J Rare Dis 2024;19[1]:53. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Photomicrograph of a surgically resected xanthoma demonstrating cholesterol clefts (asterisk) and multinucleated giant cells (arrow) (Hematoxylin and eosin x 200). (Source: Koroglu M, Karakaplan M, Gündüz E, et al. Cerebrotendinous xanthomatosis patients with late diagnosed in single orthopedic clinic: two novel variants in the CYP27A1 gene. Orphanet J Rare Dis 2024;19[1]:53. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Intraoperative photograph showing an incision over the left Achilles tendon. The tendon was enlarged as a yellow, firm hypertrophic neoplasm. (Source: Koroglu M, Karakaplan M, Gündüz E, et al. Cerebrotendinous xanthomatosis patients with late diagnosed in single orthopedic clinic: two novel variants in the CYP27A1 gene. Orphanet J Rare Dis 2024;19[1]:53. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Clinical photograph of the left ankle demonstrating the fusiform swelling caused by a xanthoma. (Source: Koroglu M, Karakaplan M, Gündüz E, et al. Cerebrotendinous xanthomatosis patients with late diagnosed in single orthopedic clinic: two novel variants in the CYP27A1 gene. Orphanet J Rare Dis 2024;19[1]:53. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

T2-weighted MRI shows bilaterally symmetrical hyperintensity in the cerebellar white matter and the dentate nucleus (arrowhead). The left image was taken before therapy, and the right image after 9 months of chenodeoxycholic acid therapy. The images show that there has been no progression of lesion growth. (Source: Brlek P, Bulić L, Glavaš Weinberger D, et al. Successful treatment of a rare cholesterol homeostasis disorder due to CYP27A1 gene mutation with chenodeoxycholic acid therapy. Biomedicines 2023;11[5]:1430. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

FLAIR sequence shows bilaterally symmetrical hyperintensity in the cerebellar white matter and the dentate nucleus (arrowhead). The left image was taken before therapy, and the right image after 9 months of chenodeoxycholic acid therapy. The images show that there has been no progression of lesion growth. (Source: Brlek P, Bulić L, Glavaš Weinberger D, et al. Successful treatment of a rare cholesterol homeostasis disorder due to CYP27A1 gene mutation with chenodeoxycholic acid therapy. Biomedicines 2023;11[5]:1430. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Sagittal ankle MRI, using a "true FISP" sequence shows focal fusiform thickening of both Achilles tendons, which corresponds to xanthoma accumulations in cerebrotendinous xanthomatosis (arrowhead). "True FISP" is the Siemens trade name for a steady-state coherent sequence in which balanced gradients are used along all three axes. The left image (a) was taken before therapy, and the right image (b) after 9 months of chenodeoxycholic acid therapy. The images show that there has been no progression of lesion growth. (Source: Brlek P, Bulić L, Glavaš Weinberger D, et al. Successful treatment of a rare cholesterol homeostasis disorder due to CYP27A1 gene mutation with chenodeoxycholic acid therapy. Biomedicines 2023;11[5]:1430. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

FLAIR axial sections (A-D) show multiple chronic watershed infracts in the internal carotid artery territory bilaterally (A) and subtle periventricular white matter signal changes (B). Deep grey nuclei (C) and dentate and cerebellar white matter (D) appear normal. Time-of-flight MR angiography (E) shows complete occlusion of the intracranial segment of the left internal carotid artery. (Source: Katragadda P, Holla VV, Kamble N, Saini J, Yadav R, Pal PK. Clinical and imaging profile of patients with cerebrotendinous xanthomatosis: a video case series from India. Tremor Other Hyperkinet Mov [N Y] 2024;14:10. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

This image shows the normal ("classical") metabolic pathway of cholesterol, which is mainly regulated by CYP27A1. The absence of this enzyme leads to a significant increase in activity in the cholestanol pathway, as well as an increase in upstream cholesterol metabolites. Chenodeoxycholic acid therapy inhibits CYP7A1, thereby halting utilization of the cholestanol pathway and accumulation of cholestanol metabolites in the CNS. (Source: Brlek P, Bulić L, Glavaš Weinberger D, et al. Successful treatment of a rare cholesterol homeostasis disorder due to CYP27A1 gene mutation with chenodeoxycholic acid therapy. Biomedicines 2023;11[5]:1430. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

T2 axial images (A-C) show mild diffuse cerebral and cerebellar atrophy with symmetric dentate nuclei hyperintensities. (Source: Katragadda P, Holla VV, Kamble N, Saini J, Yadav R, Pal PK. Clinical and imaging profile of patients with cerebrotendinous xanthomatosis: a video case series from India. Tremor Other Hyperkinet Mov [N Y] 2024;14:10. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

FLAIR axial images (A-D) show hyperintensities along bilateral periventricular white matter and corticospinal tracts along internal capsules, midbrain, and pons. Bilateral globus pallidi appear hypointense on T1 (E) and hyperintense on T2 (F). Bilateral dentate nuclei appear slightly hyperintense on coronal T2 images (G, white arrow). Susceptibility-weighted imaging shows blooming in the left more than right globus pallidi lesions (H). (Source: Katragadda P, Holla VV, Kamble N, Saini J, Yadav R, Pal PK. Clinical and imaging profile of patients with cerebrotendinous xanthomatosis: a video case series from India. Tremor Other Hyperkinet Mov [N Y] 2024;14:10. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

FLAIR axials (A, C), coronal (B), and T2 axial (D) show symmetric hyperintensities in periventricular white matter, corticospinal tracts, middle cerebellar peduncle, dentate and peri-dentate white matter, and inferior olives. “Hot cross bun” sign can be seen within pons (C). Susceptibility-weighted imaging (E) shows blooming in dentate nuclei. Long-segment hyperintensity of dorsal and lateral columns is seen in the axial (F, G) and sagittal (H) T2 sequences of the spine MRI. (Source: Katragadda P, Holla VV, Kamble N, Saini J, Yadav R, Pal PK. Clinical and imaging profile of patients with cerebrotendinous xanthomatosis: a video case series from India. Tremor Other Hyperkinet Mov [N Y] 2024;14:10. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

T2 (A, C, D), FLAIR (B, E-G), and post-contrast T1 (H) sequences show symmetric T2 hyperintense and FLAIR hypointense lesions along bilateral dentate and cerebellar white matter (A, B, D, G), T2 and FLAIR hyperintensity of the corticospinal tract along periventricular white matter (E), posterior limb of internal capsule (C), cerebral peduncles (F), and pons (A and H), as well as hyperintensity of the inferior olives (B) and middle cerebellar peduncles (A and G), and rarefaction of cerebellar white matter (A and G). T2 hypointense rim noted around dentate nuclei (D). Note the “hot cross bun” appearance along the pons (A and G, inset) and olivary hyperintensity (B, inset). T1 post-contrast image showed no enhancement (H). (Source: Katragadda P, Holla VV, Kamble N, Saini J, Yadav R, Pal PK. Clinical and imaging profile of patients with cerebrotendinous xanthomatosis: a video case series from India. Tremor Other Hyperkinet Mov [N Y] 2024;14:10. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

X-ray of the spine, lateral view, of a 30-month-old child with juvenile sialidosis showing beaking in the thoracolumbar region. (Source: Pokharel P, Dawadi A, Baral B, Dhungana S, Baskota A, Poudel DR. Juvenile sialidosis: a rare case and review of the literature. Ann Med Surg [Lond] 2024;86[4]:2248-52. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

X-ray of the pelvis of a 30-month-old child with juvenile sialidosis with the hip joints showing mild rounding of hip bones bilaterally. (Source: Pokharel P, Dawadi A, Baral B, Dhungana S, Baskota A, Poudel DR. Juvenile sialidosis: a rare case and review of the literature. Ann Med Surg [Lond] 2024;86[4]:2248-52. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

X-ray of the skull of a 30-month-old child with juvenile sialidosis showing sutural diastasis (ie, abnormal widening of the skull sutures). (Source: Pokharel P, Dawadi A, Baral B, Dhungana S, Baskota A, Poudel DR. Juvenile sialidosis: a rare case and review of the literature. Ann Med Surg [Lond] 2024;86[4]:2248-52. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(Source: Pokharel P, Dawadi A, Baral B, Dhungana S, Baskota A, Poudel DR. Juvenile sialidosis: a rare case and review of the literature. Ann Med Surg [Lond] 2024;86[4]:2248-52. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

X-ray of right hand of a 30-month-old child with juvenile sialidosis: the wrist joint shows bullet-shaped phalanges. (Source: Pokharel P, Dawadi A, Baral B, Dhungana S, Baskota A, Poudel DR. Juvenile sialidosis: a rare case and review of the literature. Ann Med Surg [Lond] 2024;86[4]:2248-52. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

A 30-month-old child with juvenile sialidosis with coarse facies and wide nasal bridge. (Source: Pokharel P, Dawadi A, Baral B, Dhungana S, Baskota A, Poudel DR. Juvenile sialidosis: a rare case and review of the literature. Ann Med Surg [Lond] 2024;86[4]:2248-52. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Carrier frequency and estimated incidence of alpha-mannosidosis according to population in a global genomic database (Genome Aggregation Database) that comprises a collection of 125,748 exomes. Circle size: carrier frequency of alpha-mannosidosis. (Source: Park JE, Lee T, Ha K, Cho EH, Ki CS. Carrier frequency and incidence of alpha-mannosidosis: population database-based study-focus on the East Asian and Korean population. Front Genet 2023;14:1297543. Creative Commons Attribution [CC BY] license.)

Cranial MRI (T1-weighted) showing a mild brachycephalic appearance, inferior vermis hypoplasia, and a large cisterna magna. Symptom onset was at 32 months, and diagnosis was at 148 months. (Source: Kose E, Kasapkara ÇS, İnci A, et al. Long-term clinical evaluation of patients with alpha-mannosidosis: a multicenter study. Eur J Med Genet 2024;68:104927. Creative Commons Attribution [CC BY] license.)

Cranial MRI (T1-weighted) showing trigonocephalic appearance in a boy with mannosidosis. Symptom onset was at 36 months, and diagnosis was at 86 months. (Source: Kose E, Kasapkara ÇS, İnci A, et al. Long-term clinical evaluation of patients with alpha-mannosidosis: a multicenter study. Eur J Med Genet 2024;68:104927. Creative Commons Attribution [CC BY] license.)

Cranial MRI (T1-weighted) showing fluid intensities in optic nerve sheaths, thickening at calvarial diploic spaces in a boy with mannosidosis. Symptom onset was at 36 months, and diagnosis was at 86 months. (Source: Kose E, Kasapkara ÇS, İnci A, et al. Long-term clinical evaluation of patients with alpha-mannosidosis: a multicenter study. Eur J Med Genet 2024;68:104927. Creative Commons Attribution [CC BY] license.)

Cranial MRI (T1-weighted) showing a large cisterna magna and mild brachycephalic appearance in a boy with mannosidosis. Symptom onset was at 30 months, and diagnosis was at 62 months. (Source: Kose E, Kasapkara ÇS, İnci A, et al. Long-term clinical evaluation of patients with alpha-mannosidosis: a multicenter study. Eur J Med Genet 2024;68:104927. Creative Commons Attribution [CC BY] license.)

Cranial MRI (T1-weighted) showing enlargement of the lateral ventricles in a boy with mannosidosis. Symptom onset was at 30 months, and diagnosis was at 62 months. (Source: Kose E, Kasapkara ÇS, İnci A, et al. Long-term clinical evaluation of patients with alpha-mannosidosis: a multicenter study. Eur J Med Genet 2024;68:104927. Creative Commons Attribution [CC BY] license.)

Short T1 signals can be seen in the bilateral pallidum. (Source: Wu X, Jiao J, Xia Y, et al. Case report: a Chinese patient with glutathione synthetase deficiency and a novel glutathione synthase mutation. Front Pediatr 2023;11:1212405. Creative Commons Attribution [CC BY] license.)

Cranial MRI (T1-weighted) showing inferior vermis hypoplasia in a boy with mannosidosis. Symptom onset was at 30 months, and diagnosis was at 62 months. (Source: Kose E, Kasapkara ÇS, İnci A, et al. Long-term clinical evaluation of patients with alpha-mannosidosis: a multicenter study. Eur J Med Genet 2024;68:104927. Creative Commons Attribution [CC BY] license.)

The bilateral frontotemporal parietal lobes had a wide range of long T2 signals. The lesions on both sides are roughly symmetrical. (Source: Wu X, Jiao J, Xia Y, et al. Case report: a Chinese patient with glutathione synthetase deficiency and a novel glutathione synthase mutation. Front Pediatr 2023;11:1212405. Creative Commons Attribution [CC BY] license.)

There was a wide range of long T1 signals in the bilateral frontotemporal parietal lobes. The lesions on both sides are roughly symmetrical. (Source: Wu X, Jiao J, Xia Y, et al. Case report: a Chinese patient with glutathione synthetase deficiency and a novel glutathione synthase mutation. Front Pediatr 2023;11:1212405. Creative Commons Attribution [CC BY] license.)

Gamma-glutamyl cycle and enzyme deficiencies (highlighted in red) related to different diseases (highlighted in blue). Glutathione synthetase and glutathione synthetase deficiency are shown in the upper left of the figure. (Source: Wu X, Jiao J, Xia Y, et al. Case report: a Chinese patient with glutathione synthetase deficiency and a novel glutathione synthase mutation. Front Pediatr 2023;11:1212405. Creative Commons Attribution [CC BY] license.)

Angiokeratoma corporis diffusum on the right forearm in a woman with fucosidosis Type 2. (Source: Puente-Ruiz N, Ellis I, Bregu M, et al. Long-term outcomes in two adult siblings with fucosidosis: diagnostic odyssey and clinical manifestations. Mol Genet Metab Rep 2023;37:101009. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Dilated and tortuous retinal veins in a 31-year-old man with fucosidosis Type 2. (Source: Puente-Ruiz N, Ellis I, Bregu M, et al. Long-term outcomes in two adult siblings with fucosidosis: diagnostic odyssey and clinical manifestations. Mol Genet Metab Rep 2023;37:101009. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Angiokeratoma corporis diffusum on the right palm and right forearm in a woman with fucosidosis Type 2. (Source: Puente-Ruiz N, Ellis I, Bregu M, et al. Long-term outcomes in two adult siblings with fucosidosis: diagnostic odyssey and clinical manifestations. Mol Genet Metab Rep 2023;37:101009. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Angiokeratoma corporis diffusum on the right thigh in a woman with fucosidosis Type 2. (Source: Puente-Ruiz N, Ellis I, Bregu M, et al. Long-term outcomes in two adult siblings with fucosidosis: diagnostic odyssey and clinical manifestations. Mol Genet Metab Rep 2023;37:101009. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Dysostosis multiplex in the lumbar spine in a 20-year-old man with fucosidosis Type 2. (Source: Puente-Ruiz N, Ellis I, Bregu M, et al. Long-term outcomes in two adult siblings with fucosidosis: diagnostic odyssey and clinical manifestations. Mol Genet Metab Rep 2023;37:101009. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Brain MRI of a patient with cerebral folate deficiency from age 2 to 12 years. T2-weighted images are shown at 2 years (column 1: A1-E1), 5 years (column 2: A2-E2), 7 years (column 3: A3-E3), 10 years (column 4: A4-E4), and 12 years (column 5: A5-E5). Sagittal (panel A) images show mild to moderate thinning of the corpus callosum (white arrowhead), as well as mild cerebellar atrophy (white arrow). In panels B1-3, C1-3, and D1-3, severe lack of myelin deposition and progressive cerebral atrophy are shown. In panels B4-5, C4-5, and D4-5, improvement in myelination is seen, but incomplete myelination is still present at age 12 years. Brain volume has improved at ages 10 and 12 years (B4-5, C4-5, and D4-5). In panel E, insufficient myelin deposition is shown in E1-2 in both the pons (white double-lined arrow) and cerebellum (white dashed arrow), with improvement in the pons at age 7 years (E3-5, white double-lined arrow) and significant improvement in the cerebellum at ages 10 and 12 years (E4-5, white double-lined arrows). Progressive cerebellar atrophy is evident between ages 2 and 7 years (E1-3), with improvement in subsequent MRIs done at ages 10 and 12 years (E4-5). (Source: Potic A, Perrier S, Radovic T, et al. Hypomyelination caused by a novel homozygous pathogenic variant in FOLR1: complete clinical and radiological recovery with oral folinic acid therapy and review of the literature. Orphanet J Rare Dis 2023;18[1]:187. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Brain MRI of a patient with cerebral folate deficiency from age 2 to 6 years. T2-weighted images are shown at 2 years (column 1: A1-E1), 3 years (column 2: A2-E2), 4 years (column 3: A3-E3), and 6 years (column 4: A4-E4). Sagittal (panel A) images show mild thinning of the corpus callosum (white arrowhead) but otherwise normal midline structures. In panels B, C, D, and E, delayed myelination is shown, with complete myelination achieved only at age 6 years (B4, C4, D4, and E4). (Source: Potic A, Perrier S, Radovic T, et al. Hypomyelination caused by a novel homozygous pathogenic variant in FOLR1: complete clinical and radiological recovery with oral folinic acid therapy and review of the literature. Orphanet J Rare Dis 2023;18[1]:187. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(Contributed by Dr. Alexander Y Kim.)

Enzyme enhancement therapy is based oral use of chaperones that stabilize defective alpha-galactosidase A, promote proper folding, and transport to lysosomes where accumulated substrates can be degraded. (Source: Amodio F, Caiazza M, Monda E, et al. An overview of molecular mechanisms in Fabry disease. Biomolecules 2022;12[10]:1460. Creative Commons Attribution [CC BY] license, creativecommons.org/licenses/by/4.0.)

The accumulation of Gb3 in tissues is a major contributor to the progression of Fabry disease. However, with intravenous infusion of recombinant lysosomal enzymes, this accumulation can be partially prevented, slowing down the disease. (Source: Amodio F, Caiazza M, Monda E, et al. An overview of molecular mechanisms in Fabry disease. Biomolecules 2022;12[10]:1460. Creative Commons Attribution [CC BY] license, creativecommons.org/licenses/by/4.0.)

Once GLA gene sequencing has been performed, further steps depend on whether the results indicate a variant associated with Fabry disease or whether a variant is identified or unknown significance, or if no mutation is identified. (Source: Amodio F, Caiazza M, Monda E, et al. An overview of molecular mechanisms in Fabry disease. Biomolecules 2022;12[10]:1460. Creative Commons Attribution [CC BY] license, creativecommons.org/licenses/by/4.0.)

Starting from a diagnostic suspicion, it is possible to perform analyses that can confirm or reject the possible diagnosis of Fabry disease. Everything starts with dried blood spots on filter paper, then the path changes in the case of male or female subjects. In male subjects, it is possible to perform a fairly rapid and exhaustive screening test of the dosage of alpha-galactosidase A enzyme activity. If the result is positive (ie, low enzymatic activity), or in case of doubt, it may be decided to perform sequencing of the 7 exons of the GLA gene to identify possible mutations causing the disease. In female subjects, where enzymatic activity may not be a diagnostic index, sequencing must be performed directly.

Abbreviations: α-gal A, alpha-galactosidase A; DBS, dried blood spots; FD, Fabry disease. (Source: Amodio F, Caiazza M, Monda E, et al. An overview of molecular mechanisms in Fabry disease. Biomolecules 2022;12[10]:1460. Creative Commons Attribution [CC BY] license, creativecommons.org/licenses/by/4.0.)

The enzyme alpha-galactosidase A cleaves off the third sugar residue. In Fabry disease this enzyme is deficient, and therefore the substrate Gb3 accumulates in the lysosomes of almost all cell types. (Source: Amodio F, Caiazza M, Monda E, et al. An overview of molecular mechanisms in Fabry disease. Biomolecules 2022;12[10]:1460. Creative Commons Attribution [CC BY] license, creativecommons.org/licenses/by/4.0.)

In Fabry dsease, deficiency of GLA activity results in defects in degradation of glycosphingolipids, causing abnormal accumulation of enzyme substrate in the lysosome. (Source: Amodio F, Caiazza M, Monda E, et al. An overview of molecular mechanisms in Fabry disease. Biomolecules 2022;12[10]:1460. Creative Commons Attribution [CC BY] license, creativecommons.org/licenses/by/4.0.)

In the physiological state, inside the lysosome, alpha-galactosidase A catalyzes the hydrolysis of glycosphingolipids, with terminal alpha-galactose residues in the course of sphingolipid degradation. (Source: Amodio F, Caiazza M, Monda E, et al. An overview of molecular mechanisms in Fabry disease. Biomolecules 2022;12[10]:1460. Creative Commons Attribution [CC BY] license, creativecommons.org/licenses/by/4.0.)

Several forms of galactosemia can be caused by deficiency of GALM, GALT, GALK1, or GALE. (Source: Succoio M, Sacchettini R, Rossi A, Parenti G, Ruoppolo M. Galactosemia: biochemistry, molecular genetics, newborn screening, and treatment. Biomolecules 2022;12(7):968. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

In a patient with Gaucher disease type 1 (GBA1 genotype p.Asn409Ser/c.217delC mutations), MRI revealed diffuse bone marrow signal abnormality throughout the left femur consistent with avascular osteonecrosis. (Source: Basiri M, Ghaffari ME, Ruan J, et al. Osteonecrosis in Gaucher disease in the era of multiple therapies: biomarker set for risk stratification from a tertiary referral center. Elife 2023;12:e87537. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

A few months after initial MRI, the patient developed avascular osteonecrosis in the right femur. (Source: Basiri M, Ghaffari ME, Ruan J, et al. Osteonecrosis in Gaucher disease in the era of multiple therapies: biomarker set for risk stratification from a tertiary referral center. Elife 2023;12:e87537. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(Source: PubChem. Public domain.)

(Source: PubChem. Public domain.)

Legend: carbon, gray; hydrogen, white; oxygen, red. (Source: PubChem. Public domain.)

(Source: Public domain.)

(Source: Pike AC, Pantic N, Parizotto E, et al. Crystal structure of human short-chain acyl CoA dehydrogenase. 2007. Available at: www.rcsb.org/structure/2vig. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(Source: Chen X, Han L, Yao H. Novel compound heterozygous variants of ETHE1 causing ethylmalonic encephalopathy in a Chinese patient: a case report. Front Genet 2020;11:341. Creative Commons Attribution [CC BY] license, creativecommons.org/licenses/by/2.0.)

The red arrow indicates shadows in the temporal horn of the left lateral ventricle. (Source: Chen X, Han L, Yao H. Novel compound heterozygous variants of ETHE1 causing ethylmalonic encephalopathy in a Chinese patient: a case report. Front Genet 2020;11:341. Creative Commons Attribution [CC BY] license, creativecommons.org/licenses/by/2.0.)

(A) Surface representation of the crystallographically observed hETHE1 dimer (chain A cyan, chain B green). Metal binding residues are shown as sticks. (B) Surface representation of the active site groove showing the side chain of Tyr197 directed towards the metal (6.8 A). The iron ion is shown as an orange sphere. (Source: Pettinati I, Brem J, McDonough MA, Schofield CJ. Crystal structure of human persulfide dioxygenase: structural basis of ethylmalonic encephalopathy. Hum Mol Genet 2015;24[9]:2458-69. Creative Commons Attribution [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Active sites for both chains exist on the same face of the dimer. Chains A and B are in cyan and green, respectively. (Source: Pettinati I, Brem J, McDonough MA, Schofield CJ. Crystal structure of human persulfide dioxygenase: structural basis of ethylmalonic encephalopathy. Hum Mol Genet 2015;24[9]:2458-69. Creative Commons Attribution [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Wall-eyed stereoview of the superposition of hETHE1 (blue) and the A thaliana ETHE1-like enzyme (red) (RMSD 1.43 Å over 230 Cα atoms). The latter is from Arabidopsis thaliana, the thale cress (or mouse-ear cress or arabidopsis), a small plant from the mustard family (Brassicaceae) native to Eurasia and Africa and now used as a model organism for plant genetics. The structures reveal very similar overall folds except for small differences in the beta2–beta3 and beta9–beta10 loops. (Source: Pettinati I, Brem J, McDonough MA, Schofield CJ. Crystal structure of human persulfide dioxygenase: structural basis of ethylmalonic encephalopathy. Hum Mol Genet 2015;24[9]:2458-69. Creative Commons Attribution [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Wall-eyed stereoview of hETHE1 showing secondary structure elements and the mono iron-containing active site. Helices are blue, beta-strands are yellow, and the iron is an orange sphere. (Source: Pettinati I, Brem J, McDonough MA, Schofield CJ. Crystal structure of human persulfide dioxygenase: structural basis of ethylmalonic encephalopathy. Hum Mol Genet 2015;24[9]:2458-69. Creative Commons Attribution [CC BY 4.0] license, creativecommons.org/licenses/by/4.0)

Axial apparent diffusion coefficient MRI from a patient with ethylmalonic encephalopathy shows hyperintensities in the putama (red arrows). (Source: Wang GQ, Zhao ZY, Li YB. A case report of atypical ethylmalonic encephalopathy with peripheral neuropathy. CNS Neurosci Ther 2023;29[3]:971-3. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Axial diffusion-weighted MRI from a patient with ethylmalonic encephalopathy shows hyperintensities in the putama (red arrows). (Source: Wang GQ, Zhao ZY, Li YB. A case report of atypical ethylmalonic encephalopathy with peripheral neuropathy. CNS Neurosci Ther 2023;29[3]:971-3. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Axial T2 fluid-attenuated inversion recovery image from a patient with ethylmalonic encephalopathy shows hyperintensities in the putama (red arrows). (Source: Wang GQ, Zhao ZY, Li YB. A case report of atypical ethylmalonic encephalopathy with peripheral neuropathy. CNS Neurosci Ther 2023;29[3]:971-3. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Patient with ethylmalonic encephalopathy. Axial T2-weighted, T2 fluid-attenuated inversion recovery, diffusion-weighted MRI, and associated apparent diffusion coefficient MR of axial images of brain MRI show hyperintensities in the bilateral putamen (red arrows). (Source: Wang GQ, Zhao ZY, Li YB. A case report of atypical ethylmalonic encephalopathy with peripheral neuropathy. CNS Neurosci Ther 2023;29[3]:971-3. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Brain MRI T2‐weighted sections before living transplantation (a), and at 1 (b), 2 (c), 3 (d), and 5 (e) years of follow‐up. Before liver transplantation, frontotemporal atrophy and symmetric hyperintense lesions involving the putamina and the caudate nuclei were detectable. (Source: Olivieri G, Martinelli D, Longo D, et al. Ethylmalonic encephalopathy and liver transplantation: long-term outcome of the first treated patient. Orphanet J Rare Dis 2021;16:229. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Legend: carbon, gray; hydrogen, white; oxygen, red. (Source: PubChem. Public domain.)

