Congenital disorders of glycosylation …

Erik A Eklund MD PhD

Neurogenetic Disorders

Updated 03.02.2023
Released 06.01.2013
Expires For CME 03.02.2026

Congenital disorders of glycosylation

Author: Erik A Eklund MD PhD

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Editor: Deepa S Rajan MD

Congenital disorders of glycosylation

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Introduction

Overview

The congenital disorders of glycosylation constitute a large group of inherited disorders with multiorgan expression of symptoms. In most patients, there are signs of nervous system involvement where typical manifestations include structural abnormalities (eg, rapidly progressive cerebellar atrophy), developmental delay, intellectual disability, stroke-like episodes, epileptic seizures, and demyelinating neuropathy. Patient presentations can demonstrate significant differences between and within the different subgroups. In this article, the author explains the basic genetic and biochemical background to these syndromes and describes the most common subtypes in terms of initial clinical signs, diagnostic work-up, prognosis and clinical progression, and, in a few instances, treatment.

Key points

	• The congenital disorders of glycosylation (CDG) syndromes constitute a group of severe syndromes with a broad phenotypic expression within and between subtypes.
	• A majority of the patients can be diagnosed using a transferrin glycosylation test.
	• There is no specific treatment in most subtypes.
	• CDG should be excluded in all patients with unclear intellectual disability in combination with symptoms of dysfunction in other organ systems.

Historical note and terminology

Historical note. In 1980, the Belgian professor Jaak Jaeken described the first patients affected with congenital disorders of glycosylation in an abstract in Pediatric Research (37). The patients (2-year-old twin sisters) presented with psychomotor retardation, delayed bone growth, and fluctuating levels of several glycoprotein hormones. Some years later, it was shown that these patients also had deficient glycosylation of transferrin (34), and the term “carbohydrate-deficient glycoprotein syndrome” (CDGS) was eventually suggested (36). More clinical phenotypes emerged, and several subtypes were coined (CDGS-Ia, -Ib, -IIa, etc.). In 1995, the first molecular cause of CDGS was published, deficiency of phosphomannomutase 2 (CDGS-Ia; now PMM2-CDG). PMM2 catalyzes the interconversion of mannose-6-P and mannose-1-P (71). Subsequently, the cause of CDGS-IIa (MGAT2-CDG) as well as the cause and a suggested therapy (alimentary addition of mannose) of CDGS-Ib (MPI-CDG) were published (11; 55).

Nomenclature. In 1999, the first international workshop on CDGS was held, and the participating scientists agreed on a modified nomenclature, including a change in the translation of the acronym CDG to “congenital disorder of glycosylation.” Naming subtypes was based on CDG type (I or II, see below) and chronological order of detection (next available lower-case letter); that is, CDGS-Ia became CDG-Ia, CDGS-IIa became CDG-IIa, and so forth.

Biochemically, one can distinguish between 2 pathological patterns of transferrin underglycosylation, coined CDG type I and type II. Type I deficiencies suggest errors in the synthesis or transfer of the dolichol-linked precursor for N-glycosylation (located to the cytosol or the endoplasmic reticulum), whereas type II deficiencies impair trimming or modification of the protein-bound oligosaccharides (late endoplasmic reticulum and the Golgi). Patients with an unknown gene deficiency were referred to as either CDG-Ix or IIx. Due to improved diagnostic techniques, the number of subtypes increased rapidly during the beginning of this century (22).

In 2009, yet another nomenclature was suggested because glycosylation disorders were identified in other glycosylation pathways (such as O-linked glycosylation and lipid glycosylation) in addition to defects of enzymes and transporters in N-linked protein glycosylation. The revised nomenclature uses the official gene symbol followed by “-CDG” as designation of the individual subtypes; hence, CDG-Ia is now referred to as PMM2-CDG, CDG-Ib is MPI-CDG, CDG-IIa is MGAT2-CDG, and so forth (35). In 2022, there is still an ongoing debate as to which genetic disorders should qualify as a CDG syndrome, where the list of CDGs now has surpassed 160 different genetic syndromes with more than 220 different phenotypes (25). A digital discussion involving +40 glyco-scientists and physicians was organized by professors Freeze, Jaeken, and Matthijs to discuss this matter further (25). It was agreed that the classification of a disorder as a ”CDG” requires that there is a measurable effect on any type of glycosylation but that one should be inclusive rather than exclusive. Examples of genetic/biochemical criteria to be classified as a CDG were (example of gene): (1) gene evolved in any glycosylation pathway (ALG1, B3GLCT, B4GALT7, DPM1, EXT1/2, FKRP, MOGS, MPI, OGT, PAPSS2, PGM1, PIGA, PIGL, PMM2, POMT1, SLC35A2, SRD5A3, STT3A); (2) glyco-gene conserved in evolution (ALG13); (3) gene in ER, Golgi, post-Golgi trafficking altering the synthesis of any glycan (COG4, COG7, GET4, SEC23B, TRAPPC11); or (4) gene involved in metal ion or pH homeostasis that alters glycan synthesis (ATP6AP2, ATP6VOA2, SLC39A8, TMEM199). Examples of nonqualifying genes were: part of a glycosylation-altering molecular complex, but lacking evidence of altered glycans (TRAPP6B, TRAPPC12) (25).

Clinical manifestations

Presentation and course

Clinical manifestations. The congenital disorders of glycosylation are multi-organ syndromes where the clinical presentations differ widely both within and between the different subtypes (24; 30; 23; 19).

