Neurobehavioral & Cognitive Disorders

The image identifies the location of the striate cortex (V1), early occipital visual regions (V2, V3), and two parallel pathways. One that leads dorsally to the posterior parietal regions for the "where and visually-guided action" pathway and one that leads ventrally to posterior and inferior temporal regions for the "what" pathway. (Contributed by Dr. Victoria Pelak. Modified with permission from: Pelak VS. The clinical approach to the identification of higher-order visual dysfunction in neurodegenerative disease. Curr Neurol Neurosci Rep 2022;22[4]:229-42.)

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.)

A mother is holding off a boa constrictor wrapped around her and her three small children. Flames surround them. A liquor store is in the background on the right. A still is behind them on the right, with the inscription "The worm of the still." (Source: Harper's Weekly 1887;31:760. Courtesy of the U.S. National Library of Medicine, Bethesda, Maryland. Public domain.)

Carleton was the author of "The Serpent of the Still" (1906). (Source: The Magazine of Poetry 1890;2. Public domain.)

(Alcohol addiction) Two old men, one is leaning on a staff and the other is embracing a tankard; their unkempt appearance is indicative of the ravages of alcoholism. (Source: "Human passions delineated in above 120 figures...designed in the Hogarthian style.." by Tim Bobbin [ie, pseudonym of English caricaturist and satirical poet John Collier, 1708-1786] and engraved by Thomas Sanders. London, 1773. Courtesy of the U.S. National Library of Medicine, Bethesda, Maryland. Public domain.)

(Alcohol addiction) Two men, one is happily embracing his tankard of liquor, the other is sad at having none. (Source: "Human passions delineated in above 120 figures...designed in the Hogarthian style.." by Tim Bobbin [ie, pseudonym of English caricaturist and satirical poet John Collier, 1708-1786] and engraved by Thomas Sanders. London, 1773. Courtesy of the U.S. National Library of Medicine, Bethesda, Maryland. Public domain.)

Anti-alcohol poster sponsored by the U.S. National Institute on Alcohol Abuse and Alcoholism. (Source: Courtesy of the U.S. Library of Congress, Washington, D.C. Public domain.)

Huge distillation apparatus; black men, representing the West Indies, distill sugar and molasses. At right representatives of agriculture, holding corn and barley, fall back in fear. Spirits representing the effects of alcohol emanate from a large vat. Artist Samuel De Wilde (1748-1832). Published by S Tipper, England, 1808. (Source: Courtesy of the U.S. National Library of Medicine, Bethesda, Maryland. Public domain.)

Print shows an archway of the nine steps of a drunkard's progress, beginning with a man in fancy dress having "a glass with a friend" and then his gradual decline in society with poverty and disease, criminal activity, becoming a bum, and his eventual "death by suicide"; a weeping woman and child are under the archway. (Source: Lithograph published by N Currier, New York. Courtesy of the U.S. Library of Congress, Washington, D.C. Public domain.)

(Source: Caasis and Lubrecht, New York, c1884. Courtesy of the U.S. Library of Congress, Washington, D.C. Public domain.)

Print shows an archway of the nine steps of a drunkard's progress, beginning with a man in a fancy dress having "a glass with a friend" and then his gradual decline in society with poverty and disease, criminal activity, becoming a bum, and his eventual "death by suicide"; two men, one on horseback and another with sacks, are in foreground. (Source: EB and EC Kellogg, Hartford, Connecticut, c1846. Courtesy of the U.S. Library of Congress, Washington, D.C. Public domain.)

Stereograph showing a studio scene of a policeman intervening in a fight, against a painted backdrop. By GW Edmondson, Plymouth, Richland County, Ohio, c1874? (Source: Courtesy of the U.S. Library of Congress, Washington, D.C. Public domain.)

Illustration by British caricaturist and book illustrator George Cruikshank (1792-1878). A man, ruined by alcohol and placed in an institution, is huddled before a locked cage that protects a stove. He is visited by a son and daughter. Through a doorway, a wide-eyed maniac sits on the floor, and a man holding a key waits outside the door. (Source: Courtesy of the U.S. National Library of Medicine, Bethesda, Maryland. Public domain.)

Two men and a woman are sitting around a small table on which is a large punch bowl; each is holding a glass. On the right is seated a fat man with both feet and his left hand bandaged. In the center, a young woman is holding her stomach. On the left, a man appears to be near death. The fat man with gout on the right claims that "PUNCH cures the GOUT," to which the woman adds "the COLIC," and the sickly man adds "and the TISICK." Note that "tisick" in British English is archaic for a splutter (a short explosive spitting or choking noise) or a cough. Cartoon by British caricaturist and printmaker James Gillray (1756-1815), who was famous for his etched political and social satires. (Source: Courtesy of the U.S. National Library of Medicine, Bethesda, Maryland. Public domain.)

Two men and a woman are sitting around a table drinking to their health; the man on the right suffers from gout. The man on the left, holding a glass of alcohol, claims "This good Appetite gives [sic]." The woman in the middle, holding a glass of alcohol, adds, "Cures the vapors also." The snarling man on the right, also holding a glass of alcohol, asks, "Will it Cure the Cursed Pain I have got in my toe?" Artist William Heath (1795-1840), London, 1810. (Source: Courtesy of the U.S. National Library of Medicine, Bethesda, Maryland. Public domain.)

The bum drinks the alcohol from the cigar lighter. A bowery is a city district known for cheap bars and derelicts. The Strobridge Lithographing Company, Cincinnati and New York. (Source: Courtesy of the U.S. Library of Congress, Washington, D.C. Public domain.)

Two cartoon panels illustrate the effects of overindulging in alcohol. "Night" (left panel) depicts a laughing man with friends seated at a table set with decanters labeled "Port" and "Sherry," holding a goblet of wine in his raised right hand and fruit in his left hand. "Morning" (right panel) depicts the same man lying in bed tormented by two imp-like figures personifying wine; "Sherry" hammers the man's head while "Port" prods his stomach with a red-hot poker. This indicates some of the symptoms of a hangover: headache and nausea. Published by Thomas McLean in London in the 1830s. (Source: Courtesy of the U.S. National Library of Medicine, Bethesda, Maryland. Public domain.)

Designed and engraved by John Warner Barber (1798-1885). Print shows a man identified as "King Alcohol" and a skeleton representing Death standing on barrels labeled "Strong Beer, Wines, Rum, Gin, Brandies, Whiskies, compounded liquors," with "social class" and "moderate drinkers" on the left, as well as the "suicide and murderous fighter," and on the right, the "dead and drunken," their broken families, ruined homes, and their graves. "Hope" at lower left mourns the "60,000 annually in the U.[S.] States." "King Alcohol" holds a tankard in his raised right hand with a snake coiled around his arm; printed above is a reference to Proverbs XXIII 32 ("In the end, it will bite like a snake and poison like a viper."). (Source: Courtesy of the U.S. Library of Congress, Washington, D.C. Public domain.)

Drawing from between 1860 and 1902. Artist Thomas Nast (1840-1902). Forms part of the Cabinet of American illustration (Library of Congress). (Source: Courtesy of the U.S. Library of Congress, Washington, D.C. Public domain.)

Motion picture poster for "Absinthe" shows a man seated, with hand on head, at table with three glasses of absinthe. Metropolitan Division, U.S. Lithograph Company. (Source: Courtesy of the U.S. Library of Congress, Washington, D.C. Public domain.)