Scheme of the rate-limiting step of MAO-catalyzed serotonin degradation, involving a hydride transfer between the reacting carbon atom of serotonin (SRO) vicinal to the amino group, to the nitrogen atom of the flavin adenine dinucleotide (FAD) cofactor inside the MAO active site. (Source: Prah A, Pregeljc D, Stare J, Mavri J. Brunner syndrome caused by point mutation explained by multiscale simulation of enzyme reaction. Sci Rep 2022;12[1]:21889. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Monoamine oxidase enzyme with serotonin (SRO) docked in the active site (shown in inset on the left) and reacting with the flavin adenine dinucleotide (FAD) cofactor. The locations of the mutated residues of two mutation variants (R45W and E446K) are marked with red squares. In R45W, an arginine amino acid from the wild-type enzyme (WT) is replaced by tryptophan, whereas in E446K glutamate is replaced by lysine. (Source: Prah A, Pregeljc D, Stare J, Mavri J. Brunner syndrome caused by point mutation explained by multiscale simulation of enzyme reaction. Sci Rep 2022;12[1]:21889. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Natural history, disease progression, and symptom and sign timeline in each phenotype of cerebrotendinous xanthomatosis (classical, spinal, and “non-neurological” forms), according to age of symptom onset. (Source: Nobrega PR, Bernardes AM, Ribeiro RM, et al. Cerebrotendinous xanthomatosis: a practice review of pathophysiology, diagnosis, and treatment. Front Neurol 2022;13:1049850. Creative Commons Attribution License [CC BY], creativecommons.org/licenses/by/4.0.)

Arrowheads indicate foamy macrophages. (Source: Chun MY, Heo NJ, Seo SW, et al. Case report: Cerebrotendinous xanthomatosis with a novel mutation in the CYP27A1 gene mimicking behavioral variant frontotemporal dementia. Front Neurol 2023;14:1131888. Creative Commons Attribution [CC BY] license, creativecommons.org/licenses/by/4.0. Image cropped from original.)

Axial FLAIR image showing normal dentate nuclei with no cerebellar atrophy (arrow). (Source: Mahadevan N, Thiruvadi V, Paranthakan C, Rejha A, Magesh A. Cerebrotendinous xanthomatosis: report of two siblings with the same mutation but variable presentation. Cureus 2023;15[1]:e33378. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Sagittal T1-weighted MRI showing left Achilles tendon xanthoma with intermediate signal intensity (arrow). (Source: Mahadevan N, Thiruvadi V, Paranthakan C, Rejha A, Magesh A. Cerebrotendinous xanthomatosis: report of two siblings with the same mutation but variable presentation. Cureus 2023;15[1]:e33378. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Arrows indicate bilateral Achilles tendon xanthomas. (Source: Mahadevan N, Thiruvadi V, Paranthakan C, Rejha A, Magesh A. Cerebrotendinous xanthomatosis: report of two siblings with the same mutation but variable presentation. Cureus 2023;15[1]:e33378. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Sagittal T1-weighted MRI. Arrow indicates Achilles tendon xanthoma. (Source: Mahadevan N, Thiruvadi V, Paranthakan C, Rejha A, Magesh A. Cerebrotendinous xanthomatosis: report of two siblings with the same mutation but variable presentation. Cureus 2023;15[1]:e33378. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Arrows indicate bilateral Achilles tendon xanthomas. (Source: Mahadevan N, Thiruvadi V, Paranthakan C, Rejha A, Magesh A. Cerebrotendinous xanthomatosis: report of two siblings with the same mutation but variable presentation. Cureus 2023;15[1]:e33378. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(Source: Fernandez-Eulate G, Martin GC, Dureau P, et al. Prospective cholestanol screening of cerebrotendinous xanthomatosis among patients with juvenile-onset unexplained bilateral cataracts. Orphanet J Rare Dis 2022;17[1]:434. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(Source: Fernandez-Eulate G, Martin GC, Dureau P, et al. Prospective cholestanol screening of cerebrotendinous xanthomatosis among patients with juvenile-onset unexplained bilateral cataracts. Orphanet J Rare Dis 2022;17[1]:434. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

T2 cervical spine MRI shows a narrow foramen magnum, diffuse cervical spinal canal stenosis, platyspondyly, kyphosis, and scoliosis. (Contributed by Dr. Agnes Chen.)

Photos demonstrating coarse facial features, sternal and chest wall deformity, kyphosis, genu valgum, and severe short stature (height 102.5 cm). (Contributed by Dr. Agnes Chen.)

(A) Small white crystals deposited in urine. (B) Small crystals after centrifugal precipitation. (C) Photomicrograph (x200) of square columnar magnesium ammonium phosphate (struvite) crystal with strong refraction (black arrow). (Source: Li L, Qiao X, Liu F, et al. Description of the molecular and phenotypic spectrum of Lesch-Nyhan disease in eight Chinese patients. Front Genet 2022;13:868942. Creative Commons Attribution License [CC BY], https://creativecommons.org/licenses/by/4.0.)

Renal ultrasound revealed enlargement of both kidneys, enhanced echoes of the renal parenchyma, and an unclear boundary between medulla and cortex of both kidneys. (Source: Yang L, Guo H. Case report: early-onset renal failure as presenting sign of Lesch-Nyhan disease in infancy. Front Pediatr 2022;10:1080486. Creative Commons Attribution License [CC BY], https://creativecommons.org/licenses/by/4.0.)

Axial T2-weighted brain magnetic resonance image of a 2-month-old boy with Lesch-Nyhan disease showing diffuse white matter hyperintensity. (Source: Yang L, Guo H. Case report: early-onset renal failure as presenting sign of Lesch-Nyhan disease in infancy. Front Pediatr 2022;10:1080486. Creative Commons Attribution License [CC BY], https://creativecommons.org/licenses/by/4.0.)

(Source: Ferrao J, Rodrigues Barros C, Figueiredo L, Fernandes A. Oral self-mutilation in Lesch-Nyhan syndrome: a case report. Cureus 2022;14[8]:e27874. Creative Commons Attribution License [CC BY], https://creativecommons.org/licenses/by/4.0. Note: Image cropped from original.)

Large irregular ulcerative lesion in a 12-year-old boy with Lesch-Nyhan disease. (Source: Ferrao J, Rodrigues Barros C, Figueiredo L, Fernandes A. Oral self-mutilation in Lesch-Nyhan syndrome: a case report. Cureus 2022;14[8]:e27874. Creative Commons Attribution License [CC BY], https://creativecommons.org/licenses/by/4.0.)

Large irregular ulcerative lesion, mouth closed, in a 12-year-old boy with Lesch-Nyhan disease. (Source: Ferrao J, Rodrigues Barros C, Figueiredo L, Fernandes A. Oral self-mutilation in Lesch-Nyhan syndrome: a case report. Cureus 2022;14[8]:e27874. Creative Commons Attribution License [CC BY], https://creativecommons.org/licenses/by/4.0.)

Twelve-year-old boy with Lesch-Nyhan disease. (Source: Ferrao J, Rodrigues Barros C, Figueiredo L, Fernandes A. Oral self-mutilation in Lesch-Nyhan syndrome: a case report. Cureus 2022;14[8]:e27874. Creative Commons Attribution License [CC BY], https://creativecommons.org/licenses/by/4.0.)

Lip scar at the 2-month follow-up, in a 12-year-old boy with Lesch-Nyhan disease. (Source: Ferrao J, Rodrigues Barros C, Figueiredo L, Fernandes A. Oral self-mutilation in Lesch-Nyhan syndrome: a case report. Cureus 2022;14[8]:e27874. Creative Commons Attribution License [CC BY], https://creativecommons.org/licenses/by/4.0.)

Tongue at the 2-month follow-up in a 12-year-old boy with Lesch-Nyhan disease. (Source: Ferrao J, Rodrigues Barros C, Figueiredo L, Fernandes A. Oral self-mutilation in Lesch-Nyhan syndrome: a case report. Cureus 2022;14[8]:e27874. Creative Commons Attribution License [CC BY], https://creativecommons.org/licenses/by/4.0.)

This girl presented with typical characteristics of the disease: global developmental delay, self-mutilation, hyperuricemia, hypotonia, speech delay, spasticity, and seizures. (Source: AlBakheet A, AlQudairy H, Alkhalifah J, Almoaily S, Kaya N, Rahbeeni Z. Detailed genetic and clinical analysis of a novel de novo variant in HPRT1: case report of a female patient from Saudi Arabia with Lesch-Nyhan syndrome. Front Genet 2023;13:1044936. Creative Commons Attribution License [CC BY], https://creativecommons.org/licenses/by/4.0.)

Abdomen ultrasound indicates bilateral echogenic foci within the left renal collecting system. (Source: AlBakheet A, AlQudairy H, Alkhalifah J, Almoaily S, Kaya N, Rahbeeni Z. Detailed genetic and clinical analysis of a novel de novo variant in HPRT1: case report of a female patient from Saudi Arabia with Lesch-Nyhan syndrome. Front Genet 2023;13:1044936. Creative Commons Attribution License [CC BY], https://creativecommons.org/licenses/by/4.0.)

Abdomen ultrasound indicates bilateral echogenic foci within the right renal collecting system. (Source: AlBakheet A, AlQudairy H, Alkhalifah J, Almoaily S, Kaya N, Rahbeeni Z. Detailed genetic and clinical analysis of a novel de novo variant in HPRT1: case report of a female patient from Saudi Arabia with Lesch-Nyhan syndrome. Front Genet 2023;13:1044936. Creative Commons Attribution License [CC BY], https://creativecommons.org/licenses/by/4.0.)

Analysis of X-inactivation of blood DNA from the affected 4-year-old girl and her parents as signified by the human androgen receptor (AR) locus.

The methylation status of the methylation-sensitive enzyme’s restriction sites near the polymorphic CAG repeat in the first exon of the AR locus correlates with X chromosome inactivation. DNA was amplified before and after HhaI digestion. The same experiment was performed using the fibroblast DNA, which was only available from the affected individual.

When the genomic DNA from the whole blood samples was amplified without HhaI digestion, two polymorphic alleles at the AR locus [AR1 (260) and AR2 (280)] were demonstrated, with the AR1 allele from the mother and the AR2 allele from the father. However, after HhaI digestion in the blood from the affected girl and the mother, only the AR1 allele could be amplified, indicating the presence of non-random X-inactivation. (Source: AlBakheet A, AlQudairy H, Alkhalifah J, Almoaily S, Kaya N, Rahbeeni Z. Detailed genetic and clinical analysis of a novel de novo variant in HPRT1: case report of a female patient from Saudi Arabia with Lesch-Nyhan syndrome. Front Genet 2023;13:1044936. Creative Commons Attribution License [CC BY], https://creativecommons.org/licenses/by/4.0.)

Frequency of therapeutic approaches to self-injurious oral trauma in 19 Italian patients with Lesch-Nyhan disease according to a structured telephone interview of their parents.

Key: (1) Tooth extraction. (2) Painkilling drugs for palliative rather than symptomatic relief. (3) Orthodontic appliances (eg, an acrylic maxillary device, designed and constructed with an occlusal plate raising the bite, or a soft resin mouth guard). (4) Dental re-contouring (ie, filing the teeth to make them less likely to cut the oral and perioral tissues). (5) Obstructive methods (eg, placing objects between the teeth to prevent biting lesions).

(Source: Isola G, Piccardo I, De Mari A, Alberti G, Migliorati M. Oral self-mutilation in Lesch-Nyhan patients: a cross-sectional study. J Clin Med 2022;11[20]:5981. (Creative Commons Attribution License [CC BY], https://creativecommons.org/licenses/by/4.0.)

Uric acid crystals in a human urine sample with a pH of 5, detected by an automated urinalysis system. (Source: Doruk Salancı on January 22, 2014. Creative Commons Attribution-Share Alike 3.0 Unported license, creativecommons.org/licenses/by-sa/3.0/deed.en.)

(Source: Iqbal Osman on August 9, 2012. In: Queremel Milani DA, Jialal I. Urinalysis. [Updated 2022 May 8]. In: StatPearls [Internet]. Treasure Island [FL]: StatPearls Publishing, 2022. https://www.ncbi.nlm.nih.gov/books/NBK557685. Creative Commons Attribution 2.0 Generic license, https://creativecommons.org/licenses/by/2.0/deed.en.)

Abundant uric acid crystals in a human urine sediment with a pH of 5, as detected by an automated urinalysis system. Some amorphous urate crystals that are either clumped or dispersed can also be observed. (Source: Doruk Salanci on December 16, 2013. Creative Commons Attribution-Share Alike 3.0 Unported license, https://creativecommons.org/licenses/by-sa/3.0/deed.en.)

Pap stain. (Source: Photomicrograph by User: Nephron on WIkipedia. Creative Commons Attribution-Share Alike 3.0 Unported license, https://creativecommons.org/licenses/by-sa/3.0/deed.en.)

Pap stain. (Source: Photomicrograph by User: Nephron on WIkipedia. Creative Commons Attribution-Share Alike 3.0 Unported license, https://creativecommons.org/licenses/by-sa/3.0/deed.en.)

(A) Concave proximal ends of the ribs, irregular shape of the centrums (ie, bodies of the vertebrae), and bilateral shallow acetabulum with irregular margin. (B) and (C) Anterior beaking of the lower thoracic and lumbar vertebrae, respectively. (Source: Mao SJ, Zhao J, Shen Z, Zou CC. An unusual presentation of fucosidosis in a Chinese boy: a case report and literature review [childhood fucosidosis]. BMC Pediatr 2022;22[1]:403. Creative Commons Attribution 4.0 International License, creativecommons.org/licenses/by/4.0.)

(A) Palms with a dense red rash. (B) Fingers that couldn’t be fully extended. (Source: Mao SJ, Zhao J, Shen Z, Zou CC. An unusual presentation of fucosidosis in a Chinese boy: a case report and literature review [childhood fucosidosis]. BMC Pediatr 2022;22[1]:403. Creative Commons Attribution 4.0 International License, creativecommons.org/licenses/by/4.0.)

(A) Abnormal facial features (ie, thick arched eyebrows, flat nose, swollen eyelids, exophthalmos, epicanthus, low-set ears, and short neck). (B) Gingival hyperplasia. (C) Anteroposterior chest x-ray: small chest shape, short floating ribs, and irregular bilateral proximal humerus. (D) Pelvis anteroposterior x-ray: sharp and deep bilateral sciatic incisions; small, shallow bilateral acetabula. (E) Brain MRI: small frontal lobes, wide extracerebral space, and less white matter. (F) Brain MRI: small frontal and temporal lobes, wide extracerebral space, and thin corpus callosum. (Source: Mao SJ, Zu YM, Dai YL, Zou CC. Case report: mucolipidosis II and III alpha/beta caused by pathogenic variants in the GNPTAB gene [mucolipidosis]. Front Pediatr 2022;10:852701. Creative Commons Attribution License [CC BY], creativecommons.org/licenses/by/4.0.)

(A) Abnormal facial features (ie, closed anterior fontanelle, prominent zygomatic process, long eyelashes, sparse hair, upturned nostrils, a sharp beak-like mouth, low-set ears, and short neck). (B) Wrist joint seam showing significant stenosis. (C) Spine x-ray: slight scoliosis of the spine and slightly narrow vertebral ends of ribs. (D) Spine x-ray: slight kyphosis at the junction of the thoracolumbar segment, short anterior and posterior diameters of some thoracolumbar vertebrae, and beaked shape of the anterior edge of the vertebral bodies. (E) Spine x-ray: irregular acetabula and lower edge of iliac bones. (F) Brain MRI: poor white matter development. (G) Brain MRI: small frontal and temporal lobes, wide extracerebral space, and thin corpus callosum. (Source: Mao SJ, Zu YM, Dai YL, Zou CC. Case report: mucolipidosis II and III alpha/beta caused by pathogenic variants in the GNPTAB gene [mucolipidosis]. Front Pediatr 2022;10:852701. Creative Commons Attribution License [CC BY], creativecommons.org/licenses/by/4.0.)

(Source: de Bode CJ, Dogterom EJ, Rozeboom AV, et al. Orofacial abnormalities in mucopolysaccharidosis and mucolipidosis type II and III: a systematic review. JIMD Rep 2022;63[6]:621-9. Creative Commons Attribution License, creativecommons.org/licenses/by/4.0.)

(Source: de Bode CJ, Dogterom EJ, Rozeboom AV, et al. Orofacial abnormalities in mucopolysaccharidosis and mucolipidosis type II and III: a systematic review. JIMD Rep 2022;63[6]:621-9. Creative Commons Attribution License, creativecommons.org/licenses/by/4.0.)

Classic imaging features of Alexander disease are shown in this axial T2 image, including frontally predominant white matter hyperintensities with swelling and signal changes in the basal ganglia. (Contributed by Dr. Amy Waldman.)

There is extensive T2 hyperintensity involving the bilateral supratentorial white matter, anterior predominant and less extensive in the posterior hemispheres. Also shown is abnormal signal intensity with edema in the bilateral basal ganglia. (Contributed by Dr. Amy Waldman.)

Many regions show contrast enhancement, including parts of the white matter, mainly periventricular, the basal ganglia, brainstem, and dentate nuclei. (Contributed by Dr. Amy Waldman.)

Classic imaging features of Alexander disease are shown in this axial T2 image, including frontally predominant white matter hyperintensities with swelling and signal changes in the basal ganglia. (Contributed by Dr. Amy Waldman.)

There is an asymmetric enhancing lesion involving the posterior left medulla oblongata extending to the inferior cerebellar peduncle on this T2 MRI scan. (Contributed by Dr. Amy Waldman.)

The enhancing lesion is seen in the dorsal medulla on this sagittal post-gadolinium T1 image. (Contributed by Dr. Amy Waldman.)

Medullary and upper cord atrophy are seen on this sagittal T1 image. (Contributed by Dr. Amy Waldman.)

Periventricular and caudate abnormalities on axial FLAIR imaging. (Contributed by Dr. Amy Waldman.)

(Source: Fischer E, Morrell RS. Ueber die Configuration der Rhamnose und Galactose [On the configuration of rhamnose and galactose]. Berichte der Deutschen chemischen Gesellschaft zu Berlin 1894;27:382-94. Public domain.)

(Courtesy of Wikimedia Commons. Public domain. Image restored and edited by Dr. Douglas J Lanska.)

(Courtesy of the Academy of Sciences of Turin and Wikimedia Commons. Public domain. Image restored and edited by Dr. Douglas J Lanska.)

Carl Vilhelm Scheele, statue by Johan Börjeson, in Humlegarden in Stockholm, unveiled on December 9, 1892. This picture was found in "Words and Pictures" in 1892. (Courtesy of Wikimedia Commons. Public domain. Image restored and edited by Dr. Douglas J Lanska.)

Legend: red color, reported symptom; pink color, more rare or suspected symptoms; grey color, absent symptom. Numbers of patients in red color indicate numbers calculated using references from OMIM and available literature. Abbreviations: chr, chromosome; Gal, galactose; Glc, glucose; Cer, ceramide; M, million; K, thousand. (Source: Conte F, van Buuringen N, Voermans NC, Lefeber DJ. Galactose in human metabolism, glycosylation, and congenital metabolic diseases: time for a closer look. Biochim Biophys Acta Gen Subj 2021;1865[8]:129898. CC BY License, http://creativecommons.org/licenses/by/4.0.)

Red color, reported symptom; grey color, absent symptom; the symbol “?” indicates symptoms unclearly correlated with the disease. Abbreviations: chr, chromosome; Gal, galactose; Glc, glucose; GalNAc, N-acetyl-α-D-galactosamine; GlcNAc, N-acetyl-α-D-glucosamine; 1P, phosphate on carbon 1; UDP, uridine diphosphate; proCOL, procollagen; M, million; K, thousand. (Source: Conte F, van Buuringen N, Voermans NC, Lefeber DJ. Galactose in human metabolism, glycosylation, and congenital metabolic diseases: time for a closer look. Biochim Biophys Acta Gen Subj 2021;1865[8]:129898. CC BY License, http://creativecommons.org/licenses/by/4.0.)

Examples of N-glycan structures and the four types of human mucin O-glycans, namely: [core 1] Galβ1–3GalNAcαSer/Thr; [core 2] GlcNAcβ1–6(Galβ1–3) GalNAcαSer/Thr; [core 3] GlcNAcβ1–3GalNAcαSer/Thr; [core 4] GlcNAcβ1–6(GlcNAcβ1–3)GalNAcαSer/Thr. (Source: Conte F, van Buuringen N, Voermans NC, Lefeber DJ. Galactose in human metabolism, glycosylation, and congenital metabolic diseases: time for a closer look. Biochim Biophys Acta Gen Subj 2021;1865[8]:129898. CC BY License, http://creativecommons.org/licenses/by/4.0.)

Solid line arrows indicate direct enzymatic reactions, whereas dashed line arrows indicate a series of sequential reactions. (Source: Conte F, van Buuringen N, Voermans NC, Lefeber DJ. Galactose in human metabolism, glycosylation, and congenital metabolic diseases: time for a closer look. Biochim Biophys Acta Gen Subj 2021;1865[8]:129898. CC BY License, http://creativecommons.org/licenses/by/4.0.)

Galactose is metabolized into UDP-Gal, which is used as a precursor for the glycosylation of different macromolecules. UDP-Gal can be used as a building block for synthesis of N-glycans and O-glycans. Moreover, UDP-Gal can be used to synthesize keratan sulfate, a glycosaminoglycan that, along with N- and O-glycans, is an essential component of several extracellular proteoglycans. Additionally, UDP-Gal is used to glycosylate collagens. Lastly, UDP-Gal can be used to glycosylate lipids alone or in combination with other monosaccharides, generating glycolipids. Among glycolipids, several types of glyceroglycolipids, sulfoglycolipids, and glycerolipids contain galactose in their sugar moieties. (Source: Conte F, van Buuringen N, Voermans NC, Lefeber DJ. Galactose in human metabolism, glycosylation, and congenital metabolic diseases: time for a closer look. Biochim Biophys Acta Gen Subj 2021;1865[8]:129898. CC BY License, http://creativecommons.org/licenses/by/4.0.)

Abbreviations: CO2, carbon dioxide; GALE, UDP-alpha-D-galactose 4-epimerase; GALK, galactokinase; GALT, galactose 1-phosphate uridylyltransferase; HK, hexokinase; PGM1, phosphoglucomutase isoform I; UGP, UDP-alpha-D-glucose pyrophosphorylase. Solid arrows indicate single enzymatic reactions, dashed arrows indicate a sequence of enzymatic reactions (omitted), and blue dotted arrows indicate the contribution of different biochemical pathways to the production of CO2. (Source: Conte F, van Buuringen N, Voermans NC, Lefeber DJ. Galactose in human metabolism, glycosylation, and congenital metabolic diseases: time for a closer look. Biochim Biophys Acta Gen Subj 2021;1865[8]:129898. CC BY License, http://creativecommons.org/licenses/by/4.0.)

The names of the human enzymes that catalyze each reaction are reported in blue color. The name of the synthesized compound is reported in grey color. The colored blocks indicate the chemical groups modified in each reaction. The red dot in beta-keto-D-galactonic acid indicates the anomeric carbon atom (C-1) that is removed via decarboxylation. This step has been proposed to be enzymatically achieved, although the specific mammalian decarboxylase has not been identified yet. (Source: Conte F, van Buuringen N, Voermans NC, Lefeber DJ. Galactose in human metabolism, glycosylation, and congenital metabolic diseases: time for a closer look. Biochim Biophys Acta Gen Subj 2021;1865[8]:129898. CC BY License, http://creativecommons.org/licenses/by/4.0.)

The four steps of the Leloir pathway are shown in order of activity, and they are mediated by (1) GALM, (2) GALK, (3) GALT, and (4) GALE. Legend: the anomeric carbon 1 (C-1) of galactose is indicated by a red dot; the UMP part of the molecules is indicated in green; the phosphate group is indicated in pink; the hydroxy group on carbon 4 (C-4) is indicated in yellow. (Source: Conte F, van Buuringen N, Voermans NC, Lefeber DJ. Galactose in human metabolism, glycosylation, and congenital metabolic diseases: time for a closer look. Biochim Biophys Acta Gen Subj 2021;1865[8]:129898. CC BY License, http://creativecommons.org/licenses/by/4.0.)