CDG syndromes affecting N-linked glycosylation

The table summarizes the symptoms that have been described in respective CDG subtype in N- or N/O-linked CDGs. ++ indicates a symptom that the majority of patients in the subtype presents, + indicates a symptom that several but...
CDG syndromes affecting N-linked glycosylation (2)

The table summarizes the symptoms that have been described in respective CDG subtype. ++ indicates a symptom that the majority of patients in the subtype presents, + indicates a symptom that several but not the majority of pati...
CDG syndromes affecting N-linked glycosylation (3)

The table summarizes the symptoms that have been described in respective CDG subtype. ++ indicates a symptom that the majority of patients in the subtype presents, + indicates a symptom that several but not the majority of patient...
CDG syndromes affecting N-linked glycosylation (4)

The table summarizes the symptoms that have been described in respective CDG subtype. ++ indicates a symptom that the majority of patients in the subtype presents, + indicates a symptom that several but not the majority of patient...

Even siblings with congenital disorders of glycosylation can have different presentations, perhaps indicating a modifying role of the environment and the genetic background. In most known subtypes, fewer than 20 patients have been described. Therefore, subtype-specific features are hard to postulate. Nonetheless, some features, such as developmental delay and hepatic involvement, are present in most known forms of congenital disorders of glycosylation.

PMM2-CDG. The most common and well-described subtype of congenital disorders of glycosylation is PMM2-CDG; data suggest approximately 50% of patients with CDG type I have PMM2-CDG (70). The “classic” phenotype includes muscular hypotonia, failure to thrive, developmental delay, cerebellar atrophy, esotropia, peripheral neuropathy, retinopathy, liver involvement, inverted nipples, and peculiar fat pads (02). However, as screening for CDG has been applied to a broader population, many patients with PMM2-CDG have different phenotypes (28). In classic PMM2-CDG, patients have been described to go through 4 stages: the infantile multisystemic stage, the childhood ataxia or intellectual disability stage, the teenage leg atrophy stage, and the adult hypogonadal stage (36). PMM2-CDG survival into adulthood is estimated at 75% to 80%, and the highest mortality rates are in the early years, particularly in patients with a more pronounced visceral form of disease (13; 02). An international clinical guideline for the diagnosis, treatment, and follow-up of PMM2-CDG has been published (02).

Patients with PMM2-CDG are usually born after normal pregnancies with normal birth weights (28; 26). In some instances, hydrops fetalis (46) or pericardial effusions (42) have been noted prenatally or in the neonate, and there are descriptions of cardiomyopathy being present at birth (01; 42). Also, prolonged hypoglycemia has been described as the first symptom of PMM2-CDG (06; 52). During infancy, the predominant neurologic features of PMM2-CDG are hypotonia and developmental delay (particularly gross motor skills), with evolving facial hypotonia, esotropia, and unusual eye movements. Neuroimaging often shows a diminished cerebellar vermis in a process that is now believed to be rapidly progressive atrophy. Further, global atrophy and hydrocephalus with acquired microcephaly are common (24; 23). Other common findings are failure to thrive, inverted nipples, and subcutaneous fat pads. Most patients show some visceral involvement (cardiac, hepatic, renal, or intestinal), which may be catastrophic (36; 28; 24). Infections can precipitate episodes of pericardial effusions with cardiac failure, hepatic failure, coma, and thrombotic or hemorrhagic events, and patients are often susceptible to infections. Muscle reflexes usually diminish early and are most often completely absent by 1 year of age.

Partial seizures and stroke-like episodes often become apparent later in the first decade of life. The etiology of the stroke-like episodes is unclear and possibly multifactorial, but they typically occur during or after infections or head trauma (24). One paper suggests that the cause may be underglycosylation of the voltage-sensitive calcium channel encoded by CACNA1A (33). Patients may present with hemiplegia, unconsciousness, or blindness, and the episodes last from hours to several days but usually resolve completely (in rare instances secondary sequelae may persist). In this phase of the disease, the visceral findings usually regress (24; 23).

In adolescence and adulthood, the patients have fixed neurologic deficits, including severe cerebellar ataxia, peripheral neuropathy with distal wasting, and intellectual disability. Patients often develop signs of retinopathy and fixed strabismus. A large proportion becomes legally blind. Many show kyphoscoliosis. Patients’ communication skills vary, but most often they speak in short sentences in a staccato manner, often incomprehensible to persons without a relation to the patient. Peripheral neuropathy is evident, and the overwhelming majority gradually depends on a wheelchair for locomotion.

Female patients with PMM2-CDG lack pubertal development and show primary ovarian failure with hypergonadotropic hypogonadism (14; 48). Puberty can be hormonally induced; however, the risk of causing thrombotic events should be considered, especially in patients who have had stroke-like episodes in the past. Male patients undergo puberty; however, it may sometimes be delayed. Testosterone levels are in the low to normal range (14; 48).

ALG6-CDG. ALG6-CDG is the second most common N-linked CDG, with more than 100 known patients to date. The phenotype of this disorder is generally milder than that of PMM2-CDG (43); however, several have died due to its complications (50).

The main findings in ALG6-CDG include a moderate degree of intellectual disability, ataxia, hypotonia, esotropia, epilepsy, and proximal muscle weakness (50). Severe protein-losing enteropathy in the context of gastroenteritis has been described (15; 50). The primary findings in the few known adult patients with ALG6-CDG were intellectual disability, deep-vein thrombosis, benign intracranial hypertension, virilization, and skeletal anomalies (67).