Anti-alcohol poster sponsored by the U.S. National Institute on Alcohol Abuse and Alcoholism, 1975. (Source: Courtesy of the U.S. Library of Congress, Washington, D.C. Public domain.)

Painted by Francis William Edmonds (1806-1863) and engraved by Thomas Doney (active 1844-1852). Print showing a man in a woodworking shop sitting in front of a bottle of alcohol resting on a shelf in a window. (Source: Published by R.F. Fraser, New York, c1846. Courtesy of the U.S. Library of Congress, Washington, D.C. Public domain.)

Anti-alcohol poster sponsored by the U.S. National Institute on Alcohol Abuse and Alcoholism, 1973. (Source: Courtesy of the U.S. Library of Congress, Washington, D.C. Public domain.)

Death, appearing as a doctor with a top hat and cane, is standing before a stout man sitting in a chair. The man is holding a glass, and on the table next to him are the remnants of overindulgence. Cartoon by French artist Joseph Guillaume Bourdet (1799-1869), 183-. (Source: Courtesy of the U.S. National Library of Medicine, Bethesda, Maryland. NLM Unique ID: 101393102. Public domain.)

From engraver and publisher Johann Theodor de Bry (1561-1623), after Nicolaas Braeu, after Flemish painter Karel van Mander (1548-1606), 1596. Title: [The epicurians celebrate this rite from a herd of swine]. From: Emblemata Saecularia [Secular emblems], 1596. A drunken young man lies vomiting in a ditch. He is held by his buddy, who points to two men carrying away a large barrel of beer in the background. Two sober barrel carriers are able to carry a full barrel of beer, while a drunkard cannot tolerate anything (anymore). The moral: beware of intemperate drinking with all the bad consequences that entails. Emblem No. 14 in Emblemata Saecularia (1596) and no. 35 in the second edition (1611). (Source: Courtesy of the Rijkmuseum, Amsterdam, The Netherlands. Object number RP-P-BI-5200. Public domain.)

Death is pouring alcohol down the throat of an alcoholic while another man next to him vomits from drinking too much. Copy of a print by German-Swiss painter and printmaker Hans Holbein the younger (c1497-1543) from 1538. First published in: Imagines mortis... (Images of death). Lyon: Johannes Frellon, 1547. (Source: Courtesy of the Rijkmuseum, Amsterdam, The Netherlands. Object number RP-P-OB-21.777[V]. Public domain.)

Anonymous, after George Cruikshank. Print against the abuse of alcoholic beverages, ca 1867-1868. Under a tree composed of liquor barrels and green snakes, all kinds of different people collect the poisonous drink in their glass. In the foreground, victims lie drunk or dead on the ground. In the background, a large laughing devil with the inscription “Strong drink / People's cancer.” (Source: Courtesy of the Rijkmuseum, Amsterdam, The Netherlands. Object number RP-P-1962-352. Public domain.)

People reaching for alcoholic drink falling from a pile of barrels of liquor likened to the upas tree; skeletons litter the ground. Alcohol is compared to the upas tree, a poisonous tree allegedly fatal to approach with sap that is used as arrow poison. Colored etching by British caricaturist and book illustrator George Cruikshank (1792-1878), c1842. (Source: Courtesy of the Wellcome Library, London, UK. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

A large bottle labeled "Absinthe" leans to one side. Death sits on the bottle and pours alcohol into a goblet held by a man while dangling a spider over the man's head. Acts of insanity, murder, and suicide resulting from alcoholism are depicted. (Source: Harper's Weekly 1883;27:592. Courtesy of the U.S. National Library of Medicine, Bethesda, Maryland. Public domain. Figure edited by Dr. Douglas Lanska.)

Sitting under grapevines heavy with fruit is Podagra who, though looking like the wise philosopher, personifies the excess represented by Venus and Bacchus who are sitting beside him. Note the cane for Podagra (gout) and the large glass of alcohol (presumably wine) for Bacchus. (Source: From the frontispiece of Scriptum apologetico-politicum de podagra oder das so benahmte ... Zipperlein (1687) by Johann Andreas Schlegel [fl 1657-1681]. Courtesy of the U.S. National Library of Medicine, Bethesda, Maryland. Public domain. Figure edited and cropped by Dr. Douglas Lanska.)

"Commit him for manslaughter in the greatest degree." Shows an unhappy bottle of rum in a prison yard with a chain on its ankle carrying two buckets of water. (Source: Harper's Weekly 1874;18:264. Courtesy of the U.S. National Library of Medicine, Bethesda, Maryland. Public domain. Figure edited by Dr. Douglas Lanska.)

Experienced Party: "No, it isn't regular drinking that hurts a man; it's this way you fellers have of drinking between drinks." (Source: Harper's Weekly 1865;9:32. Courtesy of the U.S. National Library of Medicine, Bethesda, Maryland. Public domain. Figure edited by Dr. Douglas Lanska.)

(Source: Harper's Weekly 1870;14:344. Courtesy of the U.S. National Library of Medicine, Bethesda, Maryland. Public domain.)

Man with bottle in his back pocket looking at his black eye in mirror. Stereo image by Ingersoll View Company, St Paul, Minnesota, c1902. (Source: Courtesy of the U.S. Library of Congress, Washington, D.C. Public domain.)

Man with a black eye and a bottle in back pocket, in a stuporous condition looking into mirror. Stereo image by Ingersoll View Company, St Paul, Minnesota, c1902. (Source: Courtesy of the U.S. Library of Congress, Washington, D.C. Public domain.)

(A) The sleeve gastrectomy (SG) group included 12 women, and the control group included nine women. (B and D) Area under the curve (AUC) for concentration-time curves for both groups. Whiskers indicate the standard error of the mean. The "a" indicates that the AUC value for the sleeve gastrectomy group was significantly different from the control group at p<.05. (C) Sleeve gastrectomy and control group participants were matched on time-to-peak blood alcohol concentrations (BAC). Analysis was conducted among seven women from each group. (E and F) Individual BAC curves. (Source: Seyedsadjadi N, Acevedo MB, Alfaro R, et al. Site of alcohol first-pass metabolism among women. JAMA Netw Open 2022;5[3]:e223711. Erratum in: JAMA Netw Open 2022;5[4]:e2212773. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Average annual number of deaths from excessive alcohol use by age group and period among males (A) and females (B). Deaths from excessive alcohol use includes all decedents whose deaths were attributed to conditions that were fully caused by alcohol use, alcohol-related acute causes of death that involved binge drinking, and alcohol-related chronic conditions that involved medium (females: more than one but less than two drinks; males: more than two but less than four drinks) or high (females: more than two drinks; males: more than four drinks) daily average drinking levels. (Source: Esser MB, Leung G, Sherk A, et al. Estimated deaths attributable to excessive alcohol use among U.S. adults aged 20 to 64 years, 2015 to 2019. JAMA Netw Open 2022;5[11]:e2239485. Public domain.)

Estimated percentage of total deaths attributable to excessive alcohol use among adults aged 20 to 49 years, United States, 2015 to 2019. (Source: Esser MB, Leung G, Sherk A, et al. Estimated deaths attributable to excessive alcohol use among U.S. adults aged 20 to 64 years, 2015 to 2019. JAMA Netw Open 2022;5[11]:e2239485. 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.)

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.)