The hydroxy group on the hemiacetal carbon (C-1) is indicated in blue in the alpha (α) anomer and in yellow in the beta (β) anomer. (Source: Conte F, van Buuringen N, Voermans NC, Lefeber DJ. Galactose in human metabolism, glycosylation, and congenital metabolic diseases: time for a closer look. Biochim Biophys Acta Gen Subj 2021;1865[8]:129898. CC BY License, http://creativecommons.org/licenses/by/4.0.)

The green boxes indicate the main biochemical functions of carbohydrates in eukaryotic cells, specifically human cells. The blue boxes indicate the main biological roles of glycans and glycoconjugates. The box labeled "pathogenesis" refers to the roles played by glycoconjugates in the pathogenesis of a wide array of human pathological conditions, including inflammation, cancer, degenerative neuromuscular disorders, and diabetes. (Source: Conte F, van Buuringen N, Voermans NC, Lefeber DJ. Galactose in human metabolism, glycosylation and congenital metabolic diseases: time for a closer look. Biochim Biophys Acta Gen Subj 2021;1865[8]:129898. CC BY License, http://creativecommons.org/licenses/by/4.0.)

The enzymes catalyzing the different steps are Scheme 1. Leloir pathway of galactose metabolism. The enzymes catalyzing the different steps are galactose mutarotase (GALM), galactokinase 1 (GALK), galactose-1-phosphate uridylyltransferase (GALT), and UDP-galactose-4-epimerase (GALE). Different forms of galactosemia derive from the impairment of each enzyme as shown by the diagram. (Source: Verdino A, D'Urso G, Tammone C, Scafuri B, Catapano L, Marabotti A. Simulation of the interactions of arginine with wild-type GALT enzyme and the classic galactosemia-related mutant p.Q188R by a computational approach. Molecules 2021;26[19]:6061. Creative Commons Attribution [CC BY] License, https://creativecommons.org/licenses/by/4.0.)

(Source: The University of Arizona Health Sciences: https://disorders.eyes.arizona.edu/disorders/galactosemia. Creative Commons Attribution-Share Alike 4.0 International License, https://creativecommons.org/licenses/by-sa/4.0/deed.en.)

Dr. Luis Federico Leloir (left) on December 10, 1970, drinking champagne from a test tube celebrating the Nobel Prize in Chemistry. (Source: Instituto Leloir via Wikimedia Commons. Public domain.)

Luis Leloir (seated) and Carlos Eugenio Cardini at the Instituto Campomar (Campomar Institute) in 1960. (Source: Instituto Leloir via Wikimedia Commons. Public domain.)

(Courtesy of Wikimedia Commons. Public domain.)

(Courtesy of Wikimedia Commons. Public domain.)

(Courtesy of Wikimedia Commons. Public domain.)

(Illustration prepared by Ed [Edgar181] on January 20, 2012. Public domain. Diagram edited by Dr. Douglas J Lanska.)

(Illustration prepared by Ed [Edgar181] on January 20, 2012. Public domain. Diagram edited by Dr. Douglas J Lanska.)

(Illustration prepared by Ed [Edgar181] on January 20, 2012. Public domain. Diagram edited by Dr. Douglas J Lanska.)

(Illustration prepared by Ed [Edgar181] on January 20, 2012. Public domain. Diagram edited by Dr. Douglas J Lanska.)

(Illustration prepared by Fvasconcellos on May 4, 2007. Public domain.)

Cartoon diagram of a dimer of Escherichia coli galactose-1-phosphate uridylyltransferase (GALT) in complex with UDP-galactose (stick models). Potassium, zinc, and iron ions are visible as purple, gray, and bronze-colored spheres, respectively. See (Thoden et al 2005). (Illustration prepared by Fvasconcellos on August 8, 2008, to match orientation in the original paper: Thoden JB, Timson DJ, Reece RJ, Holden HM. Molecular structure of human galactokinase: implications for type II galactosemia. J Biol Chem 2005;280[10]:9662-70. Public domain.)

Diagram of the galactose metabolic pathway shows the enzyme block responsible for classic galactosemia (galactose 1-phosphate uridyltransferase [GALT]) and the buildup of precursors in the pathway. (Illustration prepared by Canada Hky on November 24, 2011. Public domain.)

Cartoon diagram of a human galactokinase 1 monomer in complex with galactose (red) and an analog of adenosine triphosphate (orange). A magnesium ion is visible as a green sphere. (Illustration prepared by Fvasconcellos on August 8, 2008, to match orientation in the original paper: Thoden JB, Timson DJ, Reece RJ, Holden HM. Molecular structure of human galactokinase: implications for type II galactosemia. J Biol Chem 2005;280[10]:9662-70. Public domain.)

(Illustration prepared by Emw on December 15, 2009. Creative Commons Attribution-Share Alike 3.0 Unported License, https://creativecommons.org/licenses/by-sa/3.0/deed.en.)

(Illustration prepared by Ed [Edgar181] on October 31, 2011. Public domain.)

(Illustration prepared by Boghog2. Public domain.)

(Illustration prepared by NEUROtiker on May 2, 2007. Public domain.)

(Illustration prepared by Gracelaidlaw on May 17, 2010. Public domain.)

(Illustration prepared by Luigi Albert Maria on October 21, 2019. Creative Commons Attribution-Share Alike 4.0 International License, https://creativecommons.org/licenses/by-sa/4.0/deed.en.)

(Illustration prepared by Fvasconcellos on August 8, 2008. Public domain.)

(Illustration prepared by NadirSH on June 31, 2021. Public domain.)

(Illustration prepared by Jü on November 7, 2012. Public domain.)

(Illustration prepared by Jü on November 8, 2012. Public domain.)

(Illustration prepared by Naturwiki on October 5, 2020. Public domain.)

(Illustration prepared by NEUROtiker on March 16, 2007. Public domain.)

(Illustration prepared by NEUROtiker on February 25, 2007. Public domain.)

(Source: Wikimedia Commons. Frustaci et al 2019. Derived from: Frustaci A, Chimenti C, Ricci R, et al. Improvement in cardiac function in the cardiac variant of Fabry's disease with galactose-infusion therapy. N Engl J Med 2001;345[1]:25-32. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Illustration by Armin Kübelbeck on August 7, 2011. (Public domain.)

Samples immunoreacted with PGP 9.5 and were processed for fluorescence microscopy with Cy3 labeled secondary antibodies. Note the lack of intraepidermal nerve fibers and persistence of fibers pertaining to the subepidermal nerve plexus (arrows) in the sample from the lower leg skin of a patient with Fabry disease (upper figure). Note the dense innervation of the epidermis (arrows) in the sample from the back of the patient with Fabry disease, taken at the T12 dermatome (lower figure). Bar = 50 μm. (Source: Burlina AP, Sims KB, Politei JM, et al. Early diagnosis of peripheral nervous system involvement in Fabry disease and treatment of neuropathic pain: the report of an expert panel. BMC Neurol 2011;11:61.)

Alcian blue stain. The ganglion cells are swollen by accumulation of glycolipids. Photomicrograph by E Kaye. (Source: Burlina AP, Sims KB, Politei JM, et al. Early diagnosis of peripheral nervous system involvement in Fabry disease and treatment of neuropathic pain: the report of an expert panel. BMC Neurol 2011;11:61.)

(Source: Burlina AP, Sims KB, Politei JM, et al. Early diagnosis of peripheral nervous system involvement in Fabry disease and treatment of neuropathic pain: the report of an expert panel. BMC Neurol 2011;11:61.)

Angiokeratoma are usually distributed on the buttocks, groin, umbilicus, upper thighs (bathing trunk distribution), and, occasionally, on the lips and oral mucosa. (Source: Burlina AP, Sims KB, Politei JM, et al. Early diagnosis of peripheral nervous system involvement in Fabry disease and treatment of neuropathic pain: the report of an expert panel. BMC Neurol 2011;11:61.)

Angiokeratoma are usually distributed on the buttocks, groin, umbilicus, upper thighs (bathing trunk distribution), and, occasionally, on the lips and oral mucosa. (Source: Burlina AP, Sims KB, Politei JM, et al. Early diagnosis of peripheral nervous system involvement in Fabry disease and treatment of neuropathic pain: the report of an expert panel. BMC Neurol 2011;11:61.)

(Source: Ldmochowski on Wikimedia Commons. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Illustration by PwPhD on January 1, 2010. (Creative Commons Attribution 3.0 International [CC BY 3.0] license, creativecommons.org/licenses/by/3.0. Modified by Dr. Douglas J Lanska.)

Illustration by Domaina, Kashmiri, and SUM1 on January 21, 2020. (Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

The pedigree spans seven generations and includes six affected males and seven obligate female carriers. Symbols: circle, female; square, male; dotted circle, obligate female carrier; filled square, diseased male; arrow, propositus (II-2). (Source: Gaggl M, El-Hadi S, Aigner C, Sunder-Plassmann G. The renal history of Fabry disease. G Ital Nefrol 2016;33 Suppl 66:33.S66.14. Modified by Dr. Douglas J Lanska.)

"1, stratum corneum of epidermis; 2, stratum Malpighi; 3, papillary layer of dermis; 4, angiectasis, occupied by coagula and blood-corpuscles; 5, angiectasis, with dissepiment (ie, a partition in a part or organ; a septum); 6, oblique section of papilla." (Source: Anderson W. A case of “angeio-keratoma.” Br J Dermatol 1898;10:113-7.)

(Source: Anderson W. A case of “angeio-keratoma.” Br J Dermatol 1898;10:113-7.)

(Source: Wikipedia. Public domain.)

Photograph of patient Emil Honke in 1915 at the age of 30 years. (Source: Fabry J. Zur Klinik und Ätiologie des Angiokeratoma. Archiv für dermatologische Forschung 1916;123[2]:294-307. Photograph restored by Dr. Douglas J Lanska.)

Photograph of patient Emil Honke at the age of 13 years. (Source: Fabry J. Ein Beitrag zur Kenntniss der Purpura haemorrhagica nodularis [Purpura papulosa haemorrhagica Hebrae]. Archiv für Dermatologie und Syphilis 1898;43:187-200.)

"Carmine staining shows a club-shaped, distended small artery due to congestion." (Source: Fabry J. Ein Beitrag zur Kenntniss der Purpura haemorrhagica nodularis [Purpura papulosa haemorrhagica Hebrae]. Archiv für Dermatologie und Syphilis 1898;43:187-200.)

"Taenzer's orcein staining shows a dilated vein due to blood congestion." (Source: Fabry J. Ein Beitrag zur Kenntniss der Purpura haemorrhagica nodularis [Purpura papulosa haemorrhagica Hebrae]. Archiv für Dermatologie und Syphilis 1898;43:187-200.)

"Hemorrhage in the area of a fat lobe in the subcutis; the blood here clearly contrasts with the tissue; the preparation shows that the bleeding is confined within one acinus and does not spread to neighboring ones." (Source: Fabry J. Ein Beitrag zur Kenntniss der Purpura haemorrhagica nodularis [Purpura papulosa haemorrhagica Hebrae]. Archiv für Dermatologie und Syphilis 1898;43:187-200.)

"Hematoxylin and eosin staining. Here is a unicameral small and tapered hemorrhagic papule." (Source: Fabry J. Ein Beitrag zur Kenntniss der Purpura haemorrhagica nodularis [Purpura papulosa haemorrhagica Hebrae]. Archiv für Dermatologie und Syphilis 1898;43:187-200.)

"Carmine staining. A comparatively large hemorrhage only in the epithelial part of the skin. tissue red, bleeding brown; part of the blood has fallen out, as is usually the case; the degree of secondary hypertrophy can be clearly seen in the figure, faithfully reproduced from my preparations." (Source: Fabry J. Ein Beitrag zur Kenntniss der Purpura haemorrhagica nodularis [Purpura papulosa haemorrhagica Hebrae]. Archiv für Dermatologie und Syphilis 1898;43:187-200.)

"Weigert fibrin staining. The incision has struck some hemorrhages of the dermis, also quite close to the epidermis; the contrast between blue fabric and brown colored blur is very striking; the section shows no tissue hypertrophy in the uppermost layers of the epidermis." (Source: Fabry J. Ein Beitrag zur Kenntniss der Purpura haemorrhagica nodularis [Purpura papulosa haemorrhagica Hebrae]. Archiv für Dermatologie und Syphilis 1898;43:187-200.)

"Carmine coloring. Horny part of the epidermis. Epidermis dark red, dermis and subcutaneous connective tissue light red. An elongated, single-chamber hemorrhage in the cutis, apparently near a sebaceous duct, to the left of which is a small cutis hemorrhage, and bleeding near the sebum lobules themselves." (Source: Fabry J. Ein Beitrag zur Kenntniss der Purpura haemorrhagica nodularis [Purpura papulosa haemorrhagica Hebrae]. Archiv für Dermatologie und Syphilis 1898;43:187-200.)

"Hematoxylin staining. Cutis papillae dark blue, almost violet, epidermis light blue, blood foci greenish-yellow, section through a larger nodule, near the blood papules the epidermal papillae are elongated. Some blood dropped out. The hemorrhage is divided into several chambers by septa of an epithelial nature; low-grade parakeratosis; in the Curls foci of small cell infiltration." (Source: Fabry J. Ein Beitrag zur Kenntniss der Purpura haemorrhagica nodularis [Purpura papulosa haemorrhagica Hebrae]. Archiv für Dermatologie und Syphilis 1898;43:187-200.)

"Watercolor taken from nature and in life size from the back of the left thigh; a point is shown at the border between the gluteal region and the flexor surface of the thigh; here a whole lot of small and tiny spots come to light which the photograph cannot reproduce." (Source: Fabry J. Ein Beitrag zur Kenntniss der Purpura haemorrhagica nodularis [Purpura papulosa haemorrhagica Hebrae]. Archiv für Dermatologie und Syphilis 1898;43:187-200.)

(Scan of a private picture, courtesy of Professor Hermann Fabry, nephew and inheritor of Johannes Fabry. Photograph taken by an unknown member of the Fabry family. (Wikimedia Commons.)

(Source: Ezgu F, Alpsoy E, Bicik Bahcebasi Z, et al. Expert opinion on the recognition, diagnosis and management of children and adults with Fabry disease: a multidisciplinary Turkey perspective. Orphanet J Rare Dis 2022;17[1]:90. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0. Adapted from: Felis A, Whitlow M, Kraus A, Warnock DG, Wallace E. Current and investigational therapeutics for Fabry disease. Kidney Int Rep 2019;5[4]:407-13.)

(Source: Ezgu F, Alpsoy E, Bicik Bahcebasi Z, et al. Expert opinion on the recognition, diagnosis and management of children and adults with Fabry disease: a multidisciplinary Turkey perspective. Orphanet J Rare Dis 2022;17[1]:90. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0. Adapted from: Lidove O, Kaminsky P, Hachulla E, et al. Fabry disease “The New Great Imposter”: results of the French Observatoire in internal medicine departments [FIMeD]. Clin Genet 2012;81[6]:571-7.)

(Source: Ezgu F, Alpsoy E, Bicik Bahcebasi Z, et al. Expert opinion on the recognition, diagnosis and management of children and adults with Fabry disease: a multidisciplinary Turkey perspective. Orphanet J Rare Dis 2022;17[1]:90. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(Source: Ezgu F, Alpsoy E, Bicik Bahcebasi Z, et al. Expert opinion on the recognition, diagnosis and management of children and adults with Fabry disease: a multidisciplinary Turkey perspective. Orphanet J Rare Dis 2022;17[1]:90. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(Source: Ezgu F, Alpsoy E, Bicik Bahcebasi Z, et al. Expert opinion on the recognition, diagnosis and management of children and adults with Fabry disease: a multidisciplinary Turkey perspective. Orphanet J Rare Dis 2022;17[1]:90. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(Source: Ezgu F, Alpsoy E, Bicik Bahcebasi Z, et al. Expert opinion on the recognition, diagnosis and management of children and adults with Fabry disease: a multidisciplinary Turkey perspective. Orphanet J Rare Dis 2022;17[1]:90. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(Source: Ezgu F, Alpsoy E, Bicik Bahcebasi Z, et al. Expert opinion on the recognition, diagnosis and management of children and adults with Fabry disease: a multidisciplinary Turkey perspective. Orphanet J Rare Dis 2022;17[1]:90. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(Source: Ezgu F, Alpsoy E, Bicik Bahcebasi Z, et al. Expert opinion on the recognition, diagnosis and management of children and adults with Fabry disease: a multidisciplinary Turkey perspective. Orphanet J Rare Dis 2022;17[1]:90. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(Source: Ezgu F, Alpsoy E, Bicik Bahcebasi Z, et al. Expert opinion on the recognition, diagnosis and management of children and adults with Fabry disease: a multidisciplinary Turkey perspective. Orphanet J Rare Dis 2022;17[1]:90. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(Source: Ezgu F, Alpsoy E, Bicik Bahcebasi Z, et al. Expert opinion on the recognition, diagnosis and management of children and adults with Fabry disease: a multidisciplinary Turkey perspective. Orphanet J Rare Dis 2022;17[1]:90. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(Source: Ezgu F, Alpsoy E, Bicik Bahcebasi Z, et al. Expert opinion on the recognition, diagnosis and management of children and adults with Fabry disease: a multidisciplinary Turkey perspective. Orphanet J Rare Dis 2022;17[1]:90. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(A) Biomicroscopic appearance of “cornea verticillata” in the right eye. (B) Higher magnification image of the same patient demonstrating the whorl-like pattern of cornea verticillata. (Source: Ezgu F, Alpsoy E, Bicik Bahcebasi Z, et al. Expert opinion on the recognition, diagnosis and management of children and adults with Fabry disease: a multidisciplinary Turkey perspective. Orphanet J Rare Dis 2022;17[1]:90. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Spectrum of brain MRI findings in a 51-year-old male patient with Fabry disease. Accumulation of small basal perforating infarcts: (1) right thalamic lesion; (2) emergence of left caudate lesion in 1-year interval. (Source: Ezgu F, Alpsoy E, Bicik Bahcebasi Z, et al. Expert opinion on the recognition, diagnosis and management of children and adults with Fabry disease: a multidisciplinary Turkey perspective. Orphanet J Rare Dis 2022;17[1]:90. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

MR angiography findings in a 51-year-old male patient with Fabry disease. Arrow indicates basilary dolichoectasia. (Source: Ezgu F, Alpsoy E, Bicik Bahcebasi Z, et al. Expert opinion on the recognition, diagnosis and management of children and adults with Fabry disease: a multidisciplinary Turkey perspective. Orphanet J Rare Dis 2022;17[1]:90. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Spectrum of T2-weighted brain MRI findings in a 51-year-old male patient with Fabry disease. Chronic left mid-pons perforating infarcts (lacune type, arrow). (Source: Ezgu F, Alpsoy E, Bicik Bahcebasi Z, et al. Expert opinion on the recognition, diagnosis and management of children and adults with Fabry disease: a multidisciplinary Turkey perspective. Orphanet J Rare Dis 2022;17[1]:90. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Spectrum of diffusion-weighted brain MRI findings in a 51-year-old male patient with Fabry disease. Arrow indicates acute small-junctional infarct. (Source: Ezgu F, Alpsoy E, Bicik Bahcebasi Z, et al. Expert opinion on the recognition, diagnosis and management of children and adults with Fabry disease: a multidisciplinary Turkey perspective. Orphanet J Rare Dis 2022;17[1]:90. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Spectrum of FLAIR sequence brain MRI findings in a 51-year-old male patient with Fabry disease. (Source: Ezgu F, Alpsoy E, Bicik Bahcebasi Z, et al. Expert opinion on the recognition, diagnosis and management of children and adults with Fabry disease: a multidisciplinary Turkey perspective. Orphanet J Rare Dis 2022;17[1]:90. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Hematoxylin-eosin staining, X400 magnified. (Source: Ezgu F, Alpsoy E, Bicik Bahcebasi Z, et al. Expert opinion on the recognition, diagnosis and management of children and adults with Fabry disease: a multidisciplinary Turkey perspective. Orphanet J Rare Dis 2022;17[1]:90. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Illustration by NEUROtiker on May 23, 2007. (Public domain.)

Panel A (left) shows the processing of normal alpha-galactosidase A. Newly synthesized alpha-galactosidase A is translocated into the endoplasmic reticulum, where molecular chaperones facilitate its proper folding and dimerization by specialized processing enzymes. The molecular chaperones then dissociate from the folded, dimerized enzyme, which moves to the Golgi apparatus and then to lysosomes, where the enzyme is stable and active in the acidic environment of these organelles. Panel B (right) shows the processing of mutant alpha-galactosidase A. Most mutations in the alpha-galactosidase A gene encode alpha-galactosidase A molecules that are misfolded, misassembled, or aggregated in the endoplasmic reticulum, where they are degraded, presumably by the ubiquitin-proteasome pathway. However, certain missense mutations decrease the stability of the enzyme, but the conformation of the active site is retained. Most of this type of mutant enzyme is degraded in the endoplasmic reticulum. However, these mutant forms of alpha-galactosidase A may be stabilized by chemical chaperones, such as galactose, that bind to the active site of the enzyme, promote folding, and stabilize the mutant enzyme. Some of the enzyme then reaches the lysosomes, where it retains low levels of activity. In the lysosomes, the accumulated glycosphingolipid substrates displace the chemical chaperones and are hydrolyzed by the enzyme. (Modified from Kuznetsov and Nigam. Source: Frustaci A, Chimenti C, Ricci R, et al. Improvement in cardiac function in the cardiac variant of Fabry's disease with galactose-infusion therapy. N Engl J Med 2001;345[1]:25-32. Wikimedia Commons. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

EKG findings in a 76-year-old male. (Source: Azevedo O, Cordeiro F, Gago MF, et al. Fabry disease and the heart: a comprehensive review. Int J Mol Sci 2021;22[9]:4434. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

EKG findings in a 72-year-old male. (Source: Azevedo O, Cordeiro F, Gago MF, et al. Fabry disease and the heart: a comprehensive review. Int J Mol Sci 2021;22[9]:4434. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

EKG findings in a 34-year-old male. (Source: Azevedo O, Cordeiro F, Gago MF, et al. Fabry disease and the heart: a comprehensive review. Int J Mol Sci 2021;22[9]:4434. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Illustration by Armin Kübelbeck on September 16, 2011. (Public domain.)

Illustration by Armin Kübelbeck on September 16, 2011. (Public domain.)

Hallervorden was a former member of the Nazi Party (ie, the National Socialist German Workers' Party) who had knowingly performed much of his research on the brains of executed prisoners and participated in the action T4 euthanasia program. (Kondziella D. Thirty neurological eponyms associated with the Nazi era. Eur Neurol 2009;62[1]:56-64). Photograph from Wermacht identification card issued March 1935. (Source: Wikimedia Commons. Public domain. Restored by Dr. Douglas J Lanska.)

Professor Rudolf Beneke (1861-1946) was a pathologist, and conducted research at the Universities of Leipzig, Göttingen, Königsberg, and what is today Kaliningrad (Russia), where he was successor of Ernst Christian Neumann (1834-1918) at the Institute of Pathology. (Source: Wikipedia. See: Krauspe C. Zur Geschichte der Allgemeinen Pathologie und Pathologischen Anatomie an der Albertus-Universität Königsberg. Beilage zum Osterrundbrief 1969 der Ostpreußischen Arztfamilie 1969;1:1-25.)

(Source: Courtesy of Center for the History of Medicine, Countway Library of Medicine, Boston, Massachusetts. Photograph restored and edited by Dr. Douglas J Lanska.)

(Source: Briggs LV. History of the psychopathic hospital, Boston, Massachusetts. Boston, Wirght, and Potter Printing Co., 1922. Photograph restored by Dr. Douglas J Lanska.)

