INTRODUCTION — Congenital disorders of glycosylation (CDGs) are a group of over 100 monogenic human diseases with defects in the synthesis of oligosaccharides. Oligosaccharides, or glycans, are multisugar structures attached to proteins or lipids. This process of assembly involves multistep, dynamic and regulated synthetic pathways. Human glycosylation disorders reflect the functional impact of perturbed glycosylation on human physiology and embryogenesis.
Different types of glycosylation are defined by the biomolecule, protein or lipid, linked to the oligosaccharide and the type of chemical linkage to the oligosaccharide, nitrogen (N linked) or hydroxyl (O linked).
This topic gives an overview of the pathogenesis, clinical features, diagnosis, and management of CDGs. The major groups of human glycosylation disorders including disorders of the synthesis of N-linked protein glycosylation and O-linked protein glycosylation, as well as disorders affecting multiple glycosylation pathways, glycosylphosphatidylinositol (GPI) anchor synthesis, and lipid glycosylation, with examples of specific disorders, are discussed in detail separately. (See "Specific congenital disorders of glycosylation".)
CLASSIFICATION — There are approximately 160 different types of CDGs. Each type of CDG is defined and named by a specific gene, in which pathogenic variations lead to disturbed glycosylation. As an example, in persons with PMM2-CDG all affected have a pathogenic variant in the PMM2, the gene encoding phosphomannomutase 2. An estimated 1 to 2 percent of the human genome is dedicated to encoding functional genes needed for glycosylation , making it likely that many CDGs have yet to be discovered.
CDGs are classified according to the incorrectly glycosylated biomolecule, which can include proteins, lipids, or glycosylphosphatidylinositol. Protein glycosylation occurs in two main ways: N-glycosylation, in which glycans are assembled in the membrane of the endoplasmic reticulum and then attached to the nitrogen (N-) group of asparagine residues, and O-glycosylation, where sugars are attached to the hydroxyl (O-) groups of serine or threonine.
EPIDEMIOLOGY — The prevalence and incidence of CDGs as a group have not been established . The estimated prevalence in European and African Americans is 1/10,000, based upon carrier frequencies of potentially pathogenic variants in 53 genes in which pathogenic variants are known to cause a CDG . The most frequently diagnosed CDG is caused by pathogenic variants in the PMM2 gene (PMM2-CDG), with an estimated calculated disease frequency of 1/20,000 in the Dutch and Danish population  and 1/77,000 in Estonia . However, most types of CDGs have less than 100 reported cases worldwide [5,6].
PATHOGENESIS — The pathogenesis of CDG is not completely understood. The general hypothesis is that the glycosylation process is disturbed due to pathogenic variants in genes needed for normal glycosylation, leading to target biomolecules becoming underglycosylated or misglycosylated. This under- or mis-glycosylation then leads to malfunction or abnormal localization of that glycosylated compound, which results in functional physiologic and/or embryologic consequences.
The normal assembly of an oligosaccharide-protein or oligosaccharide-lipid structure requires building and modifying oligosaccharides, shuttling them to the correct intracellular location, and attaching them to the target protein or lipid. The function of glycans includes stabilizing the protein or lipid, instructing the three-dimensional shape and folding, or targeting these biomolecules to the correct intra- or extracellular compartment . These structural and localization factors influence the physiologic impact of glycosylation. Examples of the physiologic importance of glycosylation include the endocrine axis, where the interaction of hormone peptides and their receptors depend upon glycosylation; the immune system, where cell-cell interaction is glycan dependent; and human embryonic development, which uses surface glycans to determine cell-cell recognition.
There is better evidence for the mechanisms leading to certain clinical manifestations in some CDGs:
●Growth axis – In patients with CDG due to pathogenic variants in the genes encoding phosphomannomutase 2 (PMM2-CDG) and mannose phosphate isomerase (MPI-CDG), impaired glycosylation of acid labile subunit (ALS) and insulin-like growth factor binding protein (IGFBP) 3 leads to increased clearance and reduced ternary complex formation of ALS, IGFBP-3, and insulin-like growth factor (IGF) 1. This is thought to contribute to decreased growth in these disorders .
●Muscle integrity – In the dystroglycanopathies, a subset of protein O-glycosylation disorders, the heavily mannosylated protein alpha-dystroglycan is hypoglycosylated. Alpha-dystroglycan is an extracellular peripheral membrane involved with linking the extracellular matrix and intracellular cytoskeleton and is required for muscle integrity. This hypoglycosylation greatly reduces the binding affinity of alpha-dystroglycan for extracellular matrix components, leading to membrane fragility that results in elevations in serum creatine kinase and progressive muscle weakness and wasting . Stroke-like episodes are hypothesized to be related to hypoglycosylation of a voltage-gated potassium channel .