Abbreviations: hMATE, human multidrug and toxin extrusion protein; OCT, organic cation transporter; RFC, reduced folate carrier; T+, free thiamine; TDP, thiamine diphosphate; ThTR, thiamine transporter; TMP, thiamine monophosphate. (Source: Ott M, Werneke U. Wernicke's encephalopathy: from basic science to clinical practice. Part 1: Understanding the role of thiamine. Ther Adv Psychopharmacol 2020;10:2045125320978106. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(Source: Ott M, Werneke U. Wernicke's encephalopathy: from basic science to clinical practice. Part 1: Understanding the role of thiamine. Ther Adv Psychopharmacol 2020;10:2045125320978106. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(Source: Ott M, Werneke U. Wernicke's encephalopathy: from basic science to clinical practice. Part 1: Understanding the role of thiamine. Ther Adv Psychopharmacol 2020;10:2045125320978106. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Abbreviations: α-KGDH, alpha-ketoglutarate dehydrogenase; BCAKDH, branched chain alpha-keto acid dehydrogenase; HOACol, 2-hydroxyacyl CoA lyase 1; OCT, organic cation transporter; PDHG, pyruvate dehydrogenase; RFC, reduced folate carrier; T+, free thiamine; TDP, thiamine diphosphate; ThTR, thiamine transporter; TK, thiamine kinase; TMP, thiamine monophosphate; TPC, mitochondrial thiamine pyrophosphate carrier; TTP, thiamine triphosphate. (Source: Ott M, Werneke U. Wernicke's encephalopathy: from basic science to clinical practice. Part 1: Understanding the role of thiamine. Ther Adv Psychopharmacol 2020;10:2045125320978106. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Abbreviations: H+, hydrogen ion (proton); OCT, organic cation transporter; RFC, reduced folate carrier; T+, free thiamine; TDP, thiamine diphosphate; ThTR, thiamine transporter; TMP, thiamine monophosphate; TPPT, colonic thiamine pyrophosphate transporter; TTP, thiamine triphosphate. (Source: Ott M, Werneke U. Wernicke's encephalopathy: from basic science to clinical practice. Part 1: Understanding the role of thiamine. Ther Adv Psychopharmacol 2020;10:2045125320978106. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Abbreviations: AP, alkaline/acid phosphatases; H+, hydrogen ion (proton); OCT, organic cation transporter; RFC, reduced folate carrier; T+, free thiamine; TDP, thiamine diphosphate; ThTR, thiamine transporter; TMP, thiamine monophosphate; TTP, thiamine triphosphate. (Source: Ott M, Werneke U. Wernicke's encephalopathy: from basic science to clinical practice. Part 1: Understanding the role of thiamine. Ther Adv Psychopharmacol 2020;10:2045125320978106. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Red arrows, thiamine- and magnesium-dependent reactions; black arrows, reactions not dependent on thiamine. Abbreviations: α-KGDH, alpha-ketoglutarate dehydrogenase; BCAKDH, branched-chain alpha-keto acid dehydrogenase; F6P, d-fructose 6-phosphate; G3P, d-glyceraldehyde 3-phosphate; G6P, d-glucose 6- phosphate; HOACol, 2-hydroxy acyl-CoA lyase 1; PDHG, pyruvate dehydrogenase complex; TKL, transketolase. (Source: Ott M, Werneke U. Wernicke's encephalopathy: from basic science to clinical practice. Part 1: Understanding the role of thiamine. Ther Adv Psychopharmacol 2020;10:2045125320978106. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Notes: *In red blood cells. #Thiamine phosphate esters are hydrolyzed by various phosphatases and nucleotide diphosphatases. (Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Thiamine in the form of thiamine diphosphate (TDP) is required as a cofactor for pyruvate dehydrogenase (PDH) and alpha-ketoglutaric acid dehydrogenase (KGDH), both key enzymes in Krebs cycle. Abbreviations: KGDH, alpha-ketoglutaric acid dehydrogenase; Mg2+, magnesium ion; PDH, pyruvate dehydrogenase; TDP, thiamine diphosphate. (Source: Maguire D, Talwar D, Burns A, et al. A prospective evaluation of thiamine and magnesium status in relation to clinicopathological characteristics and 1-year mortality in patients with alcohol withdrawal syndrome. J Transl Med 2019;17[1]:384. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Pseudo‐hypoxic dysregulation of glucose metabolism with increased production of lactate and excitatory glutamate in patients with alcohol withdrawal syndrome. Thiamine or magnesium deficiency may compromise thiamine-dependent enzymes and result in altered metabolism of glucose and increased lactate production. In the context of normal tissue oxygen concentrations and in the absence of an inflammatory response or intense skeletal muscle activity, thiamine or magnesium deficiency may produce a pseudo-hypoxic disruption of normal glucose metabolism resulting in increased metabolism of glucose to lactate. (Source: Maguire D, Talwar D, Burns A, et al. A prospective evaluation of thiamine and magnesium status in relation to clinicopathological characteristics and 1-year mortality in patients with alcohol withdrawal syndrome. J Transl Med 2019;17[1]:384. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Coronal FLAIR sequence showing increased signal intensity around the periventricular region of the third ventricle in Wernicke-Korsakoff encephalopathy. (Source: Palmirotta C, Turi G, Tagliente S, Pansini M, De Trane S, Lagravinese G. The effects of intensive rehabilitation combined with thiamine treatment on cognitive recovery in a case of non-alcoholic Wernicke-Korsakoff syndrome. Neurol Int 2024;16[1]:263-73. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Axial FLAIR sequence showing increased signal intensity of the periventricular region of the third ventricle in Wernicke-Korsakoff encephalopathy. (Source: Palmirotta C, Turi G, Tagliente S, Pansini M, De Trane S, Lagravinese G. The effects of intensive rehabilitation combined with thiamine treatment on cognitive recovery in a case of non-alcoholic Wernicke-Korsakoff syndrome. Neurol Int 2024;16[1]:263-73. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Axial FLAIR sequence showing increased signal intensity of the colliculi in Wernicke-Korsakoff encephalopathy. (Source: Palmirotta C, Turi G, Tagliente S, Pansini M, De Trane S, Lagravinese G. The effects of intensive rehabilitation combined with thiamine treatment on cognitive recovery in a case of non-alcoholic Wernicke-Korsakoff syndrome. Neurol Int 2024;16[1]:263-73. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Axial FLAIR sequence showing increased signal intensity of the mammillary bodies in Wernicke-Korsakoff encephalopathy. (Source: Palmirotta C, Turi G, Tagliente S, Pansini M, De Trane S, Lagravinese G. The effects of intensive rehabilitation combined with thiamine treatment on cognitive recovery in a case of non-alcoholic Wernicke-Korsakoff syndrome. Neurol Int 2024;16[1]:263-73. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Age- and sex-adjusted cumulative mortality due to alcohol-related causes in patients with Wernicke-Korsakoff syndrome (WKS) and alcohol-related dementia (ARD) from a nationwide register study in Finland. Cumulative mortality was calculated in the presence of competing events, where other causes of death were considered competing risks. Abbreviation: HR: hazard ratio. (Source: Palm A, Talaslahti T, Vataja R, et al. Antipsychotic use and mortality in persons with alcohol-related dementia or Wernicke-Korsakoff syndrome: a nationwide register study in Finland. J Clin Med 2023;12[13]:4263. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Age- and sex-adjusted subhazard ratio (sHR) in patients with Wernicke-Korsakoff syndrome (WKS) and alcohol-related dementia (ARD) compared with antipsychotic non-users, stratified by causes of death (ICD-10 diagnosis groups). The value for antipsychotic non-users is represented by the dotted line (ie, the line extending vertically from 1 on the x-axis). A competing risks regression model was used to calculate age- and sex-adjusted subhazard ratios, where other causes of death were considered competing risks. (Source: Palm A, Talaslahti T, Vataja R, et al. Antipsychotic use and mortality in persons with alcohol-related dementia or Wernicke-Korsakoff syndrome: a nationwide register study in Finland. J Clin Med 2023;12[13]:4263. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Age- and sex-adjusted cumulative mortality in patients with Wernicke-Korsakoff syndrome (WKS) and alcohol-related dementia (ARD) from a nationwide register study in Finland. Abbreviation: HR: hazard ratio. (Source: Palm A, Talaslahti T, Vataja R, et al. Antipsychotic use and mortality in persons with alcohol-related dementia or Wernicke-Korsakoff syndrome: a nationwide register study in Finland. J Clin Med 2023;12[13]:4263. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