Relatively isolated signal changes of the pyramidal tract (arrows, T2-weighted sagittal on the left, axial FLAIR image on the right). The cerebellum shows no signal changes. Case with onset at 60 years, and age 69 years at MRI). (Source: Krieg SI, Krägeloh-Mann I, Groeschel S, et al. Natural history of Krabbe disease: a nationwide study in Germany using clinical and MRI data. Orphanet J Rare Dis 2020;15[1]:243. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

White matter is primarily affected in the periventricular parieto-occipital regions (arrows in the upper right FLAIR image, and lower left sagittal and lower right T2-weighted images). The FLAIR image shows involvement of the splenium of the corpus callosum (black arrow). Cerebellar white matter is not affected (axial T2-weighted image upper left). This patient had onset at 5 years, and was 5 years 1 month of age at MRI. (Source: Krieg SI, Krägeloh-Mann I, Groeschel S, et al. Natural history of Krabbe disease: a nationwide study in Germany using clinical and MRI data. Orphanet J Rare Dis 2020;15[1]:243. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

At 11.5 months, the central white matter shows abnormalities, whereas the cerebellar white matter appears normal (a). One month and 1.5 months later, the parieto-occipital white matter is increasingly involved, and the cerebellar white matter is still not affected (b, c). Six months later, frontal, central, and parieto-occipital white matter as well as cerebellum are affected (d). This patient had onset at 9 months. (Source: Krieg SI, Krägeloh-Mann I, Groeschel S, et al. Natural history of Krabbe disease: a nationwide study in Germany using clinical and MRI data. Orphanet J Rare Dis 2020;15[1]:243. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Axial images (T2-weighted image on left, and FLAIR on right) show cystic degeneration of the pyramidal tract (white arrows), severe atrophy with enlarged insulae, and diffusely affected white matter. This patient had onset at 4 months and was 8 months of age at MRI. (Source: Krieg SI, Krägeloh-Mann I, Groeschel S, et al. Natural history of Krabbe disease: a nationwide study in Germany using clinical and MRI data. Orphanet J Rare Dis 2020;15[1]:243. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Cerebellar changes in an early infantile patient during the disease course (onset 4 months). The T2-weighted axial MRI at age 5.5 months shows hyperintensity in the dentate nucleus (a), which had disappeared 8 months later (b). (Source: Krieg SI, Krägeloh-Mann I, Groeschel S, et al. Natural history of Krabbe disease: a nationwide study in Germany using clinical and MRI data. Orphanet J Rare Dis 2020;15[1]:243. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

White matter changes are prominent in the central region (small white arrows in lower images), cerebellar white matter (white arrows in upper images), and signal changes of the dentate nucleus (black arrows in upper images). T2-weighted magnetic resonance images in axial section (lower images), coronal section (upper left), and sagittal section (upper right). This patient had onset at 2 months and was 5 months of age at MRI. (Source: Krieg SI, Krägeloh-Mann I, Groeschel S, et al. Natural history of Krabbe disease: a nationwide study in Germany using clinical and MRI data. Orphanet J Rare Dis 2020;15[1]:243. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(Source: Krieg SI, Krägeloh-Mann I, Groeschel S, et al. Natural history of Krabbe disease: a nationwide study in Germany using clinical and MRI data. Orphanet J Rare Dis 2020;15[1]:243. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

The GMFC-MLD was used for the standardized evaluation of gross motor function (Kehrer C, Blumenstock G, Raabe C, Krägeloh-Mann I. Development and reliability of a classification system for gross motor function in children with metachromatic leucodystrophy. Dev Med Child Neurol 2011;53[2]:156-60). (Source: Krieg SI, Krägeloh-Mann I, Groeschel S, et al. Natural history of Krabbe disease: a nationwide study in Germany using clinical and MRI data. Orphanet J Rare Dis 2020;15[1]:243. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(Source: Krieg SI, Krägeloh-Mann I, Groeschel S, et al. Natural history of Krabbe disease: a nationwide study in Germany using clinical and MRI data. Orphanet J Rare Dis 2020;15[1]:243. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Categories are represented by symbols. The symbols for each category are linked together for better identification. (Source: Krieg SI, Krägeloh-Mann I, Groeschel S, et al. Natural history of Krabbe disease: a nationwide study in Germany using clinical and MRI data. Orphanet J Rare Dis 2020;15[1]:243. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(Source: Krieg SI, Krägeloh-Mann I, Groeschel S, et al. Natural history of Krabbe disease: a nationwide study in Germany using clinical and MRI data. Orphanet J Rare Dis 2020;15[1]:243. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

CGT catalyzes the synthesis of GalCer by adding a galactose molecule to ceramide (A). Ceramide with a hydroxy group at the two position (dashed circle) is a more efficient CGT substrate than nonhydroxyceramide. CST catalyzes the sulfation of GalCer to generate both non-hydroxy and 2-hydroxy-sulfatide (B). GalCer and sulfatide are degraded in the lysosome by the enzymes GALC and ARSA, which are deficient in KD and MLD, respectively (C, D). GALC and ARSA deficiency results in lysosomal accumulation of these glycolipids and their subsequent deacylation into the toxic byproducts psychosine and lysosulfatide by acid ceramidase (E). Previous substrate reduction approaches using L-cycloserine targets a reaction upstream from ceramide synthesis (F).

Abbreviations: ARSA, arylsulfatase A; CGT, ceramide galactosyltransferase; CST, cerebroside sulfotransferase; FA2H, fatty acid 2-hydroxylase; GALC, galactosylceramidase; GalCer, galactosylceramide; KD, Krabbe disease; MLD, metachromatic leukodystrophy.

(Souce: Babcock MC, Mikulka CR, Wang B, et al. Substrate reduction therapy for Krabbe disease and metachromatic leukodystrophy using a novel ceramide galactosyltransferase inhibitor. Sci Rep 2021;11[1]:14486. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

FLAIR sequences showed hyperintensities in the corticospinal tracts starting in the precentral gyrus and extending to corona radiata, posterior limb of internal capsules, as well as in the terminal areas of white matter. (Source: Chen J, Zhao Z, Shen H, et al. Genetic origin of patients having spastic paraplegia with or without other neurologic manifestations. BMC Neurol 2022;22[1]:180. Creative Commons Attribution 4.0 International License, http://creativecommons.org/licenses/by/4.0.)

A schematic of the various sphingolipid metabolic pathways shows the enzymes whose deficiency leads to several diseases. Note that each enzyme is assisted by one or more saposins (Saps): (1) GM2A assists both β-gal and β-hexosaminidase; (2) SapB assists sialidase, α-GAL, GALC, and β-gal; (3) SapC assists GALC, β-gal, GCase, acid ceramidase, and GALC; (4) SapD assists acid ceramidase.

Abbreviations: Cer, ceramide; DiGalCer, digalactosylceramide; Gal, galactose; GalCer, galactosylceramide; GalNAc, N-acetylgalactosamine; Gb3, globotriaosylceramide; Gb4, globotetraosylceramide; Glc, glucose; GlcCer, glucosylceramide; LacCer, lactosylceramide; Neu5Ac, N-acetylneuraminic acid; SM, sphingomyelin; SM4, 3-O-sulfogalactosylceramide; Sph, sphingosine.

(Source: Abed Rabbo M, Khodour Y, Kaguni LS, Stiban J. Sphingolipid lysosomal storage diseases: from bench to bedside. Lipids Health Dis 2021;20[1]:44. Creative Commons Attribution 4.0 International License, http://creativecommons.org/licenses/by/4.0.)

In mammalian cells, ceramide is biosynthesized de novo or generated by catabolism of complex sphingolipids. In the de novo synthesis pathway (purple block arrow), a four-enzyme sequence culminates in the formation of ceramide from the amino acid serine and palmitoyl-CoA. This pathway is located in the endoplasmic reticulum. Sphingomyelin can be hydrolyzed to ceramide in the sphingomelin hydrolysis pathway (orange block arrow), which involves only one enzyme step. Alternatively, ceramide can be produced in the salvage pathway (green block arrows), through the acylation of sphingolipid by the ceramide synthase family of enzymes. The red blocks represent cartoons of the possible structures of the molecules. The acyl-chain length of ceramide can vary greatly. (Source: Abed Rabbo M, Khodour Y, Kaguni LS, Stiban J. Sphingolipid lysosomal storage diseases: from bench to bedside. Lipids Health Dis 2021;20[1]:44. Creative Commons Attribution 4.0 International License, http://creativecommons.org/licenses/by/4.0.)

Sphingolipids contain a long-chain base, which can be saturated (sphinganine) or monounsaturated at C4 (sphingosine). N-acylation at the amino group on C2 creates ceramide, which may consist of a varying number of carbon atoms. The representative ceramide shown is the 16-carbon palmitoyl-ceramide. The addition of a phosphocholine at C1 creates the parent phosphosphingolipid sphingomyelin, and glycosylation at the same carbon generates glucosylceramide. (Source: Abed Rabbo M, Khodour Y, Kaguni LS, Stiban J. Sphingolipid lysosomal storage diseases: from bench to bedside. Lipids Health Dis 2021;20[1]:44. Creative Commons Attribution 4.0 International License, http://creativecommons.org/licenses/by/4.0.)

From left to right: The lysosomal storage disorders, the gene defect, accumulating lysosomal GSL substrates, and the deacylated lyso-GSL species.

Abbreviations: ASA, Arylsulfatase A; GALC, β-galactosylceramidase; GalCer, galactosylceramide; GBA, acid β-glucosidase; GLA, α-galactosidase A; GLB1, β-galactosidase; GB3, globotriaosylceramide; GlcCer, glucosylceramide; GM1, ganglioside GM1; GM2, ganglioside GM2; HEX, β-hexosaminidase; lyso-GSL, lyso-glycosphingolipid; SO, sphingoid.

(Source: van Eijk M, Ferraz MJ, Boot RG, Aerts JM. Lyso-glycosphingolipids: presence and consequences. Essays Biochem 2020;64[3]:565-78. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Abbreviations: ASA, Arylsulfatase A; ASAH1, acid ceramidase; GALC, β-galactosylceramidase; GBA, β-glucocerebrosidase; GLA, α-galactosidase A; GLB1, β-galactosidase; HEXA, β-hexosaminidase A; HEXB, β-hexosaminidase B; NEU3/4, neuraminidase 3/4.

(Source: van Eijk M, Ferraz MJ, Boot RG, Aerts JM. Lyso-glycosphingolipids: presence and consequences. Essays Biochem 2020;64[3]:565-78. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Abbreviations: CDase, ceramidase; Cer1P, ceramide-1-phosphate; CGS, cerebroside sulfotransferase; CGT, UDP-galactose ceramide galactosyl transferase; CK, ceramide kinase; GCS, glucosylceramide synthase; GalCer, galactosylceramide; GlcCer, glucosylceramide; Hexa, hexadecanal; LacCer, lactosylceramide; LCS, lactosylceramide synthase; PE, phosphatidylethanolamine; S1P, sphingosine-1-phosphate; S1PL, S1P lyase; SK, sphingosine kinase; SMS, sphingomyelin synthase; SO, sphingosine.

(Source: van Eijk M, Ferraz MJ, Boot RG, Aerts JM. Lyso-glycosphingolipids: presence and consequences. Essays Biochem 2020;64[3]:565-78. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

The acylchain is depicted in blue and can range from C14 to C26, depending on the CERS enzyme involved in acyl chain condensation (six CERS members exist). Depending on the acyl-CoA moiety used by SPT (ie, myristoyl-CoA, palmitoyl-CoA, or stearyl-CoA), different sphingoid bases can be produced (C16:1, C18:1, or C20:1).

Abbreviations: CERS, ceramide synthase; DES, desaturase; KDR, ketoreductase; SPT, serine palmitoyltransferase.

(Source: van Eijk M, Ferraz MJ, Boot RG, Aerts JM. Lyso-glycosphingolipids: presence and consequences. Essays Biochem 2020;64[3]:565-78. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(Photomicrograph by Jensflorian on July 14, 2011. Creative Commons Attribution-Share Alike 3.0 Unported License, creativecommons.org/licenses/by-sa/3.0/deed.en.)

Image by Domaina, Kashmiri, and SUM1 on January 20, 2020, via Wikipedia. Creative Commons Attribution-Share Alike 3.0 Unported License, creativecommons.org/licenses/by-sa/3.0/deed.en. Modified by Dr. Douglas J Lanska.)

In 1916, Krabbe first described what is now known as globoid cell leukodystrophy or Krabbe disease. (Courtesy of the US National Library of Medicine. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Three-dimensional rendering of glucocerebrosidase with catalytic residues highlighted. (Illustration by Samschrnbrg1 on March 9, 2018. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0. Figure edited by Dr. Douglas J Lanska.)

Three-dimensional rendering of human glucocerebrosidase with three distinct domains highlighted in different colors. (Illustration by Samschrnbrg1 on March 7, 2018. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0. Figure edited by Dr. Douglas J Lanska.)

Hematoxylin and eosin stain. Necrotic bone is characterized histomorphologically by a lack of osteocytes in the lacunae. (Photomicrograph by Nephron in May 2011 via Wikimedia Commons. Creative Commons Attribution 3.0 Unported [CC BY 3.0] license, creativecommons.org/licenses/by/3.0.)

Hematoxylin and eosin stain. Necrotic bone is characterized histomorphologically by a lack of osteocytes in the lacunae. (Photomicrograph by Nephron in May 2011 via Wikimedia Commons. Creative Commons Attribution 3.0 Unported [CC BY 3.0] license, creativecommons.org/licenses/by/3.0.)

Hematoxylin and eosin stain. Necrotic bone is characterized histomorphologically by a lack of osteocytes in the lacunae. (Photomicrograph by Nephron in May 2011 via Wikimedia Commons. Creative Commons Attribution 3.0 Unported [CC BY 3.0] license, creativecommons.org/licenses/by/3.0.)

Thudichum isolated and characterized numerous compounds of the brain, such as cephalin, sphingomyelin, galactose, lactic acid, and sphingosine. In 1884, he explained his findings in a publication titled "A Treatise on the Chemical Constitution of the Brain," a book that was widely criticized in the scientific community (Thudichum 1884). After his death, Thudichum's discoveries were realized to be important scientific contributions to the study of the chemical and molecular composition of the brain.

Reference: Thudichum JL. A Treatise on the Chemical Constitution of the Brain: Based Throughout upon Original Researches. London : Bailliere, Tindall, and Cox, 1884.

(Source: Courtesy of the US National Library of Medicine. Public domain.)

A chamber and the cells it contains, high magnification (x330). Drawing by Gaucher for his thesis. (Source: Gaucher E. De l'epithélioma primitif de la rate: hypertrophie idiopathique de la rate sans leucémie. Paris: Octave Doin, 1882.)

Drawing by Gaucher for his thesis. "We see the hyperplastic connective tissue and the compartments they limit filled with epithelial cells. – In a, a bloody effusion." (Magnification x60). (Source: Gaucher E. De l'epithélioma primitif de la rate: hypertrophie idiopathique de la rate sans leucémie. Paris: Octave Doin, 1882.)

Drawing by Gaucher for his thesis. "We see in a, in one of the compartments, a bloody effusion. The section is limited on the right by the thickened outer fibrous envelope. In the large fibrous spans, we see sclerotic vessels." (Magnification x60). (Source: Gaucher E. De l'epithélioma primitif de la rate: hypertrophie idiopathique de la rate sans leucémie. Paris: Octave Doin, 1882.)

(Source: National Institutes of Health. Public domain.)

(Image by WillowW on May 19, 2006, via Wikimedia Commons. Creative Commons Attribution 3.0 Unported [CC BY 3.0] license, creativecommons.org/licenses/by/3.0.)

Mallory's aniline blue connective tissue stain (x560). Marked longitudinal fibrillation of the cytoplasm of the Gaucher cells. (Source: Bloom W. Splenomegaly [type Gaucher] and lipid-histiocytosis [type Niemann]. Am J Pathol 1925;1[6]:595-626.9.)

Hemalum and eosin stain (x240). Mayer’s hemalum solution for nuclear staining and eosin solution for counterstaining. (Source: Bloom W. Splenomegaly [type Gaucher] and lipid-histiocytosis [type Niemann]. Am J Pathol 1925;1[6]:595-626.9.)

Mutated GCase or decreased levels of GCase cause a slowdown of alpha-synuclein degradation with the resulting formation of alpha-synuclein oligomers and fibrils (Cullen et al 2011; Yap et al 2011; Murphy et al 2014). Glucosylceramide stabilizes the alpha-synuclein oligomers (Mazzulli et al 2011), which are able to bind to the mutated glucocerebrosidase molecules and inhibit the enzymatic activity of glucocerebrosidase, further decreasing enzyme activity (Mazzulli et al 2011; Yap et al 2013a; 2015). These impaired lysosomes show impaired chaperone-mediated autophagy and autophagosome fusion. This results in an increased accumulation of alpha-synuclein in the cytoplasm, forming insoluble aggregates that ultimately form Lewy bodies. These aggregates block trafficking of GCase from the endoplasmic reticulum (ER) to the Golgi (Siebert et al 2014). Mutant GCase is retained in the endoplasmic reticulum, which causes ER stress and evokes the ER stress response (unfolded protein response) (Horowitz et al 2016). Saposin C can have a modulating effect on this by binding to Gcase, thus, maintaining its activity (Yap et al 2013b; Gruschus et al 2015).

References:
Cullen V, Sardi SP, Ng J, et al. Acid β-glucosidase mutants linked to Gaucher disease, Parkinson disease, and Lewy body dementia alter alpha-synuclein processing. Ann Neurol 2011;69(6):940-53.
Gruschus JM, Jiang Z, Yap TL, et al. Dissociation of glucocerebrosidase dimer in solution by its co-factor, saposin C. Biochem Biophys Res Commun 2015;457(4):561-6.
Horowitz M, Elstein D, Zimran A, Goker-Alpan O. New directions in Gaucher disease. Hum Mutat 2016;37(11):1121-36.
Mazzulli JR, Xu YH, Sun Y, et al. Gaucher disease glucocerebrosidase and alpha-synuclein form a bidirectional pathogenic loop in synucleinopathies. Cell 2011;146:37-52.
Murphy KE, Gysbers AM, Abbott SK, et al. Reduced glucocerebrosidase is associated with increased alpha-synuclein in sporadic Parkinson's disease. Brain 2014;137(Pt 3):834-48.
Siebert M, Sidransky E, Westbroek W. Glucocerebrosidase is shaking up the synucleinopathies. Brain 2014;137(Pt 5):1304-22.
Yap TL, Gruschus JM, Velayati A, et al. Alpha-synuclein interacts with glucocerebrosidase providing a molecular link between Parkinson and Gaucher diseases. J Biol Chem 2011;286(32):28080-8.
Yap TL, Gruschus JM, Velayati A, Sidransky E, Lee JC. Saposin C protects glucocerebrosidase against α-synuclein inhibition. Biochemistry 2013b;52(41):7161-3.
Yap TL, Jiang Z, Heinrich F, et al. Structural features of membrane-bound glucocerebrosidase and alpha-synuclein probed by neutron reflectometry and fluorescence spectroscopy. J Biol Chem 2015;290(2):744-54.
Yap TL, Velayati A, Sidransky E, Lee JC. Membrane-bound alpha-synuclein interacts with glucocerebrosidase and inhibits enzyme activity. Mol Genet Metab 2013a;108(1):56-64.

(Source: Stirnemann J, Belmatoug N, Camou F, et al. A review of Gaucher disease pathophysiology, clinical presentation, and treatments. Int J Mol Sci 2017;18[2]:441. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Normally, GCase interacts with its substrate glucosylceramiide (GlcCer) as well as monomers of alpha-synuclein in lysosomes, facilitating the breakdown of both at acidic pH. (Source: Stirnemann J, Belmatoug N, Camou F, et al. A review of Gaucher disease pathophysiology, clinical presentation, and treatments. Int J Mol Sci 2017;18[2]:441. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

LIMP-2 is a lysosomal membrane protein (LMP) whose highly glycosylated intra-lysosomal part protects the lysosome’s membrane. LIMP-2 anomalies can induce a phenotype rather than GD3 (Gonzalez A, Valeiras M, Sidransky E, Tayebi N. Lysosomal integral membrane protein-2: a new player in lysosome-related pathology. Mol Genet Metab 2014;111[2]:84-91).

(Source: Stirnemann J, Belmatoug N, Camou F, et al. A review of Gaucher disease pathophysiology, clinical presentation and treatments. Int J Mol Sci 2017;18[2]:441. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0. Figure modified by Dr. Douglas J Lanska.)

Protein maturation takes place in the Golgi apparatus; the transport and delivery of GCase to lysosomes require a particular molecule, LIMP-2, which allows GCase to reach the lysosome where the acidic pH breaks the molecular link (Gonzalez A, Valeiras M, Sidransky E, Tayebi N. Lysosomal integral membrane protein-2: a new player in lysosome-related pathology. Mol Genet Metab 2014;111[2]:84-91).

(Source: Stirnemann J, Belmatoug N, Camou F, et al. A review of Gaucher disease pathophysiology, clinical presentation and treatments. Int J Mol Sci 2017;18[2]:441. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0. Figure modified by Dr. Douglas J Lanska.)

The expression of GCase varies from one cell type to another and depends on the tissue. In a mouse model of GCase deficiency (red cross), GlcCer is transformed via an alternative ceramidase pathway into glucosylsphingosine (red arrow), which is degraded by cytoplasmic GCase2 (GBA2 gene), active at a neutral pH, to sphingosine-1-phosphate (S1P), a very active metabolite (Mistry PK, Liu J, Sun L, et al. Glucocerebrosidase 2 gene deletion rescues type 1 Gaucher disease. Proc Natl Acad Sci U S A 2014;111[13]:4934-9).

Abbreviations: GCase, glucocerebrosidase; GlcCer, glucosylceramide; S1P, sphingosine-1-phosphate.

(Source: Stirnemann J, Belmatoug N, Camou F, et al. A review of Gaucher disease pathophysiology, clinical presentation and treatments. Int J Mol Sci 2017;18[2]:441. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(x60) Gaucher cells infiltrate various organs (eg, bone marrow, spleen, and liver) and are responsible for major signs of the disease). (Courtesy of Fabrice Camou and Rachid Seddik. Source: Stirnemann J, Belmatoug N, Camou F, et al. A review of Gaucher disease pathophysiology, clinical presentation and treatments. Int J Mol Sci 2017;18[2]:441. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(x60) Gaucher cells infiltrate various organs (eg, bone marrow, spleen, and liver) and are responsible for major signs of the disease). (Courtesy of Fabrice Camou and Rachid Seddik. Source: Stirnemann J, Belmatoug N, Camou F, et al. A review of Gaucher disease pathophysiology, clinical presentation and treatments. Int J Mol Sci 2017;18[2]:441. Creative Commons Attribution [CC BY] License, https://creativecommons.org/licenses/by/4.0.)

(Source: Stirnemann J, Belmatoug N, Camou F, et al. A review of Gaucher disease pathophysiology, clinical presentation and treatments. Int J Mol Sci 2017;18[2]:441. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0. Figure modified by Dr. Douglas J Lanska.)

Horizontal axis shows time in years after presentation of Gaucher disease. (Source: D'Amore S, Page K, Donald A, et al. In-depth phenotyping for clinical stratification of Gaucher disease. Orphanet J Rare Dis 2021;16[1]:431. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Controlling for gender, the hazard or risk of having a first fragility fracture after presentation of Gaucher disease was greater in patients who had splenectomy (hazard ratio of 2.83 [95% CI 1.33–5.99; p = 0.01]). Horizontal axis shows years after presentation with Gaucher disease. (Source: D'Amore S, Page K, Donald A, et al. In-depth phenotyping for clinical stratification of Gaucher disease. Orphanet J Rare Dis 2021;16[1]:431. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Horizontal axis shows years after presentation with Gaucher disease. (Source: D'Amore S, Page K, Donald A, et al. In-depth phenotyping for clinical stratification of Gaucher disease. Orphanet J Rare Dis 2021;16[1]:431. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

H-shaped vertebrae of the thoracic spine consistent with osteonecrosis. (Source: D'Amore S, Page K, Donald A, et al. In-depth phenotyping for clinical stratification of Gaucher disease. Orphanet J Rare Dis 2021;16[1]:431. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Prominent thoracic kyphosis and exaggerated lumbar lordosis with minimal lumbar curve. (Source: D'Amore S, Page K, Donald A, et al. In-depth phenotyping for clinical stratification of Gaucher disease. Orphanet J Rare Dis 2021;16[1]:431. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Extensive osteonecrosis of the right femoral head, which shows marked flattening with complete loss of joint space. (Source: D'Amore S, Page K, Donald A, et al. In-depth phenotyping for clinical stratification of Gaucher disease. Orphanet J Rare Dis 2021;16[1]:431. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Gross expansion and coarse trabeculation of the left femur. (Source: D'Amore S, Page K, Donald A, et al. In-depth phenotyping for clinical stratification of Gaucher disease. Orphanet J Rare Dis 2021;16[1]:431. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Generalized osteopenia and lytic areas in humeri. (Source: D'Amore S, Page K, Donald A, et al. In-depth phenotyping for clinical stratification of Gaucher disease. Orphanet J Rare Dis 2021;16[1]:431. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Generalized osteopenia and lytic areas in mid shafts of both femora and tibiae. Erlenmeyer flask deformity of both femurs, also known as metaphyseal flaring. (Source: D'Amore S, Page K, Donald A, et al. In-depth phenotyping for clinical stratification of Gaucher disease. Orphanet J Rare Dis 2021;16[1]:431. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Generalized osteopenia and lytic areas in iliac wings and mid shafts of both femora. Pathological fractures both upper femora. (Source: D'Amore S, Page K, Donald A, et al. In-depth phenotyping for clinical stratification of Gaucher disease. Orphanet J Rare Dis 2021;16[1]:431. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Glucosylceramides and galactosylceramides are hydrolyzed respectively by glucocerebrosidase (also named glucosylceramidase; the GBA gene encoding lysosomal glucocerebrosidase is associated with Gaucher disease) and galactosylceramidase (encoded by the GALC gene; that deficiency causes Krabbe disease) to regenerate ceramides. Ceramides are further deacetylated to sphingosines that can be broken down or recycled for sphingolipid synthesis by the salvage pathway.

Abbreviations and chromosomal locations of the responsible genes: ARSA arylsulfatase A (22q13.33); B4GALNT1 beta-1,4-N-acetyl- galactosaminyltransferase 1 (12q13.3); GAL3ST1 galactose-3-O-sulfotransferase 1 (22q12.2); GALC galactosylceramidase (14q31.3); GBA glucosylceramidase beta also named GBA1 (1q22); GBA2 glucosylceramidase beta 2 (9p13.3); GBA3 glucosylceramidase beta 3 (4p15.2); GLA galactosidase alpha (Xq22.1); GLB1 galactosidase beta 1 (3p22.3); SM4s 3-sulfo-GalCer (also known as sulfatide, galactocerebroside, 3-O-sulfogalactosylceramide, SGalCer, and SGC); ST3GAL6 ST3 beta-galactoside alpha-2,3- sialyltransferase 6 (3q12.1); UGT8 UDP glycosyltransferase 8 (4q26).