GENETICS — CDGs are monogenic disorders arising from pathogenic variants in genes encoding proteins involved with the glycosylation process. The majority of CDGs are autosomal-recessive disorders. Known exceptions are as follows:
•Dowling-Degos disease – POGLUT1-CDG (protein O-glucosyltransferase 1) and POFUT1-CDG (protein O-fucosyltransferase 1)
•Hereditary multiple exostoses syndrome – EXT1-CDG (exostosin glycosyltransferase 1) and EXT2-CDG (exostosin glycosyltransferase 2)
•Polycystic liver disease – GANAB-CDG (glucosidase II alpha subunit), SEC63-CDG (SEC63 homolog, protein translocation regulator), and PRKCSH-CDG (protein kinase C substrate 80K-H)
•ATP6AP1-CDG (ATPase H+ transporting accessory protein 1)
•C1GALT1C1-CDG (C1GALT1-specific chaperone 1)
•PIGA-CDG (phosphatidylinositol glycan anchor biosynthesis class A)
•SSR4-CDG (signal sequence receptor subunit 4)
•SLC35A2-CDG (solute carrier family 35 member A2)
•ALG13-CDG (ALG13, UDP-N-acetylglucosaminyltransferase subunit)
•MAGT1-CDG (magnesium transporter 1)
CLINICAL FEATURES — Given the ubiquitous nature of glycosylation in human biology, most CDGs exhibit multiorgan manifestations (table 1). The phenotypic spectrum is broad, both within and between types, with reported clinical presentations ranging from isolated developmental delay to multisystem manifestations [11,12]. Most patients present with neurologic findings. However, the clinical spectrum in children and adults can involve individual or multiple organ systems and may or may not affect neurodevelopment. Affected persons are now being diagnosed across multiple age groups and clinical specialties. Older affected persons may have a milder presentation, or the earlier diagnostic quest may have ended before CDG was recognized. In addition, the phenotypic spectrum is not completely known for many types of CDG, because so few affected persons have been reported. The introduction of diagnostic DNA sequencing in complex clinical cases has changed the phenotypic landscape, revealing novel clinical phenotypes in infants and adults not previously suspected of having glycosylation disorders.
Features in infants and children include:
●Failure to thrive, feeding difficulty
●Developmental delay, intellectual disability in school-age children
●Hepatopathy (elevated liver function tests, hypoalbuminemia)
●Neurologic signs (hypotonia, seizures, cerebellar findings, peripheral neuropathy, stroke-like episodes)
●Ophthalmologic signs (strabismus, cortical blindness, retinitis pigmentosa, external eye anomalies)
●Cardiac involvement (pericardial effusion, cardiac malformation, hypertrophic cardiomyopathy)
●Kidney involvement (multicystic kidneys, nephrotic syndrome, proteinuria, tubulopathy)
●Hematologic involvement (thrombosis or bleeding disorders with decreased coagulation factors including factor II, V, VII, IX, X, XI, protein C, protein S, and antithrombin [AT]-III)
●Endocrine involvement (postnatal growth failure, hypoglycemia, hypogonadotropic hypogonadism)
●Gastrointestinal involvement (chronic diarrhea, protein-losing enteropathy, gastroesophageal reflux, ascites, liver failure, portal hypertension)
●Immunologic findings (recurrent infections, lack of response to immunizations)
●Skeletal findings (osteopenia, pectus carinatum/excavatum, kyphosis/scoliosis)
●Skin abnormalities (peau d'orange, abnormal suprapubic and gluteal fat pads)
Features in adults include:
●Neurologic (cerebellar findings including ataxia, dysarthria, dysmetria, history of seizures or stroke-like episodes, peripheral neuropathy)
●Skeletal (osteopenia, pectus carinatum/excavatum, kyphosis/scoliosis)
●Hematologic (thrombosis or bleeding disorders with decreased coagulation factors including factor II, V, VII, IX, X, XI, protein C, protein S, and AT-III)
●Hepatic (cholestasis, unexplained fibrosis)
●Ophthalmologic (retinitis pigmentosa)
DIAGNOSIS — Given the diversity of the clinical presentations of CDGs and broad phenotypic spectrum, an underlying CDG should be suspected in any person with an unexplained clinical story but especially in persons who present with multisystemic disease (see 'Clinical features' above). When a CDG is suspected, the usual first step in screening is to send serum for transferrin and apolipoprotein CIII (ApoC-III) isoform analysis, although mass spectroscopy analysis of N- and O-glycan profiling is preferred, if available (table 2 and algorithm 1). Alternatively, molecular testing, in the form of single-gene sequencing if the phenotype is very specific; gene-panel sequencing; or whole exome or whole genome sequencing (WES and WGS) can be undertaken as the initial step, especially if the presentation fits a disorder that is known not to have detectable aberrant glycan species. The authors prefer WGS, with WES a close second, followed by gene panel sequencing, but the choice largely depends upon availability of each type of molecular test. Clinicians may decide to proceed with biochemical testing before molecular testing, molecular testing before biochemical confirmation, or to use both lines of testing simultaneously depending upon the accessibility of testing. Many times, both biochemical and molecular analysis are needed because of either incomplete assay sensitivity or identification of a previously undescribed genetic variant.