The "watch out!" sign is a neuroradiological sign proposed to rapidly recognize the lesional pattern of subcallosal ischemia or infarction. This is best visualized on axial diffusion-weighted imaging sequences in the acute phase (Holla VV, Pene SS, Rakesh Sharma MN. Acute amnestic syndrome: "watch out" for fornix infarct. Neurol India 2020;68[2]:498-9). Concomitant involvement in the territory of the recurrent artery of Heubner can occur in association with subcallosal artery ischemia. (Source: Mazzacane F, Ferrari F, Malvaso A, et al. Acute amnestic syndrome in fornix lesions: a systematic review of reported cases with a focus on differential diagnosis. Front Neurol 2024;15:1338291. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

"Goblet" sign is a neuroradiological sign proposed to rapidly recognize the lesional pattern of subcallosal ischemia or infarction. This is best visualized on axial diffusion-weighted imaging (DWI) sequences in the acute phase (Pardina-Vilella L, Pinedo-Brochado A, Vicente I, et al. The goblet sign in the amnestic syndrome of the subcallosal artery infarct. Neurol Sci 2018 Aug;39[8]1463-5). Concomitant involvement in the territory of the recurrent artery of Heubner can occur in association with subcallosal artery ischemia. (Source: Mazzacane F, Ferrari F, Malvaso A, et al. Acute amnestic syndrome in fornix lesions: a systematic review of reported cases with a focus on differential diagnosis. Front Neurol 2024;15:1338291. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Transient global amnesia (A, B), Wernicke-Korsakoff syndrome (C, D), limbic encephalitis (E, F), and lymphoma (G, H) can present with acute anterograde amnesia, with or without other neurologic symptoms. Bilateral hippocampal punctate diffusion lesions in a case of transient global amnesia are shown in (A) fluid-attenuated inversion recovery (FLAIR) and (B) diffusion-weighted imaging (DWI). In alcoholic Wernicke-Korsakoff syndrome, tectal plate lesions are shown in FLAIR and DWI sequences (C, D). In paraneoplastic limbic encephalitis, MRI shows bilateral hyperintensity of the hippocampi on both FLAIR (E) and DWI (F) sequences. A CNS lymphoma involving the fornix, frontal lobes, and periventricular white matter is shown in (G) (FLAIR) and (H) (DWI), appearing as a diffuse hyperintense alteration on both sequences. (Source: Mazzacane F, Ferrari F, Malvaso A, et al. Acute amnestic syndrome in fornix lesions: a systematic review of reported cases with a focus on differential diagnosis. Front Neurol 2024;15:1338291. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

FLAIR sequence in a patient with acute ischemic stroke of the fornix acquired at symptom onset shows subtle symmetrically increased signal intensity and swelling of the columns of the fornix. (Source: Mazzacane F, Ferrari F, Malvaso A, et al. Acute amnestic syndrome in fornix lesions: a systematic review of reported cases with a focus on differential diagnosis. Front Neurol 2024;15:1338291. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Diffusion-weighted imaging sequence in a patient with acute ischemic stroke of the fornix acquired at symptom onset shows symmetrically increased signal intensity and swelling of the columns of the fornix. (Source: Mazzacane F, Ferrari F, Malvaso A, et al. Acute amnestic syndrome in fornix lesions: a systematic review of reported cases with a focus on differential diagnosis. Front Neurol 2024;15:1338291. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

FLAIR sequence, obtained 1 month after onset of acute ischemic stroke of the fornix, shows gliotic lesions involving the columns of the fornix, the corpus callosum, and the right caudate nucleus. (Source: Mazzacane F, Ferrari F, Malvaso A, et al. Acute amnestic syndrome in fornix lesions: a systematic review of reported cases with a focus on differential diagnosis. Front Neurol 2024;15:1338291. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

(Source: Mazzacane F, Ferrari F, Malvaso A, et al. Acute amnestic syndrome in fornix lesions: a systematic review of reported cases with a focus on differential diagnosis. Front Neurol 2024;15:1338291. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

Diffusion-weighted imaging sequence in a patient with acute ischemic stroke of the fornix shows restricted diffusion involving the columns of the fornix, the corpus callosum, and the right caudate nucleus. These structures are included in the vascular territory of the subcallosal artery (ie, fornix and corpus callosum) and the right recurrent artery of Heubner (ie, caudate head). (Source: Mazzacane F, Ferrari F, Malvaso A, et al. Acute amnestic syndrome in fornix lesions: a systematic review of reported cases with a focus on differential diagnosis. Front Neurol 2024;15:1338291. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

The Papez circuit plays a critical role in the processing and transfer of information for long storage (Papez JW. A proposed mechanism of emotion. 1937. J Neuropsychiatry Clin Neurosci 1995;7[1]:103-12.). The Papez circuit begins in the hippocampus (A) and continues sequentially to the fornix (B), the mamillary body (C), and then through the mammillothalamic tract to the anterior nucleus of the thalamus (D). From there it connects to the cingulate gyrus (E) through anterior thalamic radiations. The cingulum (F) courses around the corpus callosum to reach the entorhinal cortex (I), which projects to the hippocampus (A), completing the circuit (Shah A, Jhawar SS, Goel A. Analysis of the anatomy of the Papez circuit and adjoining limbic system by fiber dissection techniques. J Clin Neurosci 2012;19[2]:289-98.). (Source: Mazzacane F, Ferrari F, Malvaso A, et al. Acute amnestic syndrome in fornix lesions: a systematic review of reported cases with a focus on differential diagnosis. Front Neurol 2024;15:1338291. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

The patient demonstrates the Earth buttons exercise that helps in improving mental alertness and whole-body orientation. This is often used as a gym exercise in early elementary education. The patient is asked to place his right hand on his lips and his left hand on his navel and then to use his hands to perform small, circular motions. (Source: Burile GC, Arya N, Seth NH, Fating T. Rehabilitation strategies for Wernicke-Korsakoff syndrome: physiotherapy interventions and management approaches. Cureus 2024;16[2]:e53948. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

A therapist assisting a patient with Korsakoff syndrome in performing Frenkel’s exercise in standing and reaching for the objects to which the therapist points. Frenkel's exercises are a series of gradual progressive exercises designed to increase coordination and used to retrain proprioception, particularly focused on the lower limbs. (Source: Burile GC, Arya N, Seth NH, Fating T. Rehabilitation strategies for Wernicke-Korsakoff syndrome: physiotherapy interventions and management approaches. Cureus 2024;16[2]:e53948. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

A patient with Korsakoff syndrome performing fine motor movements on a peg board. (Source: Burile GC, Arya N, Seth NH, Fating T. Rehabilitation strategies for Wernicke-Korsakoff syndrome: physiotherapy interventions and management approaches. Cureus 2024;16[2]:e53948. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

A therapist assisting a patient with Korsakoff syndrome while performing fine motor movements to improve motor function. (Source: Burile GC, Arya N, Seth NH, Fating T. Rehabilitation strategies for Wernicke-Korsakoff syndrome: physiotherapy interventions and management approaches. Cureus 2024;16[2]:e53948. 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.)