(Source: Belarbi K, Cuvelier E, Bonte MA, et al. Glycosphingolipids and neuroinflammation in Parkinson's disease. Mol Neurodegener 2020;15[1]:59. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

This diagram shows the metabolic loci for Fabry disease, metachromatic leukodystrophy, Krabbe disease, Gaucher disease, Sandhoff disease, Sialidosis, Tay Sachs disease/Sandhoff disease/GM2 gangliosidosis AB variant, and GM1 gangliosidosis. The nomenclature for gangliosides and the components are based on those of Svennerholm (1963) and IUPAC-IUBMB Joint Commission on Biochemical Nomenclature (IUPAC-IUB Joint Commission on Biochemical Nomenclature 1997; Chester 1997). Glycosphingolipids belonging to the asialo-series, ganglio-series, lacto/neo-lacto-series and globo/iso-globo-series are colored in brown, blue, purple and green, respectively. Lysosomal glycosphingolipid storage disorders resulting from an enzyme defect are indicated in brackets and in red in the figure.

Abbreviations and chromosomal locations of the responsible genes: A4GALT alpha 1,4- galactosyltransferase (22q13.2); ARSA arylsulfatase A (22q13.33); B3GALT4 beta-1,3-galactosyltransferase 4 (6p21.32); B4GALNT1 beta-1,4-N-acetyl- galactosaminyltransferase 1 (12q13.3); B4GALT6 beta-1,4-galactosyltransferase 6 (18q12.1); GAL3ST1 galactose-3-O-sulfotransferase 1 (22q12.2); GALC galactosylceramidase (14q31.3); GBA glucosylceramidase beta also named GBA1 (1q22); GBA2 glucosylceramidase beta 2 (9p13.3); GBA3 glucosylceramidase beta 3 (4p15.2); GLA galactosidase alpha (Xq22.1); GLB1 galactosidase beta 1 (3p22.3); HEXA hexosaminidase subunit alpha (15q23); HEXB hexosaminidase subunit beta (5q13.3); NEU1 neuraminidase 1 (6p21.33); NEU2 neuraminidase 2 (2q37.1); NEU3 neuraminidase 3 (11q13.5); NEU4 neuraminidase 4( 2q37.3); SM4s 3-sulfo-GalCer (also known as sulfatide, galactocerebroside, 3-O-sulfogalactosylceramide, SGalCer, and SGC); ST3GAL1 ST3 beta-galactoside alpha-2,3-sialyltransferase 1 (8q24.22); ST3GAL2 ST3 beta-galactoside alpha-2,3-sialyltransferase 2 (16q22.1); ST3GAL5 ST3 beta-galactoside alpha-2,3-sialyltransferase 5 (2p11.2); ST3GAL6 ST3 beta-galactoside alpha-2,3- sialyltransferase 6 (3q12.1); ST6GALNAC6 ST6 N-acetylgalactosaminide alpha-2,6-sialyltransferase 6 (9q34.11); ST8SIA1 ST8 alpha-N-acetyl- neuraminide alpha-2,8-sialyltransferase 1 (12p12.1); ST8SIA3 ST8 alpha-N-acetyl-neuraminide alpha-2,8-sialyltransferase 3 (ST8SIA3, 18q21.31); ST8SIA5 ST8 alpha-N-acetyl-neuraminide alpha-2,8-sialyltransferase 5 (18q21.1); UGCG UDP-glucose ceramide glucosyltransferase (9q31.3); UGT8 UDP glycosyltransferase 8 (4q26).

References:
Chester MA. IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). Nomenclature of glycolipids--recommendations 1997. Eur J Biochem 1998;257(2):293-8.
IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). Nomenclature of glycolipids recommendations 1997. J Mol Biol. 1999;286(3):963-70.
Svennerholm L. Chromatographic separation of human brain gangliosides. J Neurochem 1963;10:613–23.

(Source: Belarbi K, Cuvelier E, Bonte MA, et al. Glycosphingolipids and neuroinflammation in Parkinson's disease. Mol Neurodegener 2020;15[1]:59. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Glycosphingolipids are composed of a sphingosine, a fatty acid chain (these two forming a ceramide) and a carbohydrate moiety (X). The fatty acid attached to the sphingosine may vary in chain length and in degree of unsaturation and/or hydroxylation. (Source: Belarbi K, Cuvelier E, Bonte MA, et al. Glycosphingolipids and neuroinflammation in Parkinson's disease. Mol Neurodegener 2020;15[1]:59. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Ceramide, glucosylceramide shift between the Golgi apparatus and lysosomes. Ceramides (Cer), generated in the endoplasmic reticulum (ER), are transported to the Golgi apparatus, where UDP-glucosylceramide synthase (UGCG synthase) converts Cer to glucosylceramide (GC) on the cytosolic side of the Golgi (Halter et al 2007; Hanada 2010). After, GC is transported back into the ER. To transport ceramide to lysosome, GS, GCase, and saposin C (reaction facilitator) are embedded within intralysosomal membrane where cleavage of the lipid tail will occur (Tamargo et al 2012). Eliglustat inhibits UGCG synthase. Ambroxol increases GCase enzyme activity.

References:
Halter D, Neumann S, van Dijk SM, et al. Pre- and post-Golgi translocation of glucosylceramide in glycosphingolipid synthesis. J Cell Biol 2007;179(1):101-15.
Hanada K. Intracellular trafficking of ceramide by ceramide transfer protein. Proc Jpn Acad Ser B Phys Biol Sci 2010;86(4):426-37.
Tamargo RJ, Velayati A, Goldin E, Sidransky E. The role of saposin C in Gaucher disease. Mol Genet Metab 2012;106(3):257-63.

(Source: Ivanova MM, Dao J, Kasaci N, et al. Cellular and biochemical response to chaperone versus substrate reduction therapies in neuropathic Gaucher disease. PLoS One 2021;16[10]:e0247211. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Classification of mild type 1, severe type 1, and neuronopathic Gaucher disease (nGD) was based on genotypes. Glucosylsphingosine (lyso-Gb1) levels of subjects with wild-type GBA1 were considered to be the control.

Abbreviations: lyso-Gb1, glucosylsphingosine; nGD, neuronopathic Gaucher disease; NS, non-significant. Black dots represent the outliers.

(Source: Dinur T, Bauer P, Beetz C, et al. Gaucher disease diagnosis using Lyso-Gb1 on dry blood spot samples: time to change the paradigm? Int J Mol Sci 2022;23[3]:1627. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(Source: Revel-Vilk S, Fuller M, Zimran A. Value of glucosylsphingosine (Lyso-Gb1) as a biomarker in Gaucher disease: a systematic literature review. Int J Mol Sci 2020;21[19]:7159. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0. See also: Aerts JM, Kuo CL, Lelieveld LT, et al. Glycosphingolipids and lysosomal storage disorders as illustrated by Gaucher disease. Curr Opin Chem Biol 2019;53:204-15. Figure modified by Dr. Douglas J Lanska.)

(n = 19) (Source: Mengel E, Gaedeke J, Gothe H, et al. The patient journey of patients with Fabry disease, Gaucher disease and mucopolysaccharidosis type II: a German-wide telephone survey. PLoS One 2020;15[12]:e0244279. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Circles represent females and squares males. Filled symbols indicate affected family members and clear symbols unaffected members. Double lines in the pedigree represent a consanguineous marriage. Asterisks indicate individuals for whom a DNA sample is available, and an arrow indicates the sample selected for exome sequencing. Below each family member the PSAP c.1076A>C genotype is displayed. (Source: Liaqat K, Hussain S, Acharya A, et al. Phenotype expansion for atypical Gaucher disease due to homozygous missense PSAP variant in a large consanguineous Pakistani family. Genes (Basel) 2022;13[4]:662. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(a) MRI should include sagittal T1-weighted scan of the spine and T1-weighted scan of the head of the femur. (b) DXA should include spine and total body Z-scores, which require comparison with age- and gender-specific norms. (c) If baseline results are normal there is no need for follow-up within 6 months. (d) The recommended frequency is every 12 months for nonsymptomatic patients not receiving ERT, every 6 months for patients receiving ERT who are not yet meeting therapeutic goals, and every 6 to 12 months for patients receiving ERT who are meeting therapeutic goals. (e) The recommended frequency is every 24 months for nonsymptomatic patients not receiving ERT, every 12 months for patients receiving ERT who are not yet meeting therapeutic goals, and every 12 to 24 months for patients receiving ERT who are meeting therapeutic goals. (f) The recommended frequency for DXA is every 24 to 36 months, or less frequently if deemed appropriate based on clinical course and response to treatment.

Abbreviations: DXA, dual-energy x-ray absorptiometry; ERT, enzyme replacement therapy; GD1, Gaucher disease type 1; GD3, Gaucher disease type 3; HRQoL, health-related quality of life; lyso-Gb1, glucosylsphingosine; MRI, magnetic resonance imaging; PedsQL, Pediatric Quality of Life Inventory; PT, prothrombin time; PTT, partial thromboplastin time; SF-36, 36-item Short-Form Health Survey.

(Source: Weinreb NJ, Goker-Alpan O, Kishnani PS, et al. The diagnosis and management of Gaucher disease in pediatric patients: Where do we go from here? Mol Genet Metab 2022;136[1]:4-21. Adapted from: Kaplan P, Baris H, De Meirleir L, et al. Revised recommendations for the management of Gaucher disease in children. Eur J Pediatr 2013;172[4]:447-58. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(Source: Weinreb NJ, Goker-Alpan O, Kishnani PS, et al. The diagnosis and management of Gaucher disease in pediatric patients: Where do we go from here? Mol Genet Metab 2022;136[1]:4-21. Adapted from: Kishnani PS, Al-Hertani W, Balwani M, et al. Screening, patient identification, evaluation, and treatment in patients with Gaucher disease: results from a Delphi consensus. Mol Genet Metab. 2022;135[2]:154-62. Abbreviations: GCase, glucocerebrosidase; GD, Gaucher disease. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(a) Dysphagia, apnea, difficulty with secretions. (b) Progressive. (c) Avascular necrosis, osteopenia, pathologic fractures. Presenting signs and symptoms of Gaucher disease are summarized Gary and colleagues; some would only be expected for specific Gaucher disease subtypes (eg, overt neurologic symptoms only expected in GD2 and/or GD3) (Gary SE, Ryan E, Steward AM, Sidransky E. Recent advances in the diagnosis and management of Gaucher disease. Expert Rev Endocrinol Metab 2018;13[2]:107-18.).

Abbreviations: GD, Gaucher disease; LAL, lysosomal acid lipase; LSD, lysosomal storage disease.

(Source: Weinreb NJ, Goker-Alpan O, Kishnani PS, et al. The diagnosis and management of Gaucher disease in pediatric patients: Where do we go from here? Mol Genet Metab 2022;136[1]:4-21. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

The infant’s epidermal detachment ("collodion baby") is characteristic of perinatal Gaucher disease type 2. (Source: Sugiura T, Fujiwara A, Yo T, et al. Gaucher disease carrier with gestational thrombocytopenia and anemia: a case report. J Med Case Rep 2022;16[1]:203. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

The infant’s epidermal detachment ("collodion baby") is characteristic of perinatal Gaucher disease type 2. (Source: Sugiura T, Fujiwara A, Yo T, et al. Gaucher disease carrier with gestational thrombocytopenia and anemia: a case report. J Med Case Rep 2022;16[1]:203. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

The upper panel of the schematic shows all pathogenic variants in patients in whom a congenital myasthenic syndrome was the main feature, whereas the mutations in the lower panel are the pathogenic variants in patients diagnosed with D/L-2-HGA. (Source: Li W, Zhang M, Zhang L, et al. A case report of an intermediate phenotype between congenital myasthenic syndrome and D-2- and L-2-hydroxyglutaric aciduria due to novel SLC25A1 variants. BMC Neurol 2020;20[1]:278. Creative Commons Attribution 4.0 License, https://creativecommons.org/licenses/by/4.0. The figure has been modified by Dr. Douglas J Lanska.)

The patient had severe ptosis with compensatory over-activation of the frontalis muscle as well as mild facial weakness. This is case 1 from family 3. (Source: Balaraju S, Töpf A, McMacken G, et al. Congenital myasthenic syndrome with mild intellectual disability caused by a recurrent SLC25A1 variant. Eur J Hum Genet 2020;28[3]:373-7. Creative Commons Attribution 4.0 License, https://creativecommons.org/licenses/by/4.0.)

The patient had ptosis and mild facial weakness. This is case 2 from family 2. (Source: Balaraju S, Töpf A, McMacken G, et al. Congenital myasthenic syndrome with mild intellectual disability caused by a recurrent SLC25A1 variant. Eur J Hum Genet 2020;28[3]:373-7. Creative Commons Attribution 4.0 License, https://creativecommons.org/licenses/by/4.0.)

The patient had symmetrical facial weakness and ophthalmoparesis. This is case 1 from family 2. (Source: Balaraju S, Töpf A, McMacken G, et al. Congenital myasthenic syndrome with mild intellectual disability caused by a recurrent SLC25A1 variant. Eur J Hum Genet 2020;28[3]:373-7. Creative Commons Attribution 4.0 License, https://creativecommons.org/licenses/by/4.0.)

(Source: Guo J, Zhang R, Yang Z, Duan Z, Yin D, Zhou Y. Biological roles and therapeutic applications of IDH2 mutations in human cancer. Front Oncol 2021;11:644857. Creative Commons Attribution License [CC BY].)

Mutation of either IDH1 or IDH2 imparts a "neomorphic enzymatic activity" on the encoded enzymes, resulting in the gain-of-function ability to convert alpha-ketoglutarate (α-KG) into the oncometabolite 2-hydroxyglutarate (2-HG), while simultaneously converting NADPH to NADP+.

Abbreviations: 2-HG, 2-hydroxyglutarate; α-KG, alpha-ketoglutarate; IDH, isocitrate dehydrogenase; NADP+/NADPH nicotinamide adenine dinucleotide phosphate; PDH, pyruvate dehydrogenase.

(Source: Guo J, Zhang R, Yang Z, Duan Z, Yin D, Zhou Y. Biological roles and therapeutic applications of IDH2 mutations in human cancer. Front Oncol 2021;11:644857. Creative Commons Attribution License [CC BY].)

The mitochondrial enzyme D-2 hydroxyglutarate dehydrogenase catalyzes the irreversible oxidation of D-2-hydroxyglutarate; inactivation of this enzyme by mutations causes D-2-hydroxyglutaric aciduria type I. D-2-hydroxyglutarate can be produced from alpha-ketoglutarate by four different enzymes. Hydroxyacid-oxoacid transhydrogenase (HOT) oxidizes 4-hydroxybutyrate using alpha-ketoglutarate as an electron acceptor. 3-P- glycerate dehydrogenase, an enzyme involved in the serine synthesis pathway (not shown), has side activity on alpha-ketoglutarate due to the structural similarity of alpha-ketoglutarate with the normal product of this enzyme (ie, 3-phosphohydroxypyruvate). Mutated forms of IDH2 in D-2-hydroxyglutaric aciduria type II and mutated forms of IDH1 and IDH2 in glioblastomas and various other cancers efficiently catalyze the reduction of alpha-ketoglutarate to D-2-hydroxyglutarate; in this situation, the metabolic capacity of D-2-hydroxyglutarate dehydrogenase is exceeded, and D-2-hydroxyglutarate accumulates. (Source: Veiga-da-Cunha M, Van Schaftingen E, Bommer GT. Inborn errors of metabolite repair. J Inherit Metab Dis 2020;43[1]:14-24. Creative Commons Attribution License.)

The predicted structure of the protein L2HGDH in cartoon (a) and surface mode (b). The mutation site 136 of the protein (shown in red spheres) is located in the pocket (shown in a black ellipse) of the FAD/NAD(P)-binding domain (highlighted in orange). (Source: Peng W, Ma XW, Yang X, et al. Two novel L2HGDH mutations identified in a rare Chinese family with L-2-hydroxyglutaric aciduria. BMC Med Genet 2018;19[1]:167. Creative Commons Attribution 4.0 License, https://creativecommons.org/licenses/by/4.0.)

T2-weighted MRI in the index case of a Chinese family with L-2-hydroxyglutaric aciduria showed symmetrical, high-signal changes in the cerebellar dentate nuclei, and the right cerebellar hemisphere and vermis showed dysplasia. (Source: Peng W, Ma XW, Yang X, et al. Two novel L2HGDH mutations identified in a rare Chinese family with L-2-hydroxyglutaric aciduria. BMC Med Genet 2018;19[1]:167. Creative Commons Attribution 4.0 License, https://creativecommons.org/licenses/by/4.0.)

T2-weighted MR images in the index case of a Chinese family with L-2-hydroxyglutaric aciduria revealed symmetrical, high-signal changes in the subcortical white matter and basal ganglia, and the lateral ventricular wall showed multiple nodular, gray-matter heterotopia. (Source: Peng W, Ma XW, Yang X, et al. Two novel L2HGDH mutations identified in a rare Chinese family with L-2-hydroxyglutaric aciduria. BMC Med Genet 2018;19[1]:167. Creative Commons Attribution 4.0 License, https://creativecommons.org/licenses/by/4.0.)

T2-weighted MR images in the index case of a Chinese family with L-2-hydroxyglutaric aciduria revealed symmetrical, high-signal changes in the subcortical white matter and basal ganglia, and the lateral ventricular wall showed multiple nodular, gray-matter heterotopia. (Source: Peng W, Ma XW, Yang X, et al. Two novel L2HGDH mutations identified in a rare Chinese family with L-2-hydroxyglutaric aciduria. BMC Med Genet 2018;19[1]:167. Creative Commons Attribution 4.0 License, https://creativecommons.org/licenses/by/4.0.)

(Source: Ullah MI, Nasir A, Ahmad A, et al. Identification of novel L2HGDH mutation in a large consanguineous Pakistani family--a case report. BMC Med Genet 2018;19[1]:25. Creative Commons Attribution 4.0 License, https://creativecommons.org/licenses/by/4.0.)

(Source: Ullah MI, Nasir A, Ahmad A, et al. Identification of novel L2HGDH mutation in a large consanguineous Pakistani family--a case report. BMC Med Genet 2018;19[1]:25. Creative Commons Attribution 4.0 License, https://creativecommons.org/licenses/by/4.0.)

(Source: Ullah MI, Nasir A, Ahmad A, et al. Identification of novel L2HGDH mutation in a large consanguineous Pakistani family--a case report. BMC Med Genet 2018;19[1]:25. Creative Commons Attribution 4.0 License, https://creativecommons.org/licenses/by/4.0.)

(Source: Ullah MI, Nasir A, Ahmad A, et al. Identification of novel L2HGDH mutation in a large consanguineous Pakistani family--a case report. BMC Med Genet 2018;19[1]:25. Creative Commons Attribution 4.0 License, https://creativecommons.org/licenses/by/4.0.)

The computationally predicted L2HGDH c.178G>A mutation is indicated by the black circle. (Source: Ullah MI, Nasir A, Ahmad A, et al. Identification of novel L2HGDH mutation in a large consanguineous Pakistani family--a case report. BMC Med Genet 2018;19[1]:25. Creative Commons Attribution 4.0 License, https://creativecommons.org/licenses/by/4.0.)

EEG in case VI:4 shows epileptiform changes. (Source: Ullah MI, Nasir A, Ahmad A, et al. Identification of novel L2HGDH mutation in a large consanguineous Pakistani family--a case report. BMC Med Genet 2018;19[1]:25. Creative Commons Attribution 4.0 License, https://creativecommons.org/licenses/by/4.0.)

T2-weighted MRI in case VI:4 shows diffuse hyperintense signal abnormality in the subcortical white matter and bilateral symmetrical T2 hyperintense signals in bilateral basal ganglia. (Source: Ullah MI, Nasir A, Ahmad A, et al. Identification of novel L2HGDH mutation in a large consanguineous Pakistani family--a case report. BMC Med Genet 2018;19[1]:25. Creative Commons Attribution 4.0 License, https://creativecommons.org/licenses/by/4.0.)

In mutated L2HGDH, interacting sites within the FAD domain are lost due to the resulting frameshift and protein truncation. However, the mutant enzyme predictably showed interaction with its substrate at different positions (ie, Arg-42, Cys-38, Gly-40, and Cys-27) through conventional hydrogen bonds and at Gly-28 through a carbon-hydrogen bond. (Source: Muzammal M, Ali MZ, Brugger B, et al. A novel protein-truncating mutation in L2HGDH causes L-2-hydroxyglutaric aciduria in a consanguineous Pakistani family. Metab Brain Dis 2022;37[1]:243-52. Creative Commons Attribution 4.0 License, https://creativecommons.org/licenses/by/4.0.)

Interaction studies for L2HGDH and its substrate L-2-hydroxyglutarate predicted five amino acids (ie, Gln-89, Tyr-195, Val-404, Ala-402, and Gly-403) of wild-type L2HGDH are involved in the interaction with its substrate via conventional hydrogen bonding. All these binding sites are within the FAD-dependent enzyme domain. (Source: Muzammal M, Ali MZ, Brugger B, et al. A novel protein-truncating mutation in L2HGDH causes L-2-hydroxyglutaric aciduria in a consanguineous Pakistani family. Metab Brain Dis 2022;37[1]:243-52. Creative Commons Attribution 4.0 License, https://creativecommons.org/licenses/by/4.0.)

Key: (a) Normal L2HGDH protein model; (b) mutant L2HGDH protein model; (c) superimposed structure. Due to misfolding the 3D structures of wild type and mutated L2HGDH failed to overlap when superimposed, confirming that the identified frameshift mutation results in structural distortion of L2HGDH. (Source: Muzammal M, Ali MZ, Brugger B, et al. A novel protein-truncating mutation in L2HGDH causes L-2-hydroxyglutaric aciduria in a consanguineous Pakistani family. Metab Brain Dis 2022;37[1]:243-52. Creative Commons Attribution 4.0 License, https://creativecommons.org/licenses/by/4.0.)

The images show extensive white matter abnormalities. (Source: Muzammal M, Ali MZ, Brugger B, et al. A novel protein-truncating mutation in L2HGDH causes L-2-hydroxyglutaric aciduria in a consanguineous Pakistani family. Metab Brain Dis 2022;37[1]:243-52. Creative Commons Attribution 4.0 License, https://creativecommons.org/licenses/by/4.0.)

(Source: Muzammal M, Ali MZ, Brugger B, et al. A novel protein-truncating mutation in L2HGDH causes L-2-hydroxyglutaric aciduria in a consanguineous Pakistani family. Metab Brain Dis 2022;37[1]:243-52. Creative Commons Attribution 4.0 License, https://creativecommons.org/licenses/by/4.0.)

(Source: Muzammal M, Ali MZ, Brugger B, et al. A novel protein-truncating mutation in L2HGDH causes L-2-hydroxyglutaric aciduria in a consanguineous Pakistani family. Metab Brain Dis 2022;37[1]:243-52. Creative Commons Attribution 4.0 License, https://creativecommons.org/licenses/by/4.0.)

Pedigree analysis shows an autosomal recessive mode of disease segregation. The genotype status is represented as -/- (homozygous deletion) or -/G (heterozygous carrier). (Source: Muzammal M, Ali MZ, Brugger B, et al. A novel protein-truncating mutation in L2HGDH causes L-2-hydroxyglutaric aciduria in a consanguineous Pakistani family. Metab Brain Dis 2022;37[1]:243-52. Creative Commons Attribution 4.0 License, https://creativecommons.org/licenses/by/4.0. Figure modified by Dr. Douglas J Lanska.)

The scheme shows how L-2-hydroxyglutarate is formed and degraded. It also shows the initial steps of the major lysine catabolic pathway (via saccharopine) present in mammalian tissues and of the minor pathway (via L-pipecolate) present in brain and the inhibition exerted by L-2-hydroxyglutarate. (1) Lysine-alpha-ketoglutarate reductase; (2) Saccharopine dehydrogenase; (3) alpha-aminoadipate semialdehyde dehydrogenase; (4) alpha-aminoadipate transaminase; (5) imine reductase; (6) L-pipecolate oxidase. (Source: Rzem R, Achouri Y, Marbaix E, et al. A mouse model of L-2-hydroxyglutaric aciduria, a disorder of metabolite repair. PloS One 2015;10[3]: e0119540. Creative Commons Attribution 4.0 License, https://creativecommons.org/licenses/by/4.0.)

(Public domain.)

Mutations inactivating metabolite repair enzymes lead to various diseases. An example is L-2-hydroxyglutaric aciduria in which mutations in L-2-hydroxyglutarate dehydrogenase prevent the conversion of toxic L-2 hydroxy-glutarate to alpha-ketoglutarate, ultimately resulting in leukoencephalopathy. (Source: Veiga-da-Cunha M, Van Schaftingen E, Bommer GT. Inborn errors of metabolite repair. J Inherit Metab Dis 2020;43[1]:14-24. Creative Commons Attribution License.)

2-Hydroxyglutarate (2-HG) derives from the promiscuity of lactate dehydrogenase A (LDHA), malate dehydrogenase 1 (MDH1), and PHGDH in the cytoplasm and malate dehydrogenase 2 (MDH2) in the mitochondria. Mutations of IDH1 and IDH2 endow them with neomorphic enzyme activity to convert alpha-KG to D-2HG (Dang et al 2009; Ward et al 2010; Showalter et al 2017; Du and Hu 2021). L-2HG and D-2HG are removed from the mitochondria by L2HGDH and D2HGDH, respectively. Abbreviations: D-2HG, D-2-hydroxyglutarate; D2HGDH, D-2-hydroxyglutarate dehydrogenase; FAD/FADH2, flavin adenine dinucleotide; 2-HG, 2-hydroxyglutarate; IDH, isocitrate dehydrogenase; L-2HG, L-2-hydroxyglutarate; L2HGDH, L-2-hydroxyglutarate dehydrogenase; LDHA, lactate dehydrogenase A; MDH, malate dehydrogenase; NAD+/NADH, nicotinamide adenine dinucleotide ; NADP+/NADPH, nicotinamide adenine dinucleotide phosphate; PHGDH, phosphoglycerate dehydrogenase.