Serum transferrin isoform analysis is the most readily available and oldest clinical screen for CDGs. Unfortunately, it is only able to detect some N-glycosylation and mixed glycosylation defects. It is reliable for PMM2-CDG , the most common type, and MPI-CDG, a treatable type. Mass spectrometric methods, capable of identifying individual oligosaccharides and complete glycans by mass and charge, have replaced transferrin isoelectric focusing as the standard transferrin method for screening for CDGs .
If the screening isoform analysis is suggestive of a glycosylation defect, the typical next step is to confirm the diagnosis with enzymatic analysis for PMM2 or MPI and/or molecular sequencing. Molecular gene panel tests, WES, or WGS may be undertaken even if transferrin and ApoC-III isoform analysis and N- and O-glycan analysis are normal because there are significant false-negative rates in N- and O-linked glycan analysis, including the majority of cases of ALG13-CDG, RFT1-CDG, and SRD5A3-CDG . Certain CDGs do not show transferrin isoform abnormalities (MOGS-CDG, TUSC3-CDG [tumor suppressor candidate 3], SLC35A1-CDG, SLC35C1-CDG) . False negatives can also occur in the first three weeks of life . There are also reported cases where initially abnormal transferrin glycosylation normalizes without improvement in symptoms.
False-positive transferrin isoform analysis results occur in persons with galactosemia, inborn errors of fructose metabolism, chronic alcohol consumption, certain bacterial (neuraminidase-producing) infections, and in cases of mutations in the transferrin protein.
Outside of N-linked glycosylation disorders, diagnostic screening is more complicated. Screening for congenital muscular dystrophies (CMDs) caused by defective O-mannosylation requires a muscle biopsy with the use of monoclonal antibodies directed against the glycan . In these disorders, transferrin isoforms, ApoC-III isoforms, N-glycan profiling, and O-glycan profiling are expected to be normal. There is also no simple biomarker for defects in glycosaminoglycan (GAG) biosynthesis.
Many persons have been diagnosed with CDGs from next-generation sequencing or whole exome analysis . If novel DNA sequence variants are identified in a gene associated with a CDG, the functional consequence of the mutation may be confirmed using enzymatic assays or glycan profiling. Prenatal diagnosis is possible in all types of CDG for which the molecular defect is known from a previously diagnosed proband . (See "Next-generation DNA sequencing (NGS): Principles and clinical applications" and "Genetic testing".)
DIFFERENTIAL DIAGNOSIS — All metabolic diseases have wide phenotypic spectrums and overlapping clinical features that lead to an expansive differential diagnosis. Thus, the differential diagnosis of CDG includes other inherited multisystemic disorders with similar presentations (failure to thrive, hypotonia, developmental delay, and involvement of at least one other organ system), such as mitochondrial diseases, peroxisomal diseases, and lysosomal storage diseases. Each of these disease groups has a typical constellation of clinical features that are not often seen together in CDGs. As an example, infants with mitochondrial disease may have hypotonia, advancing muscle weakness, and cardiomyopathy while children with CDG may have hypotonia and pericardial effusion. Infants with peroxisomal biogenesis disorders may have characteristic dysmorphic facies, hepatic involvement, and bony stippling not seen in CDG. Infants and children with CDG do not typically have the progressive hepatosplenomegaly and dysostosis multiplex often seen in lysosomal storage diseases. The astute clinician will more easily find specific phenotypic features that