ALG1-CDG. This subtype was described in 2004 by 3 independent groups and was initially considered an unusual and very severe subtype of CDG because 4 of 7 described cases died in early childhood (27; 39; 61). With the introduction of next-generation sequencing, however, the number of known patients has increased considerably over the last few years (more than 50 known patients). Of over 40 identified cases diagnosed since 2009, more than 70% survived beyond the first year of life (54). Many affected individuals show a PMM2-CDG-like phenotype with developmental delay/intellectual disability, microcephaly, strabismus, seizures, coagulation abnormalities, and abnormal fat distribution (51; 54). Therefore, ALG1-CDG should be excluded in any case with a “classic” CDG phenotype but normal PMM2-analysis. Interestingly, in all ALG1-CDG patients tested so far, mass spectrometric transferrin analysis shows the presence of a xeno-tetrasaccharide, specific to this subtype, which can allow for a subtype distinction before the genetic analysis is performed (05).

PGM1-CDG. This defect (phosphoglucomutase 1 deficiency) (69) was initially described as a glycogen storage disorder (later named glycogenesis type XIV) (65) and very few patients have been described. However, in 2014, Tegtmeyer and colleagues described 19 more patients from 16 families (68). The subtype (PGM1-CDG) was redefined as a mixed-type congenital disorder of glycosylation (ie, having features of both type 1 and type 2 underglycosylation). Interestingly, they suggested that these patients do not have a neurologic phenotype due to other isoforms of phosphoglucomutase being expressed in the brain. Instead, they suffer from hypoglycemia, liver pathology with hypertransaminasemia, cardiac problems including arrhythmia and dilated cardiomyopathy, muscular weakness and orofacial abnormalities such as a bifid uvula (greater than 80% of patients), and a cleft palate. A more recent paper, however, reports intellectual disability and motor delay in a significant number of the patients (17/41) (57). This is one of few congenital disorders of glycosylation subtypes that seems to respond to the alimentary addition of saccharides; in this case, galactose or lactose (68). A consensus guideline for diagnosis, follow-up, and treatment has been published (03).

Defects of the conserved oligomeric Golgi (COG) complex. In 2004, it was shown that mutations in COG subunit 7 (COG7) cause a new CDG subgroup, the COG-CDGs (78). Biochemically they had a combined N- and O-linked deficiency, with hypoglycosylation of both transferrin and apolipoprotein C-III, one of the very few serum proteins that show exclusive O-linked glycosylation. Since then, deficiencies in COG 1, 2, 4, 5, 6, and 8 have been described (58). There is a considerable variation in which organs are involved and the severity of the phenotype in those affected, but there is always a degree of developmental delay/intellectual disability (mild to severe), microcephaly, and hypotonia; often there is also epilepsy. Other findings include facial dysmorphias, skeletal dysplasia, failure to thrive, hepatomegaly, and cardiac involvement (heart failure, hypertrophy, congenital heart defects). Brain imaging can be normal, but some patients showed cerebral and cerebellar atrophy (24). A particularly interesting phenotype (Saul-Wilson syndrome) that includes skeletal dysplasia, short stature, and developmental delay was reported in 14 individuals and was caused by the same heterozygous mutation in COG4 (20), implying a yet unknown function for this particular COG subunit.

Cutis laxa syndromes. Cutis laxa is a dermatological condition with inelastic, loose, and sagging skin. Some patients with autosomal recessive cutis laxa II and wrinkled skin syndrome have mutations in ATP6V0A2, encoding the alpha2 subunit of vacuolar-type proton-ATPase. Interestingly, these patients show a combined N- and O-linked glycosylation deficiency, which merits its classification as a CDG (ATP6V0A2-CDG) (38).

The more than 20 described patients with ATP6V0A2-CDG will always have wrinkly skin and typically show a large fontanelle with delayed closure, down-slanting palpebral fissures, joint laxity, muscular hypotonia, and eye anomalies (strabismus and myopia). Microcephaly is common with variable intellectual disability and developmental delay. Half of the patients show brain abnormalities, such as partial pachygyria or cobblestone-like lissencephaly. Seizures are uncommon but can occur in older children. The early feeding difficulties, growth retardation, and skin condition usually resolves with age (49; 31).

Congenital myasthenia syndromes. Congenital myasthenic syndromes primarily present clinically by fatigable muscle weakness. They are due to impaired signal transmission at the neuromuscular synapse (18). Over the last 5 years, genes that have previously been connected to a more CDG-like phenotype have been found to cause a separate phenotype with congenital myasthenia as the major symptom. These genes include DPAGT1, GFPT1, ALG2, and ALG14 (62; 04; 12). The pathogenesis probably involves defective glycosylation of the acetylcholine receptor subunits (04). In total, more than 50 families have been identified.

SLC35A2-CDG (galactose transporter deficiency). This is the most prevalent X-linked congenital disorders of glycosylation, with about one hundred patients known (oral communication, Bobby Ng, Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, CA). Most of the patients are girls; however, boys with mosaic mutations also exist. The original description was of 3 unrelated patients with mainly neurologic and skeletal problems, including epileptic encephalopathy, developmental delay, ocular manifestations (ocular flutter, nystagmus, and retinitis pigmentosa), facial dysmorphisms, and brain malformations including cerebellar hypoplasia (53). There seems to be three distinct phenotypic groups, including either solely neurologic features, neurologic and skeletal features combined, or an exclusively skeletal phenotype (unpublished). Galactose therapy has been tried in some patients with partial response (75). Interestingly, somatic mosaicism of the SLC35A2 gene in the brain has been shown to cause focal intractable seizures in mild malformation of optical development with oligodendroglial hyperplasia in epilepsy (63; 73; 07).