References cited:
Dang L, White DW, Gross S, et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 2009;462(7274):739-44.
Du X, Hu H. The roles of 2-hydroxyglutarate. Front Cell Dev Biol 2021;9:651317.
Showalter MR, Hatakeyama J, Cajka T, et al. Replication study: The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. Elife 2017;6:e26030.
Ward PS, Patel J, Wise DR, et al. The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. Cancer Cell 2010;17(3):225-34.

(Source: Du X, Hu H. The roles of 2-hydroxyglutarate. Front Cell Dev Biol 2021;9:651317. Creative Commons Attribution License [CC BY].)

Many enzymes catalyze side reactions leading to the production of abnormal metabolites. These metabolites may be toxic (eg, if they inhibit other enzymes). Fortunately, under normal circumstances, these abnormal metabolites are generally destroyed by metabolite repair enzymes and so become unable to exert toxic effects. (Source: Veiga-da-Cunha M, Van Schaftingen E, Bommer GT. Inborn errors of metabolite repair. J Inherit Metab Dis 2020;43[1]:14-24. Creative Commons Attribution License.)

(Public domain.)

(Public domain.)

(Public domain.)

Serial Wechsler Adult Intelligence Scale-III scores in the proband and his younger sister. Legend: Thick solid line: verbal IQ (VIQ) in the proband; thick dashed line: VIQ in his younger sister; thin solid line: performance IQ (PIQ) in the proband; thin dashed line: PIQ in his younger sister. Although the verbal and performance IQ improved initially in the proband, this was not sustained. In contrast, verbal and performance IQ steadily improved over a 5-year period in the proband's younger sister, who had begun chenodeoxycholic acid therapy before her neurologic manifestations were as advanced as those of her older brother at presentation. (Source: Koyama S, Okabe Y, Suzuki Y, et al. Differing clinical features between Japanese siblings with cerebrotendinous xanthomatosis with a novel compound heterozygous CYP27A1 mutation: a case report. BMC Neurol 2022;22[1]:193. Creative Commons Attribution 4.0 International License, http://creativecommons.org/licenses/by/4.0.)

The changes in levels of serum cholestanol during a 5-year period in the proband (solid line) and his younger sister (dashed line). Both siblings had an excellent biochemical response to chenodeoxycholic acid. (Source: Koyama S, Okabe Y, Suzuki Y, et al. Differing clinical features between Japanese siblings with cerebrotendinous xanthomatosis with a novel compound heterozygous CYP27A1 mutation: a case report. BMC Neurol 2022;22[1]:193. Creative Commons Attribution 4.0 International License, http://creativecommons.org/licenses/by/4.0.)

Brain 99mTc-ethyl cysteinate dimer (99mTc-ECD) single photon emission computed tomography (SPECT) of the proband's younger sister, a 30-year-old Japanese woman with cerebrotendinous xanthomatosis treated with chenodeoxycholic acid. SPECT revealed mild frontoparietal hypoperfusion, without abnormal cerebellar hypoperfusion. (Source: Koyama S, Okabe Y, Suzuki Y, et al. Differing clinical features between Japanese siblings with cerebrotendinous xanthomatosis with a novel compound heterozygous CYP27A1 mutation: a case report. BMC Neurol 2022;22[1]:193. Creative Commons Attribution 4.0 International License, http://creativecommons.org/licenses/by/4.0. Figure edited by Dr. Douglas J Lanska.)

Baseline and 5-year follow-up axial, T2-weighted, brain MRI of the proband's younger sister, a 30-year-old Japanese woman with cerebrotendinous xanthomatosis treated with chenodeoxycholic acid. Unlike the case of her older brother, there were no characteristic cerebrotendinous xanthomatosis-related MRI features during a 5-year period. (Source: Koyama S, Okabe Y, Suzuki Y, et al. Differing clinical features between Japanese siblings with cerebrotendinous xanthomatosis with a novel compound heterozygous CYP27A1 mutation: a case report. BMC Neurol 2022;22[1]:193. Creative Commons Attribution 4.0 International License, http://creativecommons.org/licenses/by/4.0. Figure edited by Dr. Douglas J Lanska.)

Brain 99mTc-ethyl cysteinate dimer (99mTc-ECD) single photon emission computed tomography (SPECT) of the proband, a 32-year-old Japanese man with cerebrotendinous xanthomatosis treated with chenodeoxycholic acid. SPECT revealed marked cerebellar hypoperfusion, as well as mild frontoparietal hypoperfusion. (Source: Koyama S, Okabe Y, Suzuki Y, et al. Differing clinical features between Japanese siblings with cerebrotendinous xanthomatosis with a novel compound heterozygous CYP27A1 mutation: a case report. BMC Neurol 2022;22[1]:193. Creative Commons Attribution 4.0 International License, http://creativecommons.org/licenses/by/4.0. Figure edited by Dr. Douglas J Lanska.)

Baseline and 5-year follow-up axial, T2-weighted, brain MRI of the proband, a 32-year-old Japanese man with cerebrotendinous xanthomatosis treated with chenodeoxycholic acid. Serial brain MRI studies over this period revealed pronounced progressive atrophy in the cerebellum, in addition to expanding hyperintense lesions on T2-weighted images in the dentate nuclei, posterior limb of the internal capsule, cerebral peduncles, and inferior olives. (Source: Koyama S, Okabe Y, Suzuki Y, et al. Differing clinical features between Japanese siblings with cerebrotendinous xanthomatosis with a novel compound heterozygous CYP27A1 mutation: a case report. BMC Neurol 2022;22[1]:193. Creative Commons Attribution 4.0 International License, http://creativecommons.org/licenses/by/4.0. Figure edited by Dr. Douglas J Lanska.)

The transition of monocytes to macrophages is characterized by increased GLUT1 expression and glycolysis. Naive (unactivated) monocytes are metabolically quiescent, with low basal metabolic activity and ATP derived primarily via oxidative phosphorylation (OxPhos). Classically activated macrophages (M1) induce aerobic glycolysis, resulting in lactate production and increased production of inflammatory cytokines. Alternatively activated macrophages (M2) trigger a metabolic profile with oxidative phosphorylation (OxPhos) and an anti-inflammatory response. Legend: TNF, tumor necrosis factor; IL-6, interleukin 6; IL-1RA, interleukin-1 receptor antagonist. (Source: Vulturar R, Chis A, Pintilie S, et al. One molecule for mental nourishment and more: glucose transporter type 1-biology and deficiency syndrome. Biomedicines 2022;10[6]:1249. Creative Commons Attribution License [CC BY], https://creativecommons.org/licenses/by/4.0. Figure edited by Dr. Douglas J Lanska.)

Glucose transporters (GLUT): GLUT1 (green) is expressed in endothelial cells (part of the blood-brain barrier) and in the glial cell membrane; GLUT3 (yellow) is expressed in the neuron membrane. Monocarboxylate transporter family (MCT; blue): different isoforms (MCT1, MCT2, MCT4) are expressed in endothelial cells, neurons, astrocytes, and oligodendrocytes. (Source: Vulturar R, Chis A, Pintilie S, et al. One molecule for mental nourishment and more: glucose transporter type 1-biology and deficiency syndrome. Biomedicines 2022;10[6]:1249. Creative Commons Attribution License [CC BY], https://creativecommons.org/licenses/by/4.0. Figure edited by Dr. Douglas J Lanska.)

In this model of GLUT1 structure with 12 transmembrane domains, the main functional binding sites are (1) ATP binding sites, (2) the phosphorylation site, and (3) the sugar-binding site in position N317 of the transmembrane 8 (TM8) domain. (Source: Vulturar R, Chis A, Pintilie S, et al. One molecule for mental nourishment and more: glucose transporter type 1-biology and deficiency syndrome. Biomedicines 2022;10[6]:1249. Creative Commons Attribution License [CC BY], https://creativecommons.org/licenses/by/4.0. Figure edited by Dr. Douglas J Lanska.)

Representation of the main glucose transporters in the brain--GLUT1 and GLUT3--both belonging to the group of facilitated “passive” transporters (encoded by members of the SLC2 gene family). Legend: Transport across cell membranes (arrows); localization and known defects of Glut1 (green rectangular symbols); Glu, glucose; CSF, cerebrospinal fluid. (Source: Vulturar R, Chis A, Pintilie S, et al. One molecule for mental nourishment and more: glucose transporter type 1-biology and deficiency syndrome. Biomedicines 2022;10[6]:1249. Creative Commons Attribution License [CC BY], https://creativecommons.org/licenses/by/4.0. Figure edited by Dr. Douglas J Lanska.)

(Illustration by Domaina, Kashmiri, and SUM1 on January 21, 2020. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

MRI T2 images demonstrating delayed progression of myelination over time in a child with clinical Pelizaeus-Merzbacher disease due to PLP1 missense mutation, most notably in the corpus callosum (star) and posterior limb of the internal capsule (triangle). (A) Eight months old with undermyelination. Note near absence of myelin in the corpus callosum (star) and posterior limb of the internal capsule (triangle). (B) MRI at 24 months with minimal progression of myelination. (C) MRI at 4 years 10 months with some progression of myelination in the corpus callosum and periventricular region. (Contributed by Dr. Margie Ream.)

DNA analysis can be useful for confirmation of the diagnosis, carrier testing of at-risk relatives, and prenatal testing. (Contributed by Dr. Kimberly Chapman.)

MRI imaging from a critically ill neonate who presented with clinical and electrographic seizures and respiratory failure within 24 hours of life and was subsequently diagnosed with Zellweger syndrome, which was initially identified on newborn metabolic screen for ALD prior to return of any diagnostic testing. (A-C) Axial T2-weighted Propeller magnetic resonance imaging at multiple cerebral levels demonstrates leukodystrophic changes typical of Zellweger disease (black arrows) and one of several bilateral caudothalamic groove cysts (B, large black arrowhead) identified in this individual. (D-F) Sagittal T2 SSFSE magnetic resonance imaging of the same neonate demonstrates multiple bilateral caudothalamic groove cysts (white arrowheads). (Contributed by Dr. Kimberly Chapman.)

Protein (red line) which needs to be imported into the peroxisome complexes with Pex5-short (Pex5-s) if transported via PTS1 or Pex7 and/or Pex5 long (Pex5-L) if transported via PTS2 (Blue figures). These complexes dock with Pex13/14 (orange) and then are transported by Pex10,12, and 2 (Green) into the peroxisome. There Pex5 and Pex7 release their cargo and are recycled via translocate through the membrane via Pex2 and recycling by of Pex1, 6, and 26 (light green). (Contributed by Dr. Kimberly Chapman.)

(a) Significant increase of cholestane-triol, PPCS/lysosphingomyelin-509, bile acid levels, with normal, slightly or markedly elevated lysosphingomyelin concentration. (b) Only the ASMD profile shows a significant elevation of lysosphingomyelin. Other causes of elevated cholestane triol levels include CTX and acid lipase deficiency. (c) Importance of parental study. (d) Positive filipin can show a classical, intermediate, or variant phenotype; some heterozygotes and other diseases may show a slightly abnormal profile. Abbreviations: ASMD: acid sphingomyelinase deficiency; CTX: cerebrotendinous xanthomathosis; NP: Niemann-Pick; VUS: variant of unknown significance. (Modified from: Patterson MC, Clayton P, Gissen P, et al. Recommendations for the detection and diagnosis of Niemann-Pick disease type C. Neurol Clin Pract 2017;7(6):499-511.)

Schematic representation of the clinical aspects of Niemann-Pick disease type C, with emphasis on period of onset and type of the main first neurologic manifestations. (Modified from: Vanier MT. Niemann-Pick disease type C. Orphanet J Rare Dis 2010;5:16.)

Photo shows complete resolution of inflammatory nodules 18 months after bone marrow transplant. Dorsum view of both hands. (Source: Ehlert K, Frosch M, Fehse N, Zander A, Roth J, Vormoor J. Farber disease: clinical presentation, pathogenesis and a new approach to treatment. Pediatr Rheumatol Online J 2007;5:15. Creative Commons Attribution License. http://creativecommons.org/licenses/by/2.0.)

Palmar view. Inflammatory nodules of the thumb and fingers of the right hand of a 3-year-old girl with Farber disease, before bone marrow transplantation. (Source: Ehlert K, Frosch M, Fehse N, Zander A, Roth J, Vormoor J. Farber disease: clinical presentation, pathogenesis and a new approach to treatment. Pediatr Rheumatol Online J 2007;5:15. Creative Commons Attribution License. http://creativecommons.org/licenses/by/2.0.)

Side view of thumb. Inflammatory nodules of the right thumb of a 3-year-old girl with Farber disease, before bone marrow transplantation. (Source: Ehlert K, Frosch M, Fehse N, Zander A, Roth J, Vormoor J. Farber disease: clinical presentation, pathogenesis and a new approach to treatment. Pediatr Rheumatol Online J 2007;5:15. Creative Commons Attribution License. http://creativecommons.org/licenses/by/2.0.)

X-ray of the patient’s hands showing soft tissue swelling of both distal hands with grossly maintained joint spaces. Irregular borders of the distal metaphysis of metacarpals with scalloping of the distal ulna were observed. Abbreviations: left: L; right: R. (Source: Al-Naimi A, Toma H, Hamad SG, Ben Omran T. Farber disease mimicking juvenile idiopathic arthritis: the first reported case in Qatar and review of the literature. Case Rep Genet 2022;2022:2555235. Creative Commons Attribution License.)

(Source: Yu FP, Amintas S, Levade T, Medin JA. Acid ceramidase deficiency: Farber disease and SMA-PME. Orphanet J Rare Dis 2018;13(1):121. Creative Commons Attribution 4.0 International License. http://creativecommons.org/licenses/by/4.0.)

(Source: Yu FP, Amintas S, Levade T, Medin JA. Acid ceramidase deficiency: Farber disease and SMA-PME. Orphanet J Rare Dis 2018;13(1):121. Creative Commons Attribution 4.0 International License. http://creativecommons.org/licenses/by/4.0.)

Schematic of the acid ceramidase protein with indications of the corresponding numbers of mutations for each part. Annotations are shown for the signal peptide, alpha-subunit, and beta-subunit. (Source: Yu FP, Amintas S, Levade T, Medin JA. Acid ceramidase deficiency: Farber disease and SMA-PME. Orphanet J Rare Dis 2018;13(1):121. Creative Commons Attribution 4.0 International License. http://creativecommons.org/licenses/by/4.0.)

The locations of different mutations and their type is shown. (Source: Yu FP, Amintas S, Levade T, Medin JA. Acid ceramidase deficiency: Farber disease and SMA-PME. Orphanet J Rare Dis 2018;13(1):121. Creative Commons Attribution 4.0 International License. http://creativecommons.org/licenses/by/4.0.)

ASAH1 has 14 exons. The locations of different mutations and their type is shown. (Source: Yu FP, Amintas S, Levade T, Medin JA. Acid ceramidase deficiency: Farber disease and SMA-PME. Orphanet J Rare Dis 2018;13(1):121. Creative Commons Attribution 4.0 International License. http://creativecommons.org/licenses/by/4.0.)

Ceramides are synthesized in the endoplasmic reticulum and processed in the Golgi apparatus to form sphingomyelin and more complex sphingolipids, the glycolsphingolipids. Ceramide, sphingomyelin, and glycolsphingolipids are then distributed in all cellular compartments, with specific destinies and roles. Recycling of ceramides occurs in lysosomes. The red-colored structures represent ceramides. Abbreviations: ER - endoplasmic reticulum; GA - Golgi apparatus; INM - inner nuclear membrane; L - lysosome; LR - lipid raft; PM - plasma membrane. (Source: Paciotti S, Albi E, Parnetti L, Beccari T. Lysosomal ceramide metabolism disorders: implications in Parkinson's disease. J Clin Med 2020;9(2):594. Creative Commons Attribution [CC BY] license. http://creativecommons.org/licenses/by/4.0.)

(Image created by BQUB19 HTouibi on 23 October 2019. https://www.uniprot.org/uniprot/Q13510. [Accessed June 23, 2022]. Source: Wikimedia Commons. Creative Commons Attribution-Share Alike 4.0 International license [https://creativecommons.org/licenses/by-sa/4.0/deed.en]. Enlarged and edited to improve sharpness and contrast by Douglas J Lanska MD MS MSPH.)

(Source: Yu FP, Amintas S, Levade T, Medin JA. Acid ceramidase deficiency: Farber disease and SMA-PME. Orphanet J Rare Dis 2018;13(1):121. Creative Commons Attribution 4.0 International License. http://creativecommons.org/licenses/by/4.0.)

Major metabolic pathways of ceramide biosynthesis: the de novo pathway (pink background), the salvage pathway (light blue background), and the sphingomyelin hydrolysis pathway (green background). Genes encoding enzymes involved in these pathways are shown in italics. ASAH1, lysosomal ceramidase; ASAH2, plasma membrane ceramidase; ACER2, Golgi ceramidase; ACER3, endoplasmic reticulum and Golgi ceramidase; CERS1, 2, 5, and 6, ceramide synthases; DEGS1, dihydroceramide desaturase; CERK, ceramide kinase; SGMS1, sphingomyelin synthase 1; SMPD1, lysosomal sphingomyelin phosphodiesterase 1; SMPD2, neutral sphingomyelin phosphodiesterase 2; GBA1, glucosylceramidase beta 1; SPT1, serine palmitoyltransferase; KDSR, 3-ketodihydrosphingosine reductase; SPHK, sphingosine kinase; SGPP1, sphingosine-1-phosphate phosphatase 1. (Source: Kyriakou K, Lederer CW, Kleanthous M, Drousiotou A, Malekkou A. Acid Ceramidase Depletion Impairs Neuronal Survival and Induces Morphological Defects in Neurites Associated with Altered Gene Transcription and Sphingolipid Content. Int J Mol Sci 2020;21(5):1607. Creative Commons Attribution license [CC BY] license. http://creativecommons.org/licenses/by/4.0. Image edited considerably from original by Douglas J Lanska MD MS MSPH.)

Abbreviations: SMase - sphingomyelinase; GCS - glucosylceramide synthase. (Source: Duarte C, Akkaoui J, Yamada C, Ho A, Mao C, Movila A. Elusive roles of the different ceramidases in human health, pathophysiology, and tissue regeneration. Cells 2020;9(6):1379. Creative Commons Attribution [CC BY] license. http://creativecommons.org/licenses/by/4.0.)

Structures shown are sphingosine, a ceramide, sphingomyelins, a cerebroside, and a ganglioside. (Image created by LHcheM on August 24, 2012. Creative Commons Attribution-Share Alike 3.0 Unported license. https://cr eativecommons.org/licenses/by-sa/3.0/deed.en.)

(Image created by Ed [Edgar181] on January 23, 2012. Public domain.)

(Image created by NEUROtiker on May 23, 2007. Public domain.)

Frontal radiograph of a 7-year-old boy showing diaphyseal constriction and metaphyseal flaring on both femora (Ehrlenmeyer flask deformity). (Courtesy of Dr. Ahmed Nasman. https://radiopaedia.org/cases/erlenmeyer-flask-deformity?lang=us. [Accessed 23 June 2022]. Creative Commons Attribution-Share Alike 3.0 Unported license. https://creativecom mons.org/licenses/by-sa/3.0/deed.en.)

Bronchoscopic view of the supraglottic area showing laryngeal nodular formation and narrowing in a 20-month-old boy with Farber disease. (Source: Al-Naimi A, Toma H, Hamad SG, Ben Omran T. Farber disease mimicking juvenile idiopathic arthritis: the first reported case in Qatar and review of the literature. Case Rep Genet 2022;2022:2555235. Creative Commons Attribution License.)

Subcutaneous skin nodules near interphalangeal, metacarpal, and wrist joints in a patient with Farber disease. (Source: Kraoua I, Younes TB, Garcia v. Farber disease: a fatal childhood disorder with nervous system involvement. J Rare Dis Res Treat 2020;5(3):1-4. Creative Commons Attribution 4.0 International License.)

(Source: Al-Naimi A, Toma H, Hamad SG, Ben Omran T. Farber disease mimicking juvenile idiopathic arthritis: the first reported case in Qatar and review of the literature. Case Rep Genet 2022;2022:2555235. Creative Commons Attribution 4.0 International License. http://creativecommons.org/licenses/by/4.0.)

The typical clinical manifestations by organ type that have been reported in cases of Farber disease and spinal muscular atrophy with progressive myoclonic epilepsy in the published literature. Farber disease symptoms are organized by neurologic symptoms, ophthalmic symptoms, cardinal triad symptoms, respiratory symptoms, hematopoietic symptoms, gastrointestinal involvement, dermatological manifestations, liver disease, motor neuron and muscle weakness, and bone disease phenotypes.

Abbreviations: CNS - central nervous system; EMG - electromyography; FD - Farber disease; JIA - juvenile idiopathic arthritis; PNS - peripheral nervous system; SMA-PME - spinal muscular atrophy with progressive myoclonic epilepsy; and SNPs - single nucleotide polymorphisms.

(Source: Yu FP, Amintas S, Levade T, Medin JA. Acid ceramidase deficiency: Farber disease and SMA-PME. Orphanet J Rare Dis 2018;13(1):121. Creative Commons Attribution 4.0 International License. http://creativecommons.org/licenses/by/4.0.)

Dr. Sidney Farber MD was the founder of Children's Hospital Cancer Research Foundation in the 1950s and 1960s. The Photograph was taken in 1960 for the National Cancer Institute of the US National Institutes of Health. In 1957, Farber described the first patient with Farber lipogranulomatosis. Farber disease is now recognized as a genetically determined deficiency of the lysosomal enzyme acid ceramidase. (Public domain.)

On the left, an anterior-posterior x-ray of hemipelvis of an 8-year-old healthy control is shown. On the center and right images, ossification abnormalities (indicated by a white arrow) of the proximal femoral head are observed in two 8-year-old siblings with mucolipidosis III alpha/beta. In addition, abnormal ossification can be noted in the greater trochanter (star). (Source: Oussoren E, Wagenmakers MA, Link B, et al. Hip disease in mucopolysaccharidoses and mucolipidoses: a review of mechanisms, interventions and future perspectives. Bone 2021;143:115729. Image edited by Douglas J Lanska MD MS MSPH to exclude normal control x-rays taken at age 2 years (because there were no comparable images at that age for the mucolipidosis III alpha/beta cases), to exclude x-rays of cases with mucopolysaccharidoses that were included in the original figure, and to relabel and reformat the resulting condensed set of images. Creative Commons Attribution [CC BY] license. http://creativecommons.org/licenses/by/4.0.)

In the leftmost column, anterior-posterior x-rays are shown of hemipelvises of healthy controls at age 2, 4, and 8 years. These are placed next to age-matched x-rays of hemipelvises from two patients with mucolipidosis II (center column) and one patient with mucolipidosis III (rightmost column). The pelvic bones are abnormally shaped in all patients, with flared iliac wings and with a hypoplastic basis of the os ilium. The acetabula are dysplastic in all patients, as indicated by a white arrow at the outer border of the acetabulum. The shape of the acetabulum is the most dramatically altered and severely dysplastic in the mucolipidosis II patient (center column). In all patients, the femoral head is too large to fit in this dysplastic acetabulum. There is flattening and enlargement of the femoral head. The abnormal growth of the femoral head results in a valgus position of the femoral neck. (Source: Oussoren E, Wagenmakers MA, Link B, et al. Hip disease in mucopolysaccharidoses and mucolipidoses: a review of mechanisms, interventions and future perspectives. Bone 2021;143:115729. Image edited by Douglas J Lanska MD MS MSPH to exclude cases with mucopolysaccharidoses that were included in the original figure. Creative Commons Attribution [CC BY] license. http://creativecommons.org/licenses/by/4.0.)

Early manifestations of pelvic bone abnormalities are shown on anterior-posterior x-rays of the pelvis of a 13-day-old mucolipidosis II patient compared to an age-related healthy control. The basis of the os ilium in the patient is hypoplastic, and the acetabulum is shallow and dysplastic. (Source: Oussoren E, Wagenmakers MA, Link B, et al. Hip disease in mucopolysaccharidoses and mucolipidoses: a review of mechanisms, interventions and future perspectives. Bone 2021;143:115729. Image edited by Douglas J Lanska MD MS MSPH to exclude cases with mucopolysaccharidoses that were included in the original figure. Creative Commons Attribution [CC BY] license. http://creativecommons.org/licenses/by/4.0.)

T2-weighted sagittal images (top row) and plain lateral radiographs (bottom row) of a 38-year-old woman with mucolipidosis III alpha/beta. Her symptoms include clumsiness and gait disturbance. Preoperative images are on the left (A, C), and comparison images taken 2 years postoperatively are on the right (B, D). Her myelopathic symptoms resolved immediately after surgery. The sagittal cervical alignment became lordotic after surgery, which was maintained until the final follow-up 6 years postoperatively. (Source: Terai H, Tamai K, Hoshino M, et al. Clinical outcomes of laminoplasty for patients with lysosomal storage disease including mucopolysaccharidosis and mucolipidoses: a retrospective cohort study. Orphanet J Rare Dis 2021;16(1):401. Creative Commons Attribution License. http://creativecommons.org/licenses/by/4.0.)