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.)

MRI sequences demonstrating chronic infarcts of the inferior frontal gyrus bilaterally (R: Right, L: Left). (Source: Milanlioglu A, Aydın MN, Gökgül A, Hamamcı M, Erkuzu MA, Tombul T. Ischemic bilateral opercular syndrome. Case Rep Med 2013;2013:513572. 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.)

An 81-year-old right-handed man presented with acute sound volume loss, inability to swallow and speak, inability to move his tongue, and difficulty chewing food. His past medical history was remarkable for a prior stroke, diabetes mellitus, hypertension, and coronary artery disease. Four years previously he had a right hemiparesis but recovered fully. Diffusion-weighted magnetic resonance imaging demonstrating right frontal opercular restricted diffusion diagnosed as acute opercular infarct (R: Right, L: Left). (Source: Milanlioglu A, Aydın MN, Gökgül A, Hamamcı M, Erkuzu MA, Tombul T. Ischemic bilateral opercular syndrome. Case Rep Med 2013;2013:513572. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

A 48-year-old man with diabetes and hypertension had right-sided hemiplegia 1 year before he developed Foix-Chavany-Marie syndrome acutely 2 days before admission. CT of the brain showed bilateral infarcts in the posterior limb of the internal capsule (shown in blue arrow and red circle). (Source: Sanker V, Srinivasan A, Emara M, Jagannath P, Mathew R. Atypical presentations of Foix-Chavany-Marie syndrome (FCMS) in stroke. Cureus 2023;15[4]:e38030. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

A 66-year-old man with diabetes, hypertension, and tobacco use had right-sided hemiplegia 1 year before he developed Foix-Chavany-Marie syndrome acutely 2 days before admission. CT of the brain showed an acute left perisylvian infarct and a chronic right internal capsular anterior limb infarct (shown in blue arrow and red circles). (Source: Sanker V, Srinivasan A, Emara M, Jagannath P, Mathew R. Atypical presentations of Foix-Chavany-Marie syndrome (FCMS) in stroke. Cureus 2023;15[4]:e38030. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0.)

A 19-year-old patient developed cardiac arrest. When extubated, she was noted to be cortically blind. Diffusion-weighted MRI and corresponding ADC map (6 days after cardiac arrest) showed evidence for extensive predominantly cortical diffusion restriction most prominent in the right occipital cortex and bilateral basal ganglia. (Contributed by Dr.Sangeeta Khanna.)

(Contributed by Dr. Alexander Y Kim.)

(Contributed by Dr. Anand Viswanathan.)

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.)

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.)

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.)

(Photograph courtesy of the U.S. National Library of Medicine, Bethesda, Maryland. Public domain.)

(Photograph courtesy of the U.S. National Library of Medicine, Bethesda, Maryland. Public domain.)

Coronal section of cerebral MRI FLAIR sequence showing hyperintense signal change of the mammary bodies in a 66-year-old man with Wernicke encephalopathy complicating prolonged parenteral nutrition. (Source: Slim S, Ayed K, Triki W, et al. Gayet-Wernicke's encephalopathy complicating prolonged parenteral nutrition in patient treated for colonic cancer - a case report. BMC Nutr 2022;8[1]:83. Creative Commons Attribution 4.0 International [CC BY 4.0] license, creativecommons.org/licenses/by/4.0. Image cropped from original.)

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) 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.)

(Contributed by Dr. Marissa Natelson Love.)

Semantic variant primary progressive aphasia (Contributed by Dr. Marissa Natelson Love.)

FDG-PET hypometabolism in the frontal and temporal lobes mapped onto structural MRI. (Contributed by Dr. Marissa Natelson Love.)

Nonfluent agrammatic variant primary progressive aphasia. (Contributed by Dr. Marissa Natelson Love.)

In humans, upper motor neurons (blue) descend from the motor cortex and project onto the brainstem and spinal cord via the corticospinal tract. These corticospinal neurons form a monosynaptic pathway (in primates and humans) that innervates lower motor neurons (orange), which in turn transmit motor signals to effector muscles. Together this forms the motor circuitry within humans. Neurophysiological impairments leading to amyotrophic lateral sclerosis can arise in the corticospinal tract at various loci. In amyotrophic lateral sclerosis, cortical dysfunction ranges from hyperexcitability (increased excitability) as a result of increased excitatory signaling or reduced inhibition, disruption of synaptic vesicle dynamics, and impaired synaptic plasticity that also extends to cortico-hippocampal connections. Within the corticospinal tract, upper motor neurons are vulnerable to synaptic loss and dendrite pathology including loss of dendritic spines that may arise from increased hyperexcitability. In a feedforward mechanism of dysfunction, degeneration of lower motor neurons is mediated, at least in part, via glutamate-mediated excitotoxicity whereby, cortical dysfunction precedes that of lower motor neurons, potentially causing further neurophysiological impairments and injury in lower motor neurons. (Reproduced with author permission from: Pasniceanu IS, Atwal MS, Souza CD, et al. Emerging mechanisms underpinning neurophysiological impairments in C9ORF72 repeat expansion-mediated amyotrophic lateral sclerosis/frontotemporal dementia. Front Cell Neurosci 2021;15: 784833.)

The interaction between dipeptide repeat polypeptides (DPRs), tethering of mitochondria to the endoplasmic reticulum by the VAPB-PTPIP51 tethering proteins, calcium and glycogen synthase beta gene (GSK-3b), resulting in impaired synaptic function and neurodegeneration in C9orf72 mutations ALS-FTD. (Contributed by Dr. Peter K Panegyre.)

Three modes of action currently link phase separation to pathology with the potential to serve as pathways for intervention. (A) The phase boundary, a metric for the propensity to phase-separate, is defined by the saturation concentration and the relative interaction strengths between molecules. (B) Material properties of condensed phases include viscoelasticity, reversibility of exchange, and the dynamics and mobility of molecules within and across droplets. (C) Fiber formation may be nucleated within droplets, potentially giving rise to pathology. These three modes of action, which are sensitive to disease-associated conditions, highlight distinct avenues for regulation and therapeutic targeting of liquid phase separation in disease. (Reproduced with author permission from: Elbaum-Garfinkle, S. Matter over mind: Liquid phase separation and neurodegeneration. J Biol Chem 2019;294(18):7160-68.)

(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.)

(1) Alcohol consumed, (2) alcohol crosses into the placenta, (3) alcohol metabolizes, (4) byproducts of alcohol metabolism are detected in meconium. When alcohol crosses through the placenta, it is circulated throughout the fetus. Alcohol then metabolizes in the tissue. Byproducts of alcohol metabolism are formed in the fetus and have been detected in the meconium, the first feces of a newborn. Alcohol particularly affects the heart and brain and interferes with the fetus receiving sufficient oxygen and nourishment. Note: Fatty acid ethyl esters (FAEEs) are formed in the body by esterification of ethanol with free fatty acids and transesterification of glycerides. (Illustration by Grace Martin on June 7, 2019. Creative Commons Attribution-Share Alike 4.0 International License, https://creativecommons.org/licenses/by-sa/4.0/deed.en. Relabeled by Dr. Douglas J Lanska.)