Clinical vignette. A 7-month-old boy was seen by a child neurologist and was recognized to be hypotonic with poor head control. The boy did not reach for objects, sit, or roll over, and reflexes were decreased. A nerve biopsy showed chronic axonal neuropathy, and a brain MRI showed ventriculomegaly ex vacuo with atrophy. Sonar spectroscopy revealed high levels of lactate in the gray matter. At age 18 to 24 months, he developed myoclonic jerks with electroencephalographic slow waves consistent with seizures. At age 8.5 years, the patient had severe intellectual disability, no speech, and no bowel and bladder control. Biochemically he showed signs of liver pathology with increased serum ALT. A neurometabolic investigation (mitochondrial disease, lysosomal disease, peroxisomal disease, aciduria) was normal, as was his karyotype. Due to signs and symptoms from dysfunction of several organ systems, including the brain, glycosylation of transferrin was checked by mass spectrometry. On this analysis, the patient was found to have a type II pattern with normal chain occupancy but lacking sialic acids. Analysis of the COG complex revealed a lack of COG8, consistent with the diagnosis COG8-CDG (CDG-IIh) (40).

Prognosis and complications

In classical PMM2-CDG, approximately 80% of patients survive into adulthood. The diseases generally enter a rather stable state after puberty. In other subtypes, survival into adulthood is much reduced, where the presence of severe early-onset neurologic symptoms as epileptic encephalopathy constitute strong risk factors.

Biological basis

Glycosylation is the collective name for the processes in which carbohydrates are added to proteins and lipids, thereby modifying their properties (16; 24; 23). Almost all glycosylation takes place in the endoplasmic reticulum and the Golgi. Hence, all proteins that are translated into the endoplasmic reticulum will face the glycosylation machinery and are possible candidates of becoming glycoproteins if they have consensus sequences for glycosylation. In asparagine (N)-linked glycosylation, a precursor oligosaccharide containing 14 monosaccharides is preformed on a lipid anchor in the endoplasmic reticulum then transferred en bloc to the growing polypeptide.

N-linked glycosylation pathway with known defects

The figure depicts the biosynthesis of the 14-mer lipid-linked oligosaccharide (LLO) precursor of N-glycosylation in the endoplasmic reticulum. After completion, the oligosaccharide is transferred to an asparagine acceptor in the ...

This structure is then trimmed by glycosidases, a process vital for correct folding of many glycoproteins. The oligosaccharides are then further rebuilt in the Golgi, which is important for several aspects of the “life” of the proteins, including their initial folding and trafficking to the proper functioning and regulation of their degradation.

All eukaryotic cells contain N-linked glycoproteins. Therefore, errors in these glycosylation processes can cause signs and symptoms in many organ systems in affected patients.

Addition of carbohydrates to proteins requires a complex machinery and demands a coordinated expression of hundreds of genes. In fact, more than 1% of the expressed human genome is predicted to encode proteins involved in the glycosylation process (21). Though all syndromes due to pathologic mutations in a gene involved in glycosylation could be referred to as a congenital disorder of glycosylation, many diseases that fit this criterion have already been included in other classification systems (eg, congenital muscular dystrophies with deficiencies in O-linked mannosylation, such as muscle-eye-brain disease or Walker-Warburg syndrome). Therefore, this article focuses on disorders with defective N-linked glycosylation.

Diagnostic workup

The initial testing for congenital disorders of glycosylation should include analysis of N-glycosylation of serum transferrin. Traditionally, this is done by isoelectric focusing (IEF), a method still widely used (64). However, in some diagnostic laboratories, the method of choice is affinity chromatography followed by mass spectrometry (41). Other methods, including HPLC separation of the differently glycanated species (29) and capillary zone electrophoresis (09), have been used. When pathological, these methods will suggest either a type I, a type II, or a mixed pattern. If the pattern is suggestive of a type II or mixed pattern (ie, suggestive of a Golgi pathology), analysis of underglycosylation of apo-lipoprotein CIII (suggestive of O-linked glycosylation errors) may be deployed to further deepen the analysis (77). There are several potential problems with the transferrin analyses. A positive test can occur in uncontrolled hereditary fructose intolerance, galactosemia, certain hepatic pathologies, alcoholism, and rare mutations at the transferrin glycosylation site (56). Also, preterm infants with congenital disorders of glycosylation have normal transferrin patterns; normal transferrin has been reported in patients who were later proven to have congenital disorders of glycosylation (72); and confirmed CDG cases sometimes normalize transferrin glycosylation. This is suggestive of an optimal window for transferrin diagnosis, and unpublished results from thousands of transferrin tests at the Mayo Clinic clearly show an optimal period between 6 and 18 months of age (Raymond, K, personal communication).

If the patient has a classic type I pattern of transferrin underglycosylation, PMM2-CDG (CDG-Ia) should be ruled out or confirmed as it is the commonest subtype. Some laboratories offer enzymatic testing for PMM2 activity in white blood cells or fibroblasts, whereas others employ genetic testing of the PMM2 gene immediately. If the patient presents without or with only mild neurologic symptoms, MPI-CDG should be excluded as this is a treatable, but potentially fatal, condition. This is done using an enzyme assay on white blood cells or fibroblasts, but it is generally not available at clinical laboratories as a routine (CDG laboratories in the United States and Europe should be contacted for more information).