The anteroposterior diameters of the vertebral bodies are reduced. Ossification of the anterior upper border of the lumbar vertebral bodies is also reduced. There is already a mild gibbus deformity at the vertebral L2 body. (Source: Khan SA, Tomatsu SC. Mucolipidoses overview: past, present, and future. Int J Mol Sci 2020;21[18]:6812. Enlarged and edited by Douglas J Lanska MD MS MSPH to improve sharpness and contrast. Creative Commons Attribution [CC BY] license. http://creativecommons.org/licenses/by/4.0.)

In people with mucolipidosis II/III, defective GlcNAc-1-phosphotransferase is unable to phosphorylate lysosomal hydrolases in the cid-Golgi network. These hydrolases then leak to the extracellular matrix (ECM). The lack of these lysosomal hydrolases within lysosomes results in the accumulation of storage materials in the lysosomes and disruption of cellular metabolism. (Source: Khan SA, Tomatsu SC. Mucolipidoses overview: past, present, and future. Int J Mol Sci 2020;21[18]:6812. Adapted from: Velho RV, Harms FL, Danyukova T, et al. The lysosomal storage disorders mucolipidosis type II, type III alpha/beta, and type III gamma: update on GNPTAB and GNPTG mutations. Hum Mutat 2019;40[7]:842-64. Creative Commons Attribution [CC BY] license. http://creativecommons.org/licenses/by/4.0.)

In a healthy person, cells phosphorylate lysosomal hydrolases by GlcNAc-1-phosphotransferase in the cis-Golgi network. The uncovering enzyme removed the masking of N-acetylglucosamine (GlcNAc) to expose mannose 6-phosphate (M6P) residues in the trans-Golgi network (Velho RV, Harms FL, Danyukova T, et al. The lysosomal storage disorders mucolipidosis type II, type III alpha/beta, and type III gamma: update on GNPTAB and GNPTG mutations. Hum Mutat 2019;40(7):842-64.)
The M6P-exposed enzymes are taken up by endosomes with the M6P receptor and are delivered to lysosomes. (Source: Khan SA, Tomatsu SC. Mucolipidoses overview: past, present, and future. Int J Mol Sci 2020;21[18]:6812. Adapted from: Velho RV, Harms FL, Danyukova T, et al. The lysosomal storage disorders mucolipidosis type II, type III alpha/beta, and type III gamma: update on GNPTAB and GNPTG mutations. Hum Mutat 2019;40[7]:842-64. Creative Commons Attribution [CC BY] license. http://creativecommons.org/licenses/by/4.0.)

Starting at the lower left of the illustration, in the cis-Golgi network, GlcNAc-1-phosphotransferase phosphorylates selected mannose residues on lysosomal enzymes. In the process uridine diphosphate (UDP) is converted to uridine monophosphate (UMP). Then, N-acetylglucosamine (GlcNAc) is removed by the uncovering enzyme (UCE) in the trans-Golgi network (Rohrer J, Kornfeld R. Lysosomal hydrolase mannose 6-phosphate uncovering enzyme resides in the trans-Golgi network. Mol Biol Cell 2001;12(6):1623-31.)

The phosphorylated enzymes bind with the mannose 6-phosphate (M6P) receptor and are internalized to the endosome and finally enter the lysosomes. (Source: Khan SA, Tomatsu SC. Mucolipidoses overview: past, present, and future. Int J Mol Sci 2020;21(18):6812. Enlarged and edited by Douglas J Lanska MD MS MSPH to improve sharpness and contrast. Creative Commons Attribution [CC BY] license. http://creativecommons.org/licenses/by/4.0.)

GlcNAc-1-phosphotransferase is an alpha2β2γ2 heterohexameric transmembrane enzyme. The site-1 protease cleaves inactive precursor proteins and releases catalytically active alpha and beta subunits. (Source: Khan SA, Tomatsu SC. Mucolipidoses overview: past, present, and future. Int J Mol Sci 2020;21(18):6812. Enlarged and edited by Douglas J Lanska MD MS MSPH to improve sharpness and contrast. Creative Commons Attribution [CC BY] license. http://creativecommons.org/licenses/by/4.0.)

The patient has a coarse face, short neck, umbilical hernia, thick skin, and rigidity of joints. (Source: Khan SA, Tomatsu SC. Mucolipidoses overview: past, present, and future. Int J Mol Sci 2020;21(18):6812. Enlarged and edited by Douglas J Lanska MD MS MSPH to improve sharpness and contrast. Creative Commons Attribution [CC BY] license. http://creativecommons.org/licenses/by/4.0.)

May-Giemsa staining; x40 magnification. (Source: Khan SA, Tomatsu SC. Mucolipidoses overview: past, present, and future. Int J Mol Sci 2020;21(18):6812. Enlarged and edited by Douglas J Lanska MD MS MSPH to improve sharpness and contrast. Creative Commons Attribution [CC BY] license. http://creativecommons.org/licenses/by/4.0.)

(Source: Ambarsari CG, Cahyadi D, Sari L, et al. Late diagnosis of Lesch-Nyhan disease complicated with end-stage renal disease and tophi burst: a case report. Ren Fail 2020;42(1):113-21. Creative Commons Attribution License. http://creativecommons.org/licenses/by/4.0.)

Dorsum view. (Source: Ambarsari CG, Cahyadi D, Sari L, et al. Late diagnosis of Lesch-Nyhan disease complicated with end-stage renal disease and tophi burst: a case report. Ren Fail 2020;42(1):113-21. Creative Commons Attribution License. http://creativecommons.org/licenses/by/4.0.)

Palmar view. (Source: Ambarsari CG, Cahyadi D, Sari L, et al. Late diagnosis of Lesch-Nyhan disease complicated with end-stage renal disease and tophi burst: a case report. Ren Fail 2020;42(1):113-21. Creative Commons Attribution License. http://creativecommons.org/licenses/by/4.0.)

(Source: Ambarsari CG, Cahyadi D, Sari L, et al. Late diagnosis of Lesch-Nyhan disease complicated with end-stage renal disease and tophi burst: a case report. Ren Fail 2020;42(1):113-21. Creative Commons Attribution License. http://creativecommons.org/licenses/by/4.0.)

Hematoxylin and eosin staining. 100x magnification. (Source: Ambarsari CG, Cahyadi D, Sari L, et al. Late diagnosis of Lesch-Nyhan disease complicated with end-stage renal disease and tophi burst: a case report. Ren Fail 2020;42(1):113-21. Creative Commons Attribution License. http://creativecommons.org/licenses/by/4.0.)

Bone biopsy revealed the presence of urate crystals (arrow). Hematoxylin and eosin staining. 100x magnification. (Source: Ambarsari CG, Cahyadi D, Sari L, et al. Late diagnosis of Lesch-Nyhan disease complicated with end-stage renal disease and tophi burst: a case report. Ren Fail 2020;42(1):113-21. Creative Commons Attribution License. http://creativecommons.org/licenses/by/4.0.)

Bone biopsy revealed the presence of urate crystals (arrow). Hematoxylin and eosin staining. 100x magnification. (Source: Ambarsari CG, Cahyadi D, Sari L, et al. Late diagnosis of Lesch-Nyhan disease complicated with end-stage renal disease and tophi burst: a case report. Ren Fail 2020;42(1):113-21. Creative Commons Attribution License. http://creativecommons.org/licenses/by/4.0.)

(Source: Torres RJ, Puig JG. Skewed X inactivation in Lesch-Nyhan disease carrier females. J Hum Genet 2017;62(12):1079-83. Creative Commons Attribution License. http://creativecommons.org/licenses/by/2.0.)

(Source: Torres RJ, Puig JG. Skewed X inactivation in Lesch-Nyhan disease carrier females. J Hum Genet 2017;62(12):1079-83. Creative Commons Attribution License. http://creativecommons.org/licenses/by/2.0.)

(Source: Torres RJ, Puig JG. Skewed X inactivation in Lesch-Nyhan disease carrier females. J Hum Genet 2017;62(12):1079-83. Creative Commons Attribution License. http://creativecommons.org/licenses/by/2.0.)

(Source: Ambarsari CG, Cahyadi D, Sari L, et al. Late diagnosis of Lesch-Nyhan disease complicated with end-stage renal disease and tophi burst: a case report. Ren Fail 2020;42(1):113-21. Creative Commons Attribution License. http://creativecommons.org/licenses/by/4.0.)

Coronal CT image showing a stone within the left kidney along with measurement of CT number utilizing region of interest sampling. (Source: Shamir SB, Peng Q, Schoenfeld AH, Drzewiecki BA, Liszewski MC. CT, US and MRI of xanthine urinary stones: in-vitro and in-vivo analyses. BMC Urol 2020;20(1):157. Creative Commons Attribution 4.0 International License. http://creativecommons.org/licenses/by/4.0.)

The stone demonstrates posterior twinkle artifact on color Doppler imaging (right). (Source: Shamir SB, Peng Q, Schoenfeld AH, Drzewiecki BA, Liszewski MC. CT, US and MRI of xanthine urinary stones: in-vitro and in-vivo analyses. BMC Urol 2020;20(1):157. Creative Commons Attribution 4.0 International License. http://creativecommons.org/licenses/by/4.0.)

The stone is echogenic with posterior acoustic shadowing. (Source: Shamir SB, Peng Q, Schoenfeld AH, Drzewiecki BA, Liszewski MC. CT, US and MRI of xanthine urinary stones: in-vitro and in-vivo analyses. BMC Urol 2020;20(1):157. Creative Commons Attribution 4.0 International License. http://creativecommons.org/licenses/by/4.0.)

(Source: Ambarsari CG, Cahyadi D, Sari L, et al. Late diagnosis of Lesch-Nyhan disease complicated with end-stage renal disease and tophi burst: a case report. Ren Fail 2020;42(1):113-21. Creative Commons Attribution License. http://creativecommons.org/licenses/by/4.0.)

The x-ray shows a large soft tissue mass with intramass calcification due to a collection of sodium urate monohydrate, or uric acid. (Source: Ambarsari CG, Cahyadi D, Sari L, et al. Late diagnosis of Lesch-Nyhan disease complicated with end-stage renal disease and tophi burst: a case report. Ren Fail 2020;42(1):113-21. Creative Commons Attribution License. http://creativecommons.org/licenses/by/4.0.)

The x-ray shows a large soft tissue mass with intramass calcification due to a collection of sodium urate monohydrate, or uric acid. (Source: Ambarsari CG, Cahyadi D, Sari L, et al. Late diagnosis of Lesch-Nyhan disease complicated with end-stage renal disease and tophi burst: a case report. Ren Fail 2020;42(1):113-21. Creative Commons Attribution License. http://creativecommons.org/licenses/by/4.0.)

X-ray image of the left wrist showing a soft tissue mass adjacent to the metacarpal and proximal to the second finger due to a collection of sodium urate monohydrate, or uric acid. (Source: Ambarsari CG, Cahyadi D, Sari L, et al. Late diagnosis of Lesch-Nyhan disease complicated with end-stage renal disease and tophi burst: a case report. Ren Fail 2020;42(1):113-21. Creative Commons Attribution License. http://creativecommons.org/licenses/by/4.0.)

Dermatophagia (extreme nail-biting and biting of skin) to point of an obsessive-compulsive disorder or other condition leading to self-mutilating behavior, such as autistic spectrum disorders (as is the case in this example) or Lesch-Nyhan syndrome. (Photography by 6th Happiness on May 16, 2009. Creative Commons Attribution 3.0 Unported license. https://creativecom mons.org/licenses/by/3.0/deed.en.)

Xanthine is on the left, and urate is on the right. Overzealous use of allopurinol can lead to xanthine stones. (Source: Wikimedia Commons. Created by J3D3 on February 4, 2015. Creative Commons Attribution-Share Alike 4.0 International license.)

The human hypoxanthine-guanine phosphoribosyltransferase (HPRT) homotetramer with magnesium ions (light blue). (Source: Keough DT, Guddat LW, Kaiser MM, Hockova D, Wang TH, Janeba Z. Human HGPRT in complex with (S)-HPEPG, an acyclic nucleoside phosphonate. Protein Data Bank 2016. Available at https://www.wwpdb.org/pdb?id=pdb_00005bsk. Creative Commons Attribution-Share Alike 4.0 International. https://creativecommons.org/licenses/by-sa/4.0/deed.en.)

(Source: Torres RJ, Puig JG. Skewed X inactivation in Lesch-Nyhan disease carrier females. J Hum Genet 2017;62(12):1079-83. Creative Commons Attribution License. http://creativecommons.org/licenses/by/2.0.)

Note that males in multiple generations are affected, but obligate female carriers are unaffected. (Source: Laróvere LE, Fairbanks LD, Jinnah HA, et al. Lesch-Nyhan disease and its variants: phenotypic and mutation spectrum of hypoxanthine-guanine phosphoribosyltransferase deficiency in argentine patients. J Inborn Errors Metab Screen 2021;9:e20200027. Creative Commons Attribution License. http://creativecommons.org/licenses/by/4.0. Figure edited by Douglas J Lanska MD MS MSPH.)

Lesch-Nyhan disease is transmitted as an X-linked recessive trait

Lip manipulation (sucking/biting) and saliva over the perioral tissues are evident. (Source: Eita AA. Congenital anomalies-associated Riga-Fede disease as an early manifestation of Lesch-Nyhan syndrome: rare entities in the same pediatric patient-a case report. BMC Oral Health 2022;22(1):26. Creative Commons Attribution License. http://creativecommons.org/licenses/by/4.0.)

(Source: Eita AA. Congenital anomalies-associated Riga-Fede disease as an early manifestation of Lesch-Nyhan syndrome: rare entities in the same pediatric patient-a case report. BMC Oral Health 2022;22(1):26. Creative Commons Attribution License. http://creativecommons.org/licenses/by/4.0.)

A deformed lower lip with an extensive ulcer involving both the oral mucosa and vermillion lip border in a patient with Lesch-Nyhan disease. The ulcer has well-defined regular borders and a central yellowish membrane. A white halo surrounds the ulcer borders indicating hyperkeratosis. (Source: Eita AA. Congenital anomalies-associated Riga-Fede disease as an early manifestation of Lesch-Nyhan syndrome: rare entities in the same pediatric patient-a case report. BMC Oral Health 2022;22(1):26. Creative Commons Attribution License. http://creativecommons.org/licenses/by/4.0.)

Clinical presentation of the patient with Lesch-Nyhan disease at eight months of age. An ulcer involves the tip of the tongue with well-defined regular borders and a yellowish central membrane. The lower lip exhibits deformity. Erythematous patches are evident in the perioral skin. (Source: Eita AA. Congenital anomalies-associated Riga-Fede disease as an early manifestation of Lesch-Nyhan syndrome: rare entities in the same pediatric patient-a case report. BMC Oral Health 2022;22(1):26. Creative Commons Attribution License. http://creativecommons.org/licenses/by/4.0.)

(Source: Ambarsari CG, Cahyadi D, Sari L, et al. Late diagnosis of Lesch-Nyhan disease complicated with end-stage renal disease and tophi burst: a case report. Ren Fail 2020;42(1):113-21. Creative Commons Attribution License. http://creativecommons.org/licenses/by/4.0.)

In a 15-year-old boy with Lesch-Nyhan disease, a tophus of the left ankle burst and discharged stones. (Source: Ambarsari CG, Cahyadi D, Sari L, et al. Late diagnosis of Lesch-Nyhan disease complicated with end-stage renal disease and tophi burst: a case report. Ren Fail 2020;42(1):113-21. Creative Commons Attribution License. http://creativecommons.org/licenses/by/4.0.)

In a 15-year-old boy with Lesch-Nyhan disease, a tophus of the left ankle burst and discharged stones. (Source: Ambarsari CG, Cahyadi D, Sari L, et al. Late diagnosis of Lesch-Nyhan disease complicated with end-stage renal disease and tophi burst: a case report. Ren Fail 2020;42(1):113-21. Creative Commons Attribution License. http://creativecommons.org/licenses/by/4.0.)

(Source: Ambarsari CG, Cahyadi D, Sari L, et al. Late diagnosis of Lesch-Nyhan disease complicated with end-stage renal disease and tophi burst: a case report. Ren Fail 2020;42(1):113-21. Creative Commons Attribution License. http://creativecommons.org/licenses/by/4.0.)

(Source: Ambarsari CG, Cahyadi D, Sari L, et al. Late diagnosis of Lesch-Nyhan disease complicated with end-stage renal disease and tophi burst: a case report. Ren Fail 2020;42(1):113-21. Creative Commons Attribution License. http://creativecommons.org/licenses/by/4.0.)

(Source: Ambarsari CG, Cahyadi D, Sari L, et al. Late diagnosis of Lesch-Nyhan disease complicated with end-stage renal disease and tophi burst: a case report. Ren Fail 2020;42(1):113-21. Creative Commons Attribution License. http://creativecommons.org/licenses/by/4.0.)

(Source: Ambarsari CG, Cahyadi D, Sari L, et al. Late diagnosis of Lesch-Nyhan disease complicated with end-stage renal disease and tophi burst: a case report. Ren Fail 2020;42(1):113-21. Creative Commons Attribution License. http://creativecommons.org/licenses/by/4.0.)

He was unable to stand or walk. A pediatric neurologist diagnosed the patient with cerebral palsy at the age of 7 months based on psychomotor delay and computed tomography results showing cerebral atrophy. (Source: Ambarsari CG, Cahyadi D, Sari L, et al. Late diagnosis of Lesch-Nyhan disease complicated with end-stage renal disease and tophi burst: a case report. Ren Fail 2020;42(1):113-21. Creative Commons Attribution License. http://creativecommons.org/licenses/by/4.0.)

J(arvis) ("Jay") Seegmiller is best known for his role in discovering the biochemical basis of Lesch-Nyhan syndrome, establishing it as a disease with a defined cause. (Source: National Institutes of Health. See: Anonymous. Drs. Decker, Seegmiller head new sections of NIAMD's A&R Branch. The NIH Record 1966;18(9):8. Figure edited by Douglas J Lanska MD MS MSPH.)

The numbering convention for the carbon atoms is shown in red. (Figure created by glycoform on January 3, 2009. Public domain.)

The numbering convention for the carbon atoms is shown in red. (Figure created by glycoform on January 3, 2009. Public domain.)

(Source: PubChem. Enlarged and edited by Douglas J Lanska MD MS MSPH to improve sharpness and contrast. Public domain.)

(Source: PubChem. Enlarged and edited by Douglas J Lanska MD MS MSPH to improve sharpness and contrast. Public domain.)

(Figure created by Yikrazuul on September 20, 2014. Public domain.)

(Figure created by Miguelferig on December 9, 2011. Public domain.)

A plot of saccadic amplitude versus saccadic peak velocity shows slow horizontal saccades, particularly at larger saccadic amplitudes. (Source: Riboldi GM, Martone J, Rizzo JR, Hudson TE, Rucker JC, Frucht SJ. Looking "cherry red spot myoclonus" in the eyes: clinical phenotype, treatment response, and eye movements in sialidosis type 1. Tremor Other Hyperkinet Mov (NY) 2021;11:53. Creative Commons Attribution 4.0 International License [CC­ BY 4.0].)

Eye movement recording showing saccadic hypometria (undershoots). (Source: Riboldi GM, Martone J, Rizzo JR, Hudson TE, Rucker JC, Frucht SJ. Looking "cherry red spot myoclonus" in the eyes: clinical phenotype, treatment response, and eye movements in sialidosis type 1. Tremor Other Hyperkinet Mov (NY) 2021;11:53. Creative Commons Attribution 4.0 International License [CC­ BY 4.0].)

Eye movement recording of Case 3 showing saccadic pursuit, both horizontally (top) and vertically (bottom). (Source: Riboldi GM, Martone J, Rizzo JR, Hudson TE, Rucker JC, Frucht SJ. Looking "cherry red spot myoclonus" in the eyes: clinical phenotype, treatment response, and eye movements in sialidosis type 1. Tremor Other Hyperkinet Mov (NY) 2021;11:53. Creative Commons Attribution 4.0 International License [CC­ BY 4.0].)

Fundus photographs of the right (A) and left (B) eyes, showing bilateral cherry-red spots. (Source: Riboldi GM, Martone J, Rizzo JR, Hudson TE, Rucker JC, Frucht SJ. Looking "cherry red spot myoclonus" in the eyes: clinical phenotype, treatment response, and eye movements in sialidosis type 1. Tremor Other Hyperkinet Mov (NY) 2021;11:53. Creative Commons Attribution 4.0 International License [CC­ BY 4.0].)

(Source: Guffon N, Tylki-Szymanska A, Borgwardt L, et al. Recognition of alpha-mannosidosis in paediatric and adult patients: presentation of a diagnostic algorithm from an international working group. Mol Genet Metab 2019;126(4):470-4.) Creative Commons Attribution 4.0 International license. https://creativecommons.org/licenses/by/4.0.)

MPS = mucopolysaccharidosis. (Source: Guffon N, Tylki-Szymanska A, Borgwardt L, et al. Recognition of alpha-mannosidosis in paediatric and adult patients: presentation of a diagnostic algorithm from an international working group. Mol Genet Metab 2019;126(4):470-4.) Creative Commons Attribution 4.0 International license. https://creativecommons.org/licenses/by/4.0.)

(Created by Domaina, Kashmiri and SUM1 on January 20, 2020. Creative Commons Attribution-Share Alike 3.0 Unported license. Modified by Douglas J Lanska MD MS MSPH.)

Peptides are colored a-red, b-orange, c-yellow, d-green, and e-blue. The active site is denoted by a Zn²⁺ ion. Two mutant sites are displayed, demonstrating the effect of mutations c.215A>T: p.H72L affecting Zn²⁺ coordination in the actives site (group 1 mutation) and the prevalent mutation c.2248C>T: p.R750W, which is likely affecting peptide e-d interaction (group 2 mutation). (Created by Dr. P. Heikinheimo, University of Helsinki, Finland. It has been prepared with the program PyMol. Source: Malm D, Nilssen O. Alpha-mannosidosis. Orphanet J Rare Dis 2008;3:21. Creative Commons Attribution License. http://creativecommons.org/licenses/by/2.0. Enlarged and edited by Douglas J Lanska MD MS MSPH to improve sharpness and contrast.)

Electron micrograph of (A) a vacuolated lymphocyte from a patient with alpha-mannosidosis, and (B) a lymphocyte from a normal control. (Source: Malm D, Nilssen O. Alpha-mannosidosis. Orphanet J Rare Dis 2008;3:21. Creative Commons Attribution License. http://creativecommons.org/licenses/by/2.0. Enlarged and edited by Douglas J Lanska MD MS MSPH.)

(Created by C Burnett on March 25, 2007. Creative Commons Attribution-Share Alike 3.0 Unported license. Modified by Douglas J Lanska MD MS MSPH.)

(Created by Dna 621 on March 27, 2014. Creative Commons Attribution-Share Alike 3.0 Unported license. https://cr eativecommons.org/licenses/by-sa/3.0/deed.en. Enlarged and edited by Douglas J Lanska MD MS MSPH to improve sharpness and contrast.)

(Created by Dna 621 on March 27, 2014. Creative Commons Attribution-Share Alike 3.0 Unported license. https://cr eativecommons.org/licenses/by-sa/3.0/deed.en. Enlarged and edited by Douglas J Lanska MD MS MSPH to improve sharpness and contrast.)

(Source: Maverakis E, Kim K, Shimoda M, et al. Glycans in the immune system and The Altered Glycan Theory of Autoimmunity: a critical review. J Autoimmun 2015;57:1-13. Creative Commons Attribution [CC BY] license. http://creativecommons.org/licenses/by/4.0.)

(Created by Dna 621 on March 27, 2014. Creative Commons Attribution-Share Alike 3.0 Unported license. https://cr eativecommons.org/licenses/by-sa/3.0/deed.en.)

(Created by Dna 621 on March 27, 2014. Creative Commons Attribution-Share Alike 3.0 Unported license. https://cr eativecommons.org/licenses/by-sa/3.0/deed.en.)

(Image created by Naturwiki on October 7, 2020. Enlarged and edited by Douglas J Lanska MD MS MSPH to improve sharpness and contrast. Public domain.)

(Image created by Naturwiki on October 7, 2020. Enlarged and edited by Douglas J Lanska MD MS MSPH to improve sharpness and contrast. Public domain.)

Under physiologic conditions this 6-membered-ring form accounts for approximately 1/3 of D-mannose. (Created by NEUROtiker on March 14, 2007. Public domain.)

Under physiologic conditions this 6-membered-ring form accounts for approximately 2/3 of D-mannose. (Created by NEUROtiker on March 14, 2007. Public domain.)

Under physiologic conditions this 5-membered-ring form is uncommon. (Created by NEUROtiker on March 14, 2007. Public domain.)

Under physiologic conditions this 5-membered-ring form is uncommon. (Created by NEUROtiker on March 14, 2007. Public domain.)

A Fischer projection or Fischer projection formula is a convention used to depict a stereoformula in two dimensions without destroying the stereochemical information at chiral centers. (Public domain.)

A 26-year-old woman (proband II/1 from a Slovak family) with hereditary hearing loss and beta-mannosidosis. The dashed line represents the Auditory Steady-State Response (ASSR), and objective estimation of the hearing threshold. Full lines are pure-tone, audiometric curves at ages 13 and 26 years. The discrepancy between pure tone audiometry and ASSR thresholds measured at the same age (26 years) might result from mental retardation. (Source: Safka Brozkova D, Varga L, Uhrova Meszarosova A, et al. Variant c.2158-2A>G in MANBA is an important and frequent cause of hereditary hearing loss and beta-mannosidosis among the Czech and Slovak Roma population- evidence for a new ethnic-specific variant. Orphanet J Rare Dis 2020;15(1):222. Creative Commons Attribution 4.0 International License. Enlarged and edited by Douglas J Lanska MD MS MSPH to improve sharpness and contrast.)