(Source: Substance Abuse and Mental Health Services Administration, US Department of Health and Human Services, November 2015.)

(Source: Wikimedia Commons. Image edited by Dr. Douglas J Lanska.)

(Source: Prints and Photographs Division, Library of Congress, Washington, DC. Image edited by Dr. Douglas J Lanska.)

A saloon keeper in front of a morbid saloon window display. The window display sign says: "SHOW WINDOW EXHIBIT. WHAT OUR LIQUORS CAN DO. GENUINE SPECIMENS MADE ON THE PREMISES." In the window display are five people, four labeled with their alcohol-induced problems: madman, tramp, convict, and idiot child (fetal alcohol syndrome). The fifth person, a woman, appears depressed or confused. (Source: "Blasts" from the Ram's Horn. Chicago, The Ram's Horn Co., 1902.)

The Latin expression "Facilis descensus Averni: sed revocare gradum, Hoc opus, hic labor est." is translated below as "The descent to Perdition is easy--but to retrace one's steps--this is labor--this a task severe." The work is anonymous although the line below the image states: "Engraved by a celebrated London artist." The poem at the bottom reads as follows:

Behold! the soulless wretch—destroyer of his race—
In adamantine Chains—no more to show his face—
His Cup of Sin is full—fast flowing o'er the drim—
His light is quite extinct—there is no hope for him—
Companion of the worm—the victim od despair—
Lost to human sympathy—lost to Christian prayer—
Persued by wrath divine—hurled from the realms of light—
He sinks into the abyss—of one, eternal night. —

(Source: Alcohol, Temperance & Prohibition. Brown Digital Repository. Brown University Library, https://repository.library.brown.edu/studio/item/bdr:30155. Public domain.)

Hand-colored engraving by John Warner Barber (1798-1885), printed in New Haven, Connecticut. Biblical quotations above the image: "The drunkard shall come to poverty. Proverbs 23 Chap. 21 v." [Proverbs 23:21] and "The wages of Sin is Death. Romans 6 Chap. 23 v." [Romans 6:23]. There is an auction sign on the house, ordered by the sheriff. The family is evicted and departing with the wife in tears. Below the image is a recitation of the outcomes of alcoholism: "Poverty, Wretchedness, a Curse and Burden upon Society, Want, Beggary, Pauperism, Death." (Source: Printed Ephemera Collection, Prints and Photographs Division, Library of Congress, Washington, DC. Image edited by Dr. Douglas J Lanska.)

Hand-colored engraving by John Warner Barber (1798-1885), printed in New Haven, Connecticut. Biblical quotation above the image: "Who hath wo? Who hath sorrow? Who hath contentions? Who hath wounds without cause? ... They that tarry long at the wine. Prov. 23" [Proverbs 23]. The father is intoxicated on the floor, while his wife and children are afraid, and the home is falling apart. Below the image is a recitation of the effects of alcoholism: "Beastly Intoxication, Loss of Character, Loss of Natural Affection, Family Suffering, Brutality, Misery, Disease, Mortgages, Sheriffs, Writs &c." (Source: Printed Ephemera Collection, Prints and Photographs Division, Library of Congress, Washington, DC. Image edited by Dr. Douglas J Lanska.)

Hand-colored engraving by John Warner Barber (1798-1885), printed in New Haven, Connecticut. Biblical quotation above the image: "Wo unto them that are mighty to drink wine, and men of strength to mingle Strong Drink... Isaiah 5C.22v." [Isaiah 5:22]. Two men are drinking at a saloon, while two are brawling, one is vomiting, and one is unconscious on a bench. Below the image is a recitation of the continuation of alcoholism: "Bad Company, Profaneness, Cursing and Swearing, Quarreling & Fighting, Gambling, Obscenity, Ridicule and Hatred of Religion, The Gate of Hell."(Source: Printed Ephemera Collection, Prints and Photographs Division, Library of Congress, Washington, DC. Image edited by Dr. Douglas J Lanska.)

Hand-colored engraving by John Warner Barber (1798-1885), printed in New Haven, Connecticut. Biblical quotation above the image: "Wo unto them that rise up early in the morning that they may follow Strong Drink... Isa 5 C. 11v." [Isaiah 5:11]. The father is drinking at 8 AM, ignoring his wife and children. The sign by the liquor cabinet reads "Dr ____'s Celebrated Bitters, an infallible Remedy for Coughs, Colds, Consumptions, Asthma, Contiveness, Dropsy, Jaunders [Jaudice], Sore Eyes, Scalds, Bruises, Burns, &c. Directions: Drink one glass in the Morning. Beware of Counterfeits..." Below the image is a recitation of the beginning of alcoholism: "The Beginning of Sorrow, Neglect of Business, Idleness, Languor, Loss of Appetite, Dulness and Heaviness, a love of Strong Drink increasing. (Source: Printed Ephemera Collection, Prints and Photographs Division, Library of Congress, Washington, D.C. Image edited by Dr. Douglas J Lanska.)

Hogarth's engraving, published according to Act of Parliament on February 1, 1751 in support of what would become the "Gin Act," shows a poor London street (the area depicted is St. Giles, London) strewn with hopeless drunkards and lined with gin shops and a flourishing pawnbroker. The inhabitants of Gin Lane are being destroyed by their addiction to the foreign spirit of gin, with the engraving illustrating shocking scenes of child neglect, starvation, madness, drunken brawls, and death.

Hogarth's illustration is filled with satirical humor: the pawnbroker's shop depicted is "S. Gripe pawnbroker"; the distillery is "Kilman distillery"; a gin shop sign reads "drunk for a penny, dead drunk for two pence, clean straw for nothing"; and a drunkard's paper is headed "the downfall of Mdam. gin." The poem at the bottom reads as follows:

Gin cursed Fiend, with Fury fraught,
Makes human Race a Prey;
It enters by a deadly Draught,
And steals our Life away.

Virtue and Truth, driv'n to Despair,
It's Rage compells to fly,
But cherishes, with hellish Care,
Theft, Murder, Perjury.

Damn'd Cup! that on the Vitals preys,
That liquid Fire contains
Which Madness to the Heart conveys,
And rolls it thro' the Veins.

At that time, there was no quality control whatsoever and gin was frequently adulterated (eg, with turpentine). When it became apparent that copious gin consumption was causing social problems, social reformers and the government made efforts to control the production of the spirit. The Spirit Duties Act (commonly known as the Gin Act of 1736) imposed high taxes on sales of gin, forbade the sale of gin in quantities of less than two gallons, and required an annual payment of £50 for a retail license. These measures had little effect beyond increasing smuggling and driving the distilling trade underground. The act was repealed by the Gin Act of 1743, which set much lower taxes and fees. (Courtesy of the Wellcome Collection, London, England. 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.)

Apparent diffusion coefficient MRI of the brain in a 52-year-old, right-handed woman shows decreased signal intensity in the left frontal operculum (arrow), confirming an acute left opercular stroke. The increased signal intensity in the right frontal operculum (arrowhead) is consistent with a chronic infarct. (Source: Patel SA, Forrester A, Kang H, Collin E, Patel K. A case of Foix-Chavany-Marie syndrome with asynchronous bilateral opercular infarcts and chronic bilateral cerebellar infarcts. Cureus 2022;14[6]:e26013. Creative Commons Attribution License [CC-BY 4.0].)