If the subtype remains obscure after this initial screen, targeted whole exome or genome analysis should be performed (22) even though some laboratories still perform lipid-linked oligosaccharide analysis as part of the investigative path.

Management

In most congenital disorders of glycosylation subtypes there is no specific treatment available, and symptomatic treatment should be employed for those conditions that are associated with the CDG syndromes, including epilepsy, heart failure, and reflux. Active physiotherapy is critical for maintaining muscular function.

The aldose reductase inhibitor epalrestat, used for treating diabetic neuropathy, was found as a potential therapy for PMM2-CDG in a multispecies drug-repurposing screen (32), and a few patients have been treated with this drug with promising results (nonpublished data). A placebo-controlled study has been designed (ClinicalTrials.gov NCT04925960) and will soon start to recruit patients. Further, use of acetazolamide has shown promising results in treating ataxia in PMM2-CDG (45), and a placebo-controlled study (ClinicalTrials.gov NCT04679389) is soon to be completed.

Some patients with PMM2-CDG with recurrent stroke-like episodes are kept on acetylsalicylic acid. Osteoporosis and fractures are common in older patients, and puberty can be induced in adolescent girls to prevent this. The risk of thrombotic events should be considered, and some patients are kept on warfarin, low molecular weight heparin, or oral factor Xa inhibitors for several years after the induction. Bisphosphonates are indicated for patients who have had several fractures.

Frequent check-ups during the first years of life are vital and should include liver enzymes analysis, cardiac ultrasound, and coagulation investigations. Ophthalmologic investigation, including ERG, should be employed bi- to tri-annually.

Only a few other subtypes are currently treatable. MPI-CDG, the only subtype without neurologic deficits, shows the best results. Here, supplementing the food with mannose has a dramatic effect on coagulopathy, protein-losing enteropathy, and hypoglycemic episodes present in this subtype. In one case, when mannose was given intravenously due to fasting before surgery, the patient went into unconsciousness and experienced seizures, possibly due to the accumulation of Man-6P and intracellular depletion of ATP (60). Thus, caution must be taken in similar situations, and intravenous glucose administration may be used to reverse the effect. A clinical management guide has been published (10).

Fucose has been tried in SLC35C1-CDG (CDG-IIc), but appreciable effects have been absent in most patients (44; 66).

Galactose and lactose are currently used in PGM1-CDG and there seems to be some stabilizing effects with normalization of transaminases, coagulations factors, and hormones. Furthermore, there also seem to be beneficial effects on the episodic rhabdomyolysis and hypoglycemia (74; 76).

The 2 ultra-rare subtypes, TMEM165-CDG and SLC39A8-CDG, also seem to benefit from galactose treatment. In SLC39A8-CDG, addition of manganese is also helpful (74).