Photos of a 26-year-old woman (proband II/1 from a Slovak family) with hereditary hearing loss and beta-mannosidosis. The broad nose is visible; no angiokeratomas on the patient were visible. (Source: Safka Brozkova D, Varga L, Uhrova Meszarosova A, et al. Variant c.2158-2A>G in MANBA is an important and frequent cause of hereditary hearing loss and beta-mannosidosis among the Czech and Slovak Roma population- evidence for a new ethnic-specific variant. Orphanet J Rare Dis 2020;15(1):222. Creative Commons Attribution 4.0 International License. Edited by Douglas J Lanska MD MS MSPH to improve sharpness and contrast.)

The square symbol is for men, the circle for women. Clinically affected members with hearing loss are filled-in black. The number inside the symbols represents the number of siblings with that sex and clinical status. * - indicates a patient with beta-mannosidosis diagnosed by biochemical and enzymatic examination. P - indicates the proband, the first affected family member referred for genetic examination. The proband was tested genetically for the MANBA c.2158-2A>G variant, and her homozygous state for this variant is indicated as c.2158- 2A>G/c.2158- 2A>G. (Source: Safka Brozkova D, Varga L, Uhrova Meszarosova A, et al. Variant c.2158-2A>G in MANBA is an important and frequent cause of hereditary hearing loss and beta-mannosidosis among the Czech and Slovak Roma population- evidence for a new ethnic-specific variant. Orphanet J Rare Dis 2020;15(1):222. Creative Commons Attribution 4.0 International License. Enlarged and edited by Douglas J Lanska MD MS MSPH to improve sharpness and contrast.)

(Photograph by L Dmochowski. Creative Commons Attribution-Share Alike 4.0 International. https://creative commons.org/licenses/by-sa/4.0.)

(A) Coxarthrosis at 8 years of age. (B) Progression of coxarthrosis at age 13 years. (Source: Malm D, Nilssen O. Alpha-mannosidosis. Orphanet J Rare Dis 2008;3:21. Creative Commons Attribution License. http://creativecommons.org/licenses/by/2.0. Enlarged and edited by Douglas J Lanska MD MS MSPH.)

(A) Kyphoscoliosis with skeletal abnormalities of all vertebrae. (B) Orthopedic correction of kyphosis. (Source: Malm D, Nilssen O. Alpha-mannosidosis. Orphanet J Rare Dis 2008;3:21. Creative Commons Attribution License. http://creativecommons.org/licenses/by/2.0. Enlarged and edited by Douglas J Lanska MD MS MSPH.)

Note hearing aid. (Source: Malm D, Nilssen O. Alpha-mannosidosis. Orphanet J Rare Dis 2008;3:21. Creative Commons Attribution License. http://creativecommons.org/licenses/by/2.0. Enlarged and edited by Douglas J Lanska MD MS MSPH.)

Same twins at age 8 years. Note slight muscular atrophy of the hands. (Source: Malm D, Nilssen O. Alpha-mannosidosis. Orphanet J Rare Dis 2008;3:21. Creative Commons Attribution License. http://creativecommons.org/licenses/by/2.0. Enlarged and edited by Douglas J Lanska MD MS MSPH.)

Twins with alpha-mannosidosis aged 18 months. Note enlarged head, short neck, rounded eyebrows, saddle nose, and prominent forehead. (Source: Malm D, Nilssen O. Alpha-mannosidosis. Orphanet J Rare Dis 2008;3:21. Creative Commons Attribution License. http://creativecommons.org/licenses/by/2.0. Enlarged and edited by Douglas J Lanska MD MS MSPH.)

Swainsonine is a toxin present in certain plants (eg, "locoweed"), which when ingested by ruminants or horses produces a toxic form of mannosidosis. (Created by Jü on July 28, 2012. Public domain.)

(Illustration by Cburnett on March 25, 2007. Creative Commons Attribution- Share Alike 3.0 Unported license.)

Structural formula of adenosine triphosphate (ATP), showing its chemical components, by name and by type or class of the component compounds. A purine base (adenine) is attached to a pentose (ribose) and that is attached to three phosphate groups. The phosphate groups are organized in a chain that is linked with high-energy pyrophosphate bonds [marked in red]; pyrophosphates are phosphorus oxyanions that contain two phosphorus atoms in a P-O-P linkage. (Illustration corrected and modified by Douglas Lanska MD MS MSPH, from one on the Anatomy & Physiology, Connexions Web site. http://cnx.org/content/col11496/1.6. Jun 19, 2013. Creative Commons Attribution 3.0 Unported license.)

dGMP; also known as deoxyguanylic acid or deoxyguanylate. (Public domain.)

dAMP; also known as deoxyadenylic acid or deoxyadenylate. (Public domain.)

(Public domain.)

(Public domain.)

(Public domain.)

(Public domain.)

In aqueous solution, deoxyribose primarily exists as a mixture of three structures: the linear form and two ring forms, deoxyribofuranose with a five-membered ring, and deoxyribopyranose with a six-membered ring. The latter form is predominant. (Public domain.)

Like D-ribose, D-deoxyribose has two cyclic or ring forms, deoxyribofuranose, with a five-membered ring, and deoxyribopyranose, with a six-membered ring. The form shown has a five-membered ring, so it is a deoxyribofuranose. Deoxyribose was discovered in 1929 by Lithuanian-American biochemist Phoebus Levene. (Public domain.)

(Public domain.)

(Public domain.)

Several of the forms of D-ribose: the open-chain form (top), and Haworth projections of two of the four cyclic forms, alpha-D-ribopyranose (middle), and beta-D-ribofuranose (bottom). Ribose exists as a mixture of cyclic forms in equilibrium with its linear form, and these readily interconvert, especially in aqueous solution. The relative abundance of forms of ribose in solution is as follows: beta-D-ribopyranose (59%), alpha-D-ribopyranose (20%), beta-D-ribofuranose (13%), alpha-D-ribofuranose (7%), and open-chain (0.1%). The name "ribose" refers collectively to all of these forms, although the more specific names for each form are used when required. D-ribose was discovered in 1909 by Lithuanian-American biochemist Phoebus Levene. (Public domain.)

Inosine monophosphate (IMP) is a precursor of the purines adenosine and guanosine. (Public domain.)

(Public domain.)

(Public domain.)

The "tetranucleotide hypothesis" of the structure of DNA, proposed by Lithuanian-American biochemist Phoebus Levene in 1909, before DNA was understood to store genetic information. (Illustration created by Athel cb on 30 April 2021. Creative Commons Attribution-Share Alike 4.0 International license.)

Photo circa 1920s. (Source: U.S. National Library of Medicine, Bethesda, Maryland.)

(Source: Harries C. Oskar Piloty [obituary]. Berichte der Deutschen chemischen Gesellschaft [A and B Series] 1920;53(9):A153-68.)

Engraving from Svenska Familj-Journalen (1874). (Public domain.)

(Public domain.)

Structural formula for purine, with a numbered ring system. (Public domain.)

Photo circa 1895. (Photograph by Atelier Victoria [owner Paul Gericke, founded 1894], Berlin.) (Public domain.)

L-fucose is a hexose deoxy sugar found on N-linked glycans on the cell surface. The lack of a hydroxyl group on the carbon at the 6-position makes it a deoxy sugar.

Magnetic resonance spectroscopy showing a doublet peak around 1.2 parts per million (white arrow) in a 4-year-old girl with fucosidosis. (Source: Kaur A, Dhaliwal AS, Raynes H, Naidich TP, Kaufman DM. Diagnosis and supportive management of fucosidosis: a case report. Cureus 2019;11(11):e6139. Creative Commons Attribution License CC-BY 3.0.)

Magnetic resonance spectroscopy showing a prominent peak at 3.8 to 3.9 parts per million (white arrow) in a 4-year-old girl with fucosidosis. (Source: Kaur A, Dhaliwal AS, Raynes H, Naidich TP, Kaufman DM. Diagnosis and supportive management of fucosidosis: a case report. Cureus 2019;11(11):e6139. Creative Commons Attribution License CC-BY 3.0.)

MRI of the sagittal section showing thinning of the corpus callosum (arrow) in a 4-year-old girl with fucosidosis. (Source: Kaur A, Dhaliwal AS, Raynes H, Naidich TP, Kaufman DM. Diagnosis and supportive management of fucosidosis: a case report. Cureus 2019;11(11):e6139. Creative Commons Attribution License CC-BY 3.0.)

Atrophic enlargement of the lateral ventricles, with reduced white matter volume and abnormal white matter signal intensity in a 4-year-old girl with fucosidosis. T2-weighted MRI image of the brain in the horizontal section showing a symmetrical increase in T2 signal intensity in the subcortical and deep white matter (arrows). (Source: Kaur A, Dhaliwal AS, Raynes H, Naidich TP, Kaufman DM. Diagnosis and supportive management of fucosidosis: a case report. Cureus 2019;11(11):e6139. Creative Commons Attribution License CC-BY 3.0.)

Curvilinear bands in the globi pallidi in a 4-year-old girl with fucosidosis. MRI fluid-attenuated inversion recovery (FLAIR) image of the brain in the horizontal section showing characteristic symmetric curvilinear bands in the globi pallidi (arrows). (Source: Kaur A, Dhaliwal AS, Raynes H, Naidich TP, Kaufman DM. Diagnosis and supportive management of fucosidosis: a case report. Cureus 2019;11(11):e6139. Creative Commons Attribution License CC-BY 3.0.)

(Source: PubChem. U.S. National Library of Medicine, Bethesda, Maryland. Public domain.)

(Source: Seppi333, 29 January 2018. Creative Commons Attribution 4.0 International license. Recolored, and formatting of legend condensed by Douglas J Lanska MD MS MSPH.)

Also shown are 4 flavin adenine dinucleotide (FAD; light blue-red) + 4 Coenzyme A (CoA; green-red). (Illustration by Tiffany KA, Roberts DL, Wang M, et al. Creative Commons Attribution-Share Alike 4.0 International license. https://creativecommons.org/licenses/by-sa/4.0/deed.en)

(Source: PubChem. U.S. National Library of Medicine, Bethesda, Maryland. Public domain.)

(Source: PubChem. U.S. National Library of Medicine, Bethesda, Maryland. Public domain.)

(Source: Harbin, December 5, 2008. Public domain.)

Unusually high radioactivity is found in both Achilles tendons. PET shows abnormal soft tissue thickening in a CT window in coronal section (A) and in axial section (D) and unusually high radioactivity in both PET (B and E) and fusion windows (C and F). (Source: Nie S, Chen G, Cao X, Zhang Y. Cerebrotendinous xanthomatosis: a comprehensive review of pathogenesis, clinical manifestations, diagnosis, and management. Orphanet J Rare Dis 2014;9:179. Creative Commons Attribution 4.0 [CC BY] license.)

Histology (hematoxylin and eosin, 200x) of a tendon xanthoma in a patient with cerebrotendinous xanthomatosis reveals accumulation of xanthoma cells (fine arrows) and dispersed lipid crystal clefts (coarse arrows). (Source: Nie S, Chen G, Cao X, Zhang Y. Cerebrotendinous xanthomatosis: a comprehensive review of pathogenesis, clinical manifestations, diagnosis, and management. Orphanet J Rare Dis 2014;9:179. Creative Commons Attribution 4.0 [CC BY] license.)

Histology (hematoxylin and eosin, 100x) of a tendon xanthoma in a patient with cerebrotendinous xanthomatosis reveals accumulation of xanthoma cells (fine arrows) and dispersed lipid crystal clefts (coarse arrows). (Source: Nie S, Chen G, Cao X, Zhang Y. Cerebrotendinous xanthomatosis: a comprehensive review of pathogenesis, clinical manifestations, diagnosis, and management. Orphanet J Rare Dis 2014;9:179. Creative Commons Attribution 4.0 [CC BY] license.)

MRI of both ankles in a patient with cerebrotendinous xanthomatosis. Sagittal long-T1-weighted image (A, arrow), short-T2-weighted image (B, arrow), and axial long-T1-weighted image (C, arrow) of fusiform thickenings in the Achilles tendons in a patient with cerebrotendinous xanthomatosis. (Source: Nie S, Chen G, Cao X, Zhang Y. Cerebrotendinous xanthomatosis: a comprehensive review of pathogenesis, clinical manifestations, diagnosis, and management. Orphanet J Rare Dis 2014;9:179. Creative Commons Attribution 4.0 [CC BY] license.)

This PET image reveals hypometabolism in the cerebrum (especially in the frontal and temporal lobes) in both the sagittal section (A) and the axial section (B). (Source: Nie S, Chen G, Cao X, Zhang Y. Cerebrotendinous xanthomatosis: a comprehensive review of pathogenesis, clinical manifestations, diagnosis, and management. Orphanet J Rare Dis 2014;9:179. Creative Commons Attribution 4.0 [CC BY] license.)

This axial T2-weighted spinal MRI from a 27-year-old man with cerebrotendinous xanthomatosis shows signal changes mainly affecting the lateral corticospinal tracts. Clinical presentation: This man presented with a 3-year history of "stiffness" followed by weakness and sensory disturbances of both legs. He had a prior history of infantile-onset diarrhea that persisted. Examination revealed gaze-evoked nystagmus, a brisk jaw jerk, increased tone bilaterally in the arms and legs with pathologically brisk reflexes, extensor plantar responses, a spastic gait, and bilateral pes cavus. He eventually became wheelchair-bound due to his severe spasticity. (Source: Islam M, Hoggard N, Hadjivassiliou M. Cerebrotendinous xanthomatosis: diversity of presentation and refining treatment with chenodeoxycholic acid. Cerebellum Ataxias 2021;8[1]:5. Creative Commons Attribution 4.0 International License.)

This CT image from a 37-year-old man with cerebrotendinous xanthomatosis confirms the cerebellar calcifications suspected on MRI. (Source: Islam M, Hoggard N, Hadjivassiliou M. Cerebrotendinous xanthomatosis: diversity of presentation and refining treatment with chenodeoxycholic acid. Cerebellum Ataxias 2021;8[1]:5. Creative Commons Attribution 4.0 International License.)

This T2-weighted brain MRI from a 37-year-old man with cerebrotendinous xanthomatosis shows signal change within the cerebellar hemispheres associated with significant volume loss. There was a combination of low signal change suspected to be due to calcification and raised signal change in the rest of the cerebellar hemispheres extending into the cerebellar peduncles bilaterally. Clinical presentation: The patient had a history of learning difficulties, requiring special classes at school. He was evaluated for worsened speech and marked disequilibrium and required assistance to walk. Examination showed no cataracts or xanthomas. Neurologic examination showed marked dysarthria, limb and gait ataxia, diffusely increased tone, and pathologically brisk reflexes in both legs with bilateral extensor plantar responses. (Source: Islam M, Hoggard N, Hadjivassiliou M. Cerebrotendinous xanthomatosis: diversity of presentation and refining treatment with chenodeoxycholic acid. Cerebellum Ataxias 2021;8[1]:5. Creative Commons Attribution 4.0 International License.)

MRI of a patient with cerebrotendinous xanthomatosis shows T1-weighted (A, arrow) and T2-weighted (B, arrow) hyperintensities in the dentate nuclei. (Source: Nie S, Chen G, Cao X, Zhang Y. Cerebrotendinous xanthomatosis: a comprehensive review of pathogenesis, clinical manifestations, diagnosis, and management. Orphanet J Rare Dis 2014;9:179. Creative Commons Attribution 4.0 [CC BY] license.)

This axial T2-weighted MRI of a 42-year-old man with cerebrotendinous xanthomatosis shows bilateral hyperintense lesions involving the dentate nuclei and deep cerebellar white matter. Clinical presentation: He had a history of early-onset cataracts, cognitive difficulty, and gait instability. Examination revealed nasal speech, severe dysarthria, marked ataxia of limbs and gait, and bilateral Achilles tendon xanthomas. (Source: Islam M, Hoggard N, Hadjivassiliou M. Cerebrotendinous xanthomatosis: diversity of presentation and refining treatment with chenodeoxycholic acid. Cerebellum Ataxias 2021;8[1]:5. Creative Commons Attribution 4.0 International License.)

Supratentorial axial T2-weighted MRI of a 37-year-old woman with cerebrotendinous xanthomatosis. This axial T2-weighted MRI shows white matter tract involvement, specifically of the corticospinal tracts and optic radiations. Clinical presentation: She presented primarily because of deteriorating balance. She also had mild cognitive problems and had been labeled as having Asperger syndrome. She had a history of early-onset cataracts when she was 8 years old, which were extracted when she was 9. She suffered from diarrhea when she was a child. She had begun falling frequently and had fractured her wrist, at which point she was found to have osteoporosis. Neurologic examination revealed limb and gait ataxia, inability to tandem walk, pathologically brisk reflexes, and bilateral extensor plantar responses but no tendon xanthomas. (Source: Islam M, Hoggard N, Hadjivassiliou M. Cerebrotendinous xanthomatosis: diversity of presentation and refining treatment with chenodeoxycholic acid. Cerebellum Ataxias 2021;8[1]:5. Creative Commons Attribution 4.0 International License.)

Cholestanol (5alpha-cholestan-3beta-ol) is the metabolic end-product of cholesterol metabolism in cerebrotendinous xanthomatosis. (Source: PubChem. Public domain.)

5alpha-Cholestan-3-one is a metabolic intermediate of cholesterol metabolism in cerebrotendinous xanthomatosis. (Source: PubChem. Public domain.)

Cholest-4-en-3-one is a metabolic intermediate of cholesterol metabolism in cerebrotendinous xanthomatosis. (Source: PubChem. Public domain.)

Metabolism of cholesterol metabolites above the block in the classic pathway of bile acid biosynthesis also occurs, including from the first 2 metabolites of that pathway: 7alpha-hydroxycholesterol and 7alpha-hydroxy-4-cholesten-3-one. (Illustration by Dr. Douglas J Lanska.)

27-Hydroxycholesterol is the first metabolite (from the first and fate-limiting step) in the alternate pathway of bile acid synthesis. (Public domain.)

Selected enzymes are shown in red boxes. The red arrows show the abnormal synthetic step in cerebrotendinous xanthomatosis, due to deficiency or dysfunction of the enzyme cytochrome P450 27A1 (CYP27A1). This is the rate-limiting enzyme that initiates the alternate pathway. (Illustration by Dr. Douglas J Lanska.)

Chenodeoxycholic acid is one of the two primary bile acids. (Public domain.)

Cholic acid is one of the two primary bile acids. (Public domain.)

7 alpha-hydroxycholesterol is the first metabolite (from the first and fate-limiting step) in the classic pathway of bile acid synthesis. (Public domain.)

Selected enzymes are shown in red boxes. The red arrows show the abnormal synthetic step in cerebrotendinous xanthomatosis, which is due to deficiency or dysfunction of the enzyme cytochrome P450 27A1 (CYP27A1). The rate-limiting enzyme that initiates the classic pathways is cytochrome P450 7A1 (CYP7A1, or cholesterol 7 alpha-hydroxylase). (Illustration by Dr. Douglas J Lanska.)

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(Public domain.)

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(Public domain.)

(A) Sagittal T1-weighted, (B) proton density, and (C) STIR images show fusiform enlargement of the right Achilles tendon (arrows); the xanthoma is relatively isointense compared to muscle. (D) An axial proton density image shows diffuse fat infiltration with low-intensity tendon bundles interspersed within (arrows). Note: STIR = short tau inversion recovery. (Source: Ma C, Ren YD, Wang JC, et al. The clinical and imaging features of cerebrotendinous xanthomatosis: a case report and review of the literature. Medicine [Baltimore] 2021;100[9]:e24687. Creative Commons Attribution License 4.0 [CC BY] license.)

Cerebellar parenchymal abnormalities in a 40-year-old man with cerebrotendinous xanthomatosis. (A) and (B) Axial CT images show low-density lesions in both cerebellar hemispheres. (C) The axial T1-weighted image shows low-intensity areas in the dentate nuclei and the deep cerebellar white matter bilaterally. (D) The axial T2-weighted image shows hyperintensities in the bilateral cerebellar deep white matter and hyperintensities in the deep white matter of the cerebellum bilaterally. (E) The axial FLAIR image shows low-signal intensity consistent with cerebellar vacuolation in the same areas. (F) Susceptibility-weighted imaging reveals hypointensities in the bilateral dentate nuclei compatible with microcalcifications. (Source: Ma C, Ren YD, Wang JC, et al. The clinical and imaging features
of cerebrotendinous xanthomatosis: a case report and review of the literature. Medicine [Baltimore] 2021;100[9]:e24687. Creative Commons Attribution License 4.0 [CC BY] license.)

Brain abnormalities detected by MRI in a 40-year-old man with cerebrotendinous xanthomatosis. Axial T1-weighted (top row), T2-weighted (middle row), and FLAIR (bottom row) images show symmetric hyperintensities in the posterior limbs of internal capsules, paraventricular white matter, cerebral peduncles, and anterior pons on T2-weighted and FLAIR images (arrows) with corresponding hypointensities on T1-weighted images, which are along corticospinal tracts. (Source: Ma C, Ren YD, Wang JC, et al. The clinical and imaging features of cerebrotendinous xanthomatosis: a case report and review of the literature. Medicine [Baltimore] 2021;100[9]:e24687. Creative Commons Attribution License 4.0 [CC BY] license.)

Cerebral CT-scan in 4-year-old child. Red arrows show brain calcifications of the globus pallidus (A) and diffuse white matter abnormalities (B). (Source: Mafi S, Laroche-Raynaud C, et al. Pharmacoresistant epilepsy in childhood: think of the cerebral folate deficiency, a treatable disease. Brain Sci 2020;10(11):762). (Creative Commons Attribution 4.0 International license.)

(A) T2-weighted coronal MRI showing abnormal high signal sparing the subcortical white matter with slightly periventricular location at age 8 years before folinic acid treatment. (B) T2-weighted coronal MRI showing improvement after 2 years of folinic acid treatment (age 10). (C) T2-weighted axial MRI showing abnormal high signal in the parietal white matter was also observed at age 8 years and before folinic acid treatment. (D) T2-weighted axial MRI shows improvement after 2 years of folinic acid treatment with near-normal white matter signal (age 10). (Source: Quijada-Fraile P, O'Callaghan M, Martín-Hernández E, et al. Follow-up of folinic acid supplementation for patients with cerebral folate deficiency and Kearns-Sayre syndrome. Orphanet J Rare Dis 2014;9:217.) (Creative Commons Attribution 4.0 International license.)

Brain MRI performed in girl at 4 and 12 years old shows diffuse white matter abnormalities linked to hypomyelination. MRI with FLAIR (A–C, G–I) and T2 (D–F, J–L) sequences. Red arrows show diffuse white matter abnormalities linked to hypomyelination. (Source: Mafi S, Laroche-Raynaud C, et al. Pharmacoresistant epilepsy in childhood: think of the cerebral folate deficiency, a treatable disease. Brain Sci 2020;10(11):762.) (Creative Commons Attribution 4.0 International license.)

Red arrows and red crosses indicate the alternative pathway induced by FRα deficiency. Blue arrows indicate effects of folinic acid treatment. Legend: 5MTHF: 5-methylenetetrahydrofolate; B6: vitamin B6; B12: vitamin B12; CSF: cerebrospinal fluid; DHRF: dihydrofolate reductase; FRα: folate receptor alpha; Gly: glycine; GSH: glutathione reduced states; GSSG: glutathione oxidized states; MS: methionine synthase; MTHFD: methylenetetrahydrofolate dehydrogenase; MTHFR: methylenetetrahydrofolate reductase; MTHFS: methylenetetrahydrofolate synthase; PC: phosphatidylcholine; PCFT: proton-coupled folate transporter; PI: phosphatidylinositol; RFC: reduced folate carrier; SAH: S-adenosyl homocysteine; SAM: S-adenosyl-methionine; Ser: Serine; SHMT: serine-hydroxy methyl transferase; SM: sphingomyelin. (Source: Mafi S, Laroche-Raynaud C, et al. Pharmacoresistant epilepsy in childhood: think of the cerebral folate deficiency, a treatable disease. Brain Sci 2020;10(11):762.) (Creative Commons Attribution 4.0 International license.)

Prevalence by maternal race and ethnicity: 19 population-based birth defect surveillance programs, United States, 1995-2011. Contributing programs were based in Arkansas, Arizona, California, Colorado, Georgia, Illinois, Iowa, Kentucky, Maryland, New Jersey, New York, North Carolina, Oklahoma, Puerto Rico, South Carolina, Texas, Utah, West Virginia, and Wisconsin.

Legend: † 95% confidence interval. (Source: Williams J, Mai CT, Mulinare J, et al. Updated estimates of neural tube defects prevented by mandatory folic Acid fortification - United States, 1995-2011. MMWR Morb Mortal Wkly Rep 2015;64(1):1-5.) (Public domain.)

(Source: Photomicrograph by Ed Uthman, Houston, Texas on January 21, 2013. Creative Commons Attribution 2.0 Generic license.)

Macrocytosis is the presence of red cells that are larger than normal (macrocytes) in peripheral blood. They occur in peripheral blood as a result of premature release from the marrow. They are commonly seen in pregnant women, newborn infants, and patients with megaloblastic anemia (eg, folic acid deficiency or vitamin B12 deficiency), liver disease, alcoholism, hemolysis, aplastic anemia, and hypothyroidism. (Source: Photomicrograph by Professor Osaro Erhabor on November 15, 2014. Public domain.)

(Public domain.)