Diffusion-weighted MRI of the brain in a 52-year-old, right-handed woman shows increased signal intensity in the region of the left frontal operculum (arrow), indicating an acute stroke. The decreased signal intensity in the right frontal operculum (arrowhead) is from a prior infarct. (Source: Patel SA, Forrester A, Kang H, Collin E, Patel K. A case of Foix-Chavany-Marie syndrome with asynchronous bilateral opercular infarcts and chronic bilateral cerebellar infarcts. Cureus 2022;14[6]:e26013. Creative Commons Attribution License [CC-BY 4.0].)

Coronal images confirm bilateral symmetrical locations of the mammillothalamic tract lesions. The right mammillothalamic tract infarction in this 97-year-old man is located between the right mammillary body and the right anterior thalamic nucleus. The left mammillothalamic tract microbleeds are located between the left mammillary body and the right anterior thalamicnucleus. (Source: Yoneoka Y, Seki Y, Akiyama K. "Vascular" Korsakoff syndrome with bilaterally damaged mammillothalamic tracts: insights into the pathogenesis of "acute" Korsakoff syndrome as acute-onset irreversible anterograde amnesia. Cureus 2021;13(11):e19472. Creative Commons Attribution License [CC-BY 4.0]. Edited by Dr. Douglas Lanska.)

A 97-year-old man presenting with acute-onset “vascular” Korsakoff syndrome with bilaterally damaged mammillothalamic tracts. In the enlarged images, (A) infarction is shown over the right mammillothalamic tract; (B) a microbleed is shown over the left mammillothalamic tract; and (C) FLAIR image shows both the acute, ischemic lesion of the right mammillothalamic tract and the old left mammillothalamic tract lesion. (Source: Yoneoka Y, Seki Y, Akiyama K. "Vascular" Korsakoff syndrome with bilaterally damaged mammillothalamic tracts: insights into the pathogenesis of "acute" Korsakoff syndrome as acute-onset irreversible anterograde amnesia. Cureus 2021;13(11):e19472. Creative Commons Attribution License [CC-BY 4.0].)

A 97-year-old man presenting with acute-onset “vascular” Korsakoff syndrome with bilaterally damaged mammillothalamic tracts. Fluid attenuation inversion recovery (FLAIR) images confirmed bilateral lesions of both mammillothalamic tracts. (Source: Yoneoka Y, Seki Y, Akiyama K. "Vascular" Korsakoff syndrome with bilaterally damaged mammillothalamic tracts: insights into the pathogenesis of "acute" Korsakoff syndrome as acute-onset irreversible anterograde amnesia. Cureus 2021;13(11):e19472. Creative Commons Attribution License [CC-BY 4.0]. Edited by Dr. Douglas J Lanska.)

A 97-year-old man presenting with acute-onset “vascular” Korsakoff syndrome with bilaterally damaged mammillothalamic tracts. T2-weighted images revealed a microbleed scar over the left mammillothalamic tract. (Source: Yoneoka Y, Seki Y, Akiyama K. "Vascular" Korsakoff syndrome with bilaterally damaged mammillothalamic tracts: insights into the pathogenesis of "acute" Korsakoff syndrome as acute-onset irreversible anterograde amnesia. Cureus 2021;13(11):e19472. Creative Commons Attribution License [CC-BY 4.0]. Edited by Dr. Douglas J Lanska.)

A 97-year-old man presenting with acute-onset “vascular” Korsakoff syndrome with bilaterally damaged mammillothalamic tracts. Diffusion-weighted images on admission showed fresh cerebral infarction in the right thalamus involving the right mammillothalamic tract. (Source: Yoneoka Y, Seki Y, Akiyama K. "Vascular" Korsakoff syndrome with bilaterally damaged mammillothalamic tracts: insights into the pathogenesis of "acute" Korsakoff syndrome as acute-onset irreversible anterograde amnesia. Cureus 2021;13(11):e19472. Creative Commons Attribution License [CC-BY 4.0]. Edited by Dr. Douglas J Lanska.)

MRI in a 72-year-old man with pituitary apoplexy demonstrates a sellar and suprasellar heterogeneous lesion with high T1-signal within the mass compatible with acute hemorrhage as well as evidence of laterosellar macroadenoma. (Source: Drissi Oudghiri M, Motaib I, Elamari S, Laidi S, Chadli A. Pituitary apoplexy in geriatric patients: a report of four cases. Cureus 2021;13[12]:e20318. Creative Commons Attribution License [CC-BY 4.0].)

MRI demonstrates enhancement of a sellar and suprasellar heterogeneous lesion in a 72-year-old man with pituitary apoplexy. (Source: Drissi Oudghiri M, Motaib I, Elamari S, Laidi S, Chadli A. Pituitary apoplexy in geriatric patients: a report of four cases. Cureus 2021;13[12]:e20318. Creative Commons Attribution License [CC-BY 4.0].)

MRI in a 72-year-old man with pituitary apoplexy demonstrates a sellar and suprasellar heterogeneous lesion with high T1-signal within the mass compatible with acute hemorrhage. The patient presented with sudden onset of left ptosis with a complete third nerve palsy evident on examination. He underwent endoscopic endonasal transsphenoidal resection of the pituitary adenoma. There were no postoperative complications, and he completely recovered 10 days postoperatively. Anatomopathological examination of the resected tumor showed a nonsecreting pituitary macroadenoma. (Source: Drissi Oudghiri M, Motaib I, Elamari S, Laidi S, Chadli A. Pituitary apoplexy in geriatric patients: a report of four cases. Cureus 2021;13[12]:e20318. Creative Commons Attribution License [CC-BY 4.0].)

CT in a 31-year-old man with pituitary apoplexy precipitated by systemic chemotherapy demonstrates expansion of the sella consistent with a prior slow-growing tumor. (Source: Hamrick FA, Findlay MC, Rennert RC, Budohoski KP, Couldwell WT. Pituitary apoplexy precipitated by systemic chemotherapy. Cureus 2022;14[3]:e23004. Creative Commons Attribution License [CC-BY 4.0].)

MRI from a 31-year-old man with pituitary apoplexy precipitated by systemic chemotherapy demonstrates expansion of the sella consistent with a prior slow-growing tumor. Enhancement of the sphenoid sinus mucosa is also seen (gray arrows), which has been linked to higher intrasellar pressures and more severe pituitary apoplexy. (Source: Hamrick FA, Findlay MC, Rennert RC, Budohoski KP, Couldwell WT. Pituitary apoplexy precipitated by systemic chemotherapy. Cureus 2022;14[3]:e23004. Creative Commons Attribution License [CC-BY 4.0].)

MRI in a 31-year-old man with pituitary apoplexy precipitated by systemic chemotherapy shows a 2.0×2.8×2.1 cm sellar and suprasellar mass with upward displacement of the optic chiasm (white arrow) and internal blood products. (Source: Hamrick FA, Findlay MC, Rennert RC, Budohoski KP, Couldwell WT. Pituitary apoplexy precipitated by systemic chemotherapy. Cureus 2022;14[3]:e23004. Creative Commons Attribution License [CC-BY 4.0].)

MRI in a 31-year-old man with pituitary apoplexy precipitated by systemic chemotherapy shows a 2.0×2.8×2.1 cm sellar and suprasellar mass with upward displacement of the optic chiasm (white arrow) and internal blood products. The pituitary stalk and gland are displaced to the left, best seen on this postcontrast image. There is heterogeneous enhancement of the sellar and suprasellar mass. (Source: Hamrick FA, Findlay MC, Rennert RC, Budohoski KP, Couldwell WT. Pituitary apoplexy precipitated by systemic chemotherapy. Cureus 2022;14[3]:e23004. Creative Commons Attribution License [CC-BY 4.0].)

A 31-year-old man with a recent diagnosis of seminomatous germ cell testicular cancer with metastases to the pelvis and retroperitoneum presented to the emergency department with several days of severe, progressive bifrontal headaches, nausea, and right-sided blurry vision 1 week after initiating chemotherapy (bleomycin, etoposide, and cisplatin). Neurologic examination was normal except for decreased right temporal visual acuity. MRI showed a 2.0×2.8×2.1 cm sellar and suprasellar mass with upward displacement of the optic chiasm (white arrow) and internal blood products. He underwent urgent transnasal transsphenoidal surgery. Pathological analysis showed a partially necrotic and hemorrhagic adenoma with rare growth hormone– and adrenocorticotropic hormone–positive tumor cells, with a low proliferation rate (Mib-1 less than 2%).. (Source: Hamrick FA, Findlay MC, Rennert RC, Budohoski KP, Couldwell WT. Pituitary apoplexy precipitated by systemic chemotherapy. Cureus 2022;14[3]:e23004. Creative Commons Attribution License [CC-BY 4.0].)

(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.)

A 59-year-old woman had severe bilateral vision loss as well as altered sensorium, headaches, and seizures. The blood pressure was 203/180 mmHg. MRI revealed signal abnormality in the bilateral parieto-occipital areas, predominantly in the white matter, without infarction, which is consistent with posterior reversible encephalopathic syndrome. Visual acuity improved following treatment of hypertension. (Contributed by Dr. Sangeeta Khanna.)

A 49-year-old female developed sudden bilateral vision loss after an interventional procedure for embolization for uterine leiomyoma due to thromboembolism. CT revealed hypoattenuating ill-defined areas of low attenuation seen in the occipital lobes bilaterally, more extensive on the right side than the left. MRI showed areas of restricted diffusion with loss of gray-white matter differentiation seen predominantly involving the bilateral occipital lobes. She slowly improved to 20/100 in both eyes with conservative measures. (Contributed by Dr. Sangeeta Khanna.)

MRI demonstrates cerebral edema in affected areas, typically the posterior hemispheres best seen in T2-FLAIR sequence, generally in the absence of restricted diffusion, a sign that would be more characteristic of ischemic infarction. (Contributed by Dr. Sangeeta Khanna.)

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.)

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.)

Coronal T2-weighted MRI image of a left inferior occipital stroke in a patient with pure alexia and right hemianopia. (Contributed by Dr. Jason J S Barton.)

(Contributed by Dr. Jason J S Barton.)

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.)

(Public domain.)

(Public domain.)

(Public domain.)

(Public domain.)

(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.)

P = pathogenic, LP = likely pathogenic, UOA = urine organic acids, VLCFA = very long chain fatty acids. (From: Vanderver A, Bernard G, Helman G, et al. Randomized clinical trial of first-line genome sequencing in pediatric white matter disorders. Ann Neurol 2020;88(1):264-73.)

(Contributed by Deepa Rajan MD.)

This 28-year-old woman presented at 11 years of age with toe walking. She has mild intellectual impairment, emotional difficulties, and anger control problems; severe hypokinetic dysarthria, hypophonia, and drooling; marked bradykinesia and rigidity in the neck and all extremities; postural tremor in both hands; facial, oromandibular, and truncal dystonia; and dystonic posturing of her hands, left worse than the right, with flexion of the metacarpophalangeal and distal interphalangeal joints. When she walks, her toes touch the ground before her heels due to dystonic muscle contractions. MRI of the brain shows hypointensity in the medial globus pallidus on T2-weighted images ("eye-of-the-tiger") and hyperintensity on T1 images consistent with pantothenate kinase-associated neurodegeneration (PKAN), formerly known as Hallervorden-Spatz syndrome. PKAN is caused by a mutation in the PANK2 gene (Schneider SA, Bhatia KP, Hardy J. Complicated recessive dystonia parkinsonism syndromes. Mov Disord 2009;24(4):490-9). This patient is a cousin of two other patients with PKAN, shown in other clips, the 32-year-old man with tongue protrusion and his teenage sister. (Contributed by Dr. Joseph Jankovic.)

A 68-year-old woman presented with deep coma (E1, V1, and M2) of 2 days duration. On examination the patient had pinpoint sluggishly reacting pupils, absence of extraocular movements on oculocephalic maneuvers, ocular bobbing, and bilateral extensor plantar responses. CT of the patient’s brain documented a large pontine hematoma. The patient died on the fourth day of her illness. Ocular bobbing is a distinctive involuntary vertical eye movement seen in comatose patients with pontine lesions. It is characterized by intermittent, often conjugate, rapid downward movement of the eyes, followed by a slow return to mid-position. As compared to jerk nystagmus, ocular bobbing is much slower in frequency, with the slow phases lasting several seconds. Typical ocular bobbing is associated with extensive pontine destruction (infarction, hemorrhage, tumor, central pontine myelinolysis) or extra-axial posterior fossa masses (eg, cerebellar hemorrhage). Neuroanatomic reasons for ocular bobbing are not clear, but both mesencephalic and medullary burst neuron centers may play a part in its genesis (Rosa et al 1987). Some suggest that ocular bobbing is akin to roving eye movements when horizontal gaze has been severely disrupted. Others suggest that it is because of surviving vestibular nuclei (mediating vertical gaze) in the medulla in patients with pontine lesions. (Contributed by Dr. Ravindra Kumar Garg.)

These are two members of a family with Friedreich ataxia and dystonia. Note the ataxia, marked scoliosis (much improved with Harrington rods), high-arched feet, and dystonic writer's cramp. (Contributed by Dr. Joseph Jankovic.)

Photomicrograph of Alzheimer type 2 astrocytes in the cerebral cortex. Alzheimer type 2 astrocytes are pathologic cells found in hepatic encephalopathy and hepatolenticular degeneration (Wilson disease). These pathologic cells have a large vacuolated nucleus with chromatin displaced to one side. In this figure, Alzheimer type 2 astrocytes are shown highlighted by blue ovals. (Photomicrograph by Gambo7, courtesy of Wikimedia Commons. Creative Commons Attribution-Share Alike 4.0 International license.)

Stylized depiction of an activated NMDA receptor. Glutamate is shown in the glutamate-binding site and glycine is shown in the glycine-binding site. The allosteric site, which modulates receptor function when bound to a ligand, is not occupied. NMDA receptors require the binding of two molecules of glutamate or aspartate and two of glycine. (Creative Commons Attribution-Share Alike 3.0 Unported license.)

Schematic structure of a GABA receptor monomeric subunit embedded in a lipid bilayer (yellow lines connected to blue spheres). The four transmembrane alpha-helices (1-4) are depicted as cylinders. The disulfide bond in the N-terminal extracellular domain, which is characteristic of the family of cys-loop receptors (which includes the GABAA receptor), is depicted as a yellow line. (Figure created by Boghog2. Public domain.)

Fluid attenuated inversion recovery weighted MR images showing chronic subdural hematoma on the right side in a patient with an isodense subdural hematoma on CT scan. (Contributed by Dr. Ravindra Kumar Garg.)

Non-enhanced CT showing large chronic subdural hematoma on the right side. There is effacement of the ventricle on the same side along with a midline shift. There is marked cerebral atrophy on the opposite side. Atrophy of the brain, resulting in a space between the brain surface and the skull, increases the risk of a subdural hematoma. (Contributed by Dr. Ravindra Kumar Garg.)