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References

01: Aronica E, van Kempen AA, van der Heide M, et al. Congenital disorder of glycosylation type Ia: a clinicopathological report of a newborn infant with cerebellar pathology. Acta Neuropathol 2005;109:433-42. PMID 15714316
02: Altassan R, Péanne R, Jaeken J, et al. International clinical guidelines for the management of phosphomannomutase 2-congenital disorders of glycosylation: diagnosis, treatment and follow up. J Inherit Metab Dis 2019;42(1):5-28. PMID 30740725
03: Altassan R, Radenkovic S, Edmondson AC, et al. International consensus guidelines for phosphoglucomutase 1 deficiency (PGM1-CDG): diagnosis, follow-up, and management. J Inherit Metab Dis 2021;44(1):148-63. PMID 32681750
04: Belaya K, Finlayson S, Slater CR, et al. Mutations in DPAGT1 cause a limb-girdle congenital myasthenia syndrome with tubular aggregates. Am J Hum Genet 2012;91(1):193-201. PMID 22742743
05: Bengtson P, Ng BG, Jaeken J, Matthijs G, Freeze HH, Eklund EA. Serum transferrin carrying the xeno-tetrasaccharide NeuAc-Gal-Gal-GlcNAc2 is a biomarker of ALG1-CDG. J Inherit Metab Dis 2016;39(1):511-3.** PMID 26335155
06: Bohles H, Sewell AA, Gebhardt B, Reinecke-Luthge A, Kloppel G, Marquardt T. Hyperinsulinaemic hypoglycaemia--leading symptom in a patient with congenital disorder of glycosylation Ia (phosphomannomutase deficiency). J Inherit Metab Dis 2001;24:858-62. PMID 11916319
07: Bonduelle T, Hartlieb T, Baldassari S, et al. Frequent SLC35A2 brain mosaicism in mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE). Acta Neuropathol Commun 2021;9(1):3. PMID 33407896
08: Briones P, Vilaseca MA, Garcia-Silva MT, et al. Congenital disorders of glycosylation (CDG) may be underdiagnosed when mimicking mitochondrial disease. Eur J Paediatr Neurol 2001;5:127-31. PMID 11589167
09: Carchon HA, Chevigne R, Falmagne JB, Jaeken J. Diagnosis of congenital disorders of glycosylation by capillary zone electrophoresis of serum transferrin. Clin Chem 2004;50:101-11. PMID 14633925
10: Cechova A, Altassan R, Borgel D, et al. Consensus guideline for the diagnosis and management of mannose phosphate isomerase-congenital disorder of glycosylation. J Inherit Metab Dis 2020;43(4):671-93. PMID 32266963
11: Charuk JH, Tan J, Bernardini M, et al. Carbohydrate-deficient glycoprotein syndrome type II: an autosomal recessive N-acetylglucosaminyltransferase II deficiency different from typical hereditary erythroblastic multinuclearity, with a positive acidified-serum lysis test (HEMPAS). Eur J Biochem 1995;230:797-805. PMID 7607254
12: Cossins J, Belaya K, Hicks D, et al. Congenital myasthenic syndromes due to mutation sin ALG2 and ALG14. Brain 2013;136(Pt 3):944-56. PMID 23404334
13: de Lonlay P, Seta N, Barrot S, et al. A broad spectrum of clinical presentations in congenital disorders of glycosylation I: a series of 26 cases. J Med Genet 2001;38:14-9. PMID 11134235
14: de Zegher F, Jaeken J. Endocrinology of the carbohydrate-deficient glycoprotein syndrome type 1 from birth through adolescence. Pediatr Res 1995;37:395-401. PMID 7596677
15: Drijvers JM, Lefeber DJ, de Munnik SA, et al. Skeletal dysplasia with brachytelephalangy in a patient with a congenital disorder of glycosylation due to ALG6 gene mutations. Clin Genet 2010;77:507-9. PMID 20447155
16: Eklund EA, Freeze HH. Essentials of glycosylation. Semin Pediatr Neurol 2005;12:134-43. PMID 16584072
17: Eklund EA, Freeze HH. The congenital disorders of glycosylation: a multifaceted group of syndromes. NeuroRx 2006;3:254-63. PMID 16554263
18: Engel AG, Shen XM, Selcen D, Sine SM. Congenital myasthenic syndromes: pathogenesis, diagnosis, and treatment. Lancet Neurol 2015;14(4):420-34. PMID 25792100
19: Ferreira CR, Altassan R, Marques-Da-Silva D, Francisco R, Jaeken J, Morava E. Recognizable phenotypes in CDG. J Inherit Metab Dis 2018a;41(3):514-53. PMID 29654385
20: Ferreira CR, Xia ZJ, Clément A, et al. A recurrent de novo heterozygous COG4 substitution leads to Saul-Wilson Syndrome, disrupted vesicular trafficking, and altered proteoglycan glycosylation. Am J Hum Genet 2018b;103(4):553-67. PMID 30290151
21: Freeze HH. Genetic defects in the human glycome. Nat Rev Genet 2006;7:537-51. PMID 16755287
22: Freeze HH, Chong JX, Bamshad MJ, Ng BG. Solving glycosylation disorders: fundamental approaches reveal complicated pathways. Am J Hum Genet 2014;94(2):161-75.** PMID 24507773
23: Freeze HH, Eklund EA, Ng BG, Patterson MC. Neurological aspects of human glycosylation disorders. Annu Rev Neurosci 2015;38:105-25. PMID 25840006
24: Freeze HH, Eklund EA, Ng BG, Patterson MC. Neurology of inherited glycosylation disorders. Lancet Neurol 2012;11:453-66.** PMID 22516080
25: Freeze HH, Jaeken J, Matthijs G. CDG or not CDG. J Inherit Metab Dis 2022;45(3):383-5. PMID 35338706
26: Funke S, Gardeitchik T, Kouwenberg D, et al. Perinatal and early infantile symptoms in congenital disorders of glycosylation. Am J Med Genet A 2013;161A(3):578-84. PMID 23401092
27: Grubenmann CE, Frank CG, Hulsmeier AJ, et al. Deficiency of the first mannosylation step in the N-glycosylation pathway causes congenital disorder of glycosylation type Ik. Hum Mol Genet 2004;13:535-42. PMID 14709599
28: Grunewald S. The clinical spectrum of phosphomannomutase 2 deficiency (CDG-Ia). Biochim Biophys Acta 2009;1792:827-34. PMID 19272306
29: Helander A, Husa A, Jeppsson JO. Improved HPLC method for carbohydrate-deficient transferrin in serum. Clin Chem 2003;49:1881-90. PMID 14578320
30: Hennet T. Diseases of glycosylation beyond classical congenital disorders of glycosylation. Biochim Biophys Acta 2012;1820:1306-17. PMID 22343051
31: Hucthagowder V, Morava E, Kornak U, et al. Loss-of-function mutations in ATP6V0A2 impair vesicular trafficking, tropoelastin secretion and cell survival. Hum Mol Genet 2009;18:2149-65. PMID 19321599
32: Iyer S, Sam FS, DiPrimio N, et al. Repurposing the aldose reductase inhibitor and diabetic neuropathy drug epalrestat for the congenital disorder of glycosylation PMM2-CDG. Dis Model Mech 2019;12(11):dmm040584. PMID 31636082
33: Izquierdo-Serra, M, Martínez-Monseny AF, López L, et al. Stroke-like episodes and cerebellar syndrome in phosphomannomutase deficiency (PMM2-CDG): evidence for hypoglycosylation-driven channelopathy. Int J Mol Sci 2018;19(2). PMID 29470411
34: Jaeken J, Eggermont E, Stibler H. An apparent homozygous X-linked disorder with carbohydrate-deficient serum glycoproteins. Lancet 1987;2:1398. PMID 2890978
35: Jaeken J, Hennet T, Matthijs G, Freeze HH. CDG nomenclature: time for a change! Biochim Biophys Acta 2009;1792:825-6. PMID 19765534
36: Jaeken J, Stibler H, Hagberg B. The carbohydrate-deficient glycoprotein syndrome: a new inherited multisystemic disease with severe nervous system involvement. Acta Paediatr Scand Suppl 1991;375:1-71. PMID 1720595
37: Jaeken J, Vanderschueren-Lodeweyckx M, Casaer P, et al. Familial psychomotor retardation with markedly fluctuating serum prolactin, FSH and GH levels, partial TBG deficiency, increased arylsulphatase A and increased CSF protein: a new syndrome. Pediatr Res 1980;14:179.**
38: Kornak U, Reynders E, Dimopoulou A, et al. Impaired glycosylation and cutis laxa caused by mutations in the vesicular H+-ATPase subunit ATP6V0A2. Nat Genet 2008;40:32-4.** PMID 18157129
39: Kranz C, Denecke J, Lehle L, et al. Congenital disorder of glycosylation type Ik (CDG-Ik): a defect of mannosyltransferase I. Am J Hum Genet 2004;74:545-51. PMID 14973782
40: Kranz C, Ng BG, Sun L, et al. COG8 deficiency causes new congenital disorder of glycosylation type IIh. Hum Mol Genet 2007;16:731-41. PMID 17331980
41: Lacey JM, Bergen HR, Magera MJ, Naylor S, O'Brien JF. Rapid determination of transferrin isoforms by immunoaffinity liquid chromatography and electrospray mass spectrometry. Clinical Chemistry 2001;47:513-8. PMID 11238305
42: Malhotra A, Pateman A, Chalmers R, Coman D, Menahem S. Prenatal cardiac ultrasound finding in congenital disorder of glycosylation type 1a. Fetal Diagn Ther 2009;25:54-7. PMID 19176971
43: Marquardt T, Denecke J. Congenital disorders of glycosylation: review of their molecular bases, clinical presentations and specific therapies. Eur J Pediatr 2003;162:359-79.** PMID 12756558
44: Marquardt T, Luhn K, Srikrishna G, Freeze HH, Harms E, Vestweber D. Correction of leukocyte adhesion deficiency type II with oral fucose. Blood 1999;94:3976-85. PMID 10590041
45: Martinez-Monseny AF, Bolasell M, Callejón-Póo L, et al. AZATAX: acetazolamide safety and efficacy in cerebellar syndrome in PMM2 congenital disorder of glycosylation (PMM2-CDG). Ann Neurol 2019;85(5):740-51. PMID 30873657
46: McKenzie FA, Fietz M, Fletcher J, Smith RL, Wright IM, Jaeken J. A previously undescribed form of congenital disorder of glycosylation with variable presentation in siblings: early fetal loss with hydrops fetalis, and infant death with hypoproteinemia. Am J Med Genet A 2007;143A:2029-34. PMID 17663480
47: Meaudre E, Meyrieux V, Suprano I, Camboulives J, Paut O. Anesthesia considerations in carbohydrate-deficient glycoprotein syndrome type I. Paediatr Anaesth 2005;15(10):905-6. PMID 16176328
48: Miller BS, Freeze HH. New disorders in carbohydrate metabolism: congenital disorders of glycosylation and their impact on the endocrine system. Rev Endocr Metab Disord 2003;4:103-13. PMID 12618564
49: Morava E, Lefeber DJ, Urban Z, et al. Defining the phenotype in an autosomal recessive cutis laxa syndrome with a combined congenital defect of glycosylation. Eur J Hum Genet 2008;16:28-35. PMID 17971833
50: Morava E, Tiemes V, Tiel C, et al. ALG6-CDG: a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioral and limb anomalies. J Inherit Metab Dis 2016;39(5):713-23. PMID 27287710
51: Morava E, Vodopiutz J, Lefeber DJ, et al. Defining the phenotype in congenital disorder of glycosylation due to ALG1 mutations. Pediatrics 2012;130:e1034-9. PMID 22966035
52: Moravej H, Altassan R, Jaeken J, et al. Hypoglycemia in CDG patients due to PMM2 mutations: follow up on hyperinsulinemic patients. JIMD Rep 2019;51(1):76-81. PMID 32071842
53: Ng BG, Buckingham KJ, Raymond K, et al. Mosaicism of the UDP-galactose transporter SLC35A2 causes a congenital disorder of glycosylation. Am J Hum Genet 2013;92(4):632-6.** PMID 23561849
54: Ng BG, Shiryaev SA, Rymen D, et al. ALG1-CDG: clinical and molecular characterization of 39 unreported patients. Hum Mutat 2016;37(7):653-60. PMID 26931382
55: Niehues R, Hasilik M, Alton G, et al. Carbohydrate-deficient glycoprotein syndrome type Ib: phosphomannose isomerase deficiency and mannose therapy. J Clin Invest 1998;101:1414-20. PMID 9525984
56: Perez-Cerda C, Quelhas D, Vega AI, Ecay J, Vilarinho L, Ugarte M. Screening using serum percentage of carbohydrate-deficient transferrin for congenital disorders of glycosylation in children with suspected metabolic disease. Clin Chem 2008;54:93-100. PMID 18024528
57: Radenkovic S, Witters P, Morava E. Central nervous involvement is common in PGM1-CDG. Mol Genet Metab 2018;125(3):200-4. PMID 30262252
58: Reynders E, Foulquier F, Annaert W, Matthijs G. How Golgi glycosylation meets and needs trafficking: the case of the COG complex. Glycobiology 2011;21:853-63. PMID 21112967
59: Sakai W, Yoshikawa Y, Tokinaga Y, Yamakage M. Anesthetic management of a child with phosphomannomutase-2 congenital disorder of glycosylation (PMM2-CDG). JA Clin Rep 2017;3(1):8. PMID 29492447
60: Schroeder AS, Kappler M, Bonfert M, Borggraefe I, Schoen C, Reiter K. Seizures and stupor during intravenous mannose therapy in a patient with CDG syndrome type 1b (MPI-CDG). J Inherit Metab Dis 2010;33 Suppl 3:497-502. PMID 21240668
61: Schwarz M, Thiel C, Lubbehusen J, et al. Deficiency of GDP-Man:GlcNAc2-PP-dolichol mannosyltransferase causes congenital disorder of glycosylation type Ik. Am J Hum Genet 2004;74:472-81. PMID 14973778
62: Senderek J, Müller JS, Dusl M, et al. Hexosamine biosynthetic pathway mutations cause neuromuscular transmission defect. Am J Hum Genet 2011;88(2):162-72. PMID 21310273
63: Sim NS, Seo Y, Lim JS, et al. Brain somatic mutations in SLC35A2 cause intractable epilepsy with aberrant N-glycosylation. Neurol Genet 2018;4(6):e294. PMID 30584598
64: Stibler H, Jaeken J. Carbohydrate deficient serum transferrin in a new systemic hereditary syndrome. Arch Dis Child 1990;65:107-11. PMID 2301971
65: Stojkovic T, Vissing J, Petit F, et al. Muscle glycogenesis due to phosphoglucomutase 1 deficiency. N Engl J Med 2009;361(4):425-7. PMID 19625727
66: Sturla L, Puglielli L, Tonetti M, et al. Impairment of the Golgi GDP-L-fucose transport and unresponsiveness to fucose replacement therapy in LAD II patients. Pediatr Res 2001;49:537-42. PMID 11264438
67: Sun L, Eklund EA, Van Hove JL, Freeze HH, Thomas JA. Clinical and molecular characterization of the first adult congenital disorder of glycosylation (CDG) type Ic patient. Am J Med Genet A 2005;137:22-6. PMID 16007612
68: Tegtmeyer LC, Rust S, van Scherpenzeel M, et al. Multiple phenotypes in phosphoglucomutase 1 deficiency. N Engl J Med 2014;370(6):533-42. PMID 24499211
69: Thomson WH, MacLaurin JC, Prineas JW. Skeletal muscle glycogenesis: an investigation of two dissimilar cases. J Neurol Neurosurg Psychiatry 1963;26:60-8. PMID 13981250
70: Timal S, Hoischen A, Lehle L, et al. Gene identification in the congenital disorders of glycosylation type I by whole-exome sequencing. Hum Mol Genet 2012;21:4151-61. PMID 22492991
71: Van Schaftingen E, Jaeken J. Phosphomannomutase deficiency is a cause of carbohydrate-deficient glycoprotein syndrome type I. FEBS Lett 1995;377:318-20. PMID 8549746
72: Vermeer S, Kremer HP, Leijten QH, et al. Cerebellar ataxia and congenital disorder of glycosylation Ia (CDG-Ia) with normal routine CDG screening. J Neurol 2007;254:1356-8. PMID 17694350
73: Winawer MR, Griffin NG, Samanamud J, et al. Somatic SLC35A2 variants in the brain are associated with intractable neocortical epilepsy. Ann Neurol 2018;83(6):1133-46.** PMID 29679388
74: Witters P, Cassiman D, Morava E. Nutritional therapies in congenital disorders of glycosylation (CDG). Nutrients 2017;9(11):E1222. PMID 29112118
75: Witters P, Tahata S, Barone R, et al. Clinical and biochemical improvement with galactose supplementation in SLC35A2-CDG. Genet Med 2020;22(6):1102-7. PMID 32103184
76: Wong SY, Gadomski T, van Scherpenzeel M, et al. Oral D-galactose supplementation in PGM1-CDG. Genet Med 2017;19(11):1226-35. PMID 28617415
77: Wopereis S, Grunewald S, Morava E, et al. Apolipoprotein C-III isofocusing in the diagnosis of genetic defects in O-glycan biosynthesis. Clin Chem 2003;49:1839-45. PMID 14578315
78: Wu X, Steet RA, Bohorov O, et al. Mutation of the COG complex subunit gene COG7 causes a lethal congenital disorder. Nat Med 2004;10:518-23.** PMID 15107842

Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Author

Erik A Eklund MD PhD

Dr. Eklund of Lund University has no relevant financial relationships to disclose.
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Editor

Deepa S Rajan MD

Dr. Rajan of UPMC Children's Hospital of Pittsburgh has no relevant financial relationships to disclose.
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Former Authors

Jennifer Friedman MD

ICD & OMIM codes

ICD-9: Other specified disorders of carbohydrate transport and metabolism: 271.8
ICD-10: Other disorders of glycoprotein metabolism: E77.8

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Congenital disorders of glycosylation

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Congenital disorders of glycosylation …

Congenital disorders of glycosylation

Introduction

Overview

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Historical note and terminology

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Presentation and course

Prognosis and complications

Biological basis

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Diagnostic workup

Management

Special considerations

Pregnancy

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Congenital disorders of glycosylation

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Biological basis

Differential diagnosis

Diagnostic workup

Management

Special considerations

Pregnancy

Anesthesia

Media

References

Contributors

Author

Editor

Former Authors

ICD & OMIM codes

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Carnitine palmitoyltransferase II deficiency

Pelizaeus-Merzbacher disease

Vanishing white matter disease

Wilson disease

Aromatic L-amino acid decarboxylase deficiency

White matter abnormalities in the brain

Hypermethioninemia

POLG-related mitochondrial disorders

This is an article preview.
Start a Free Account
to access the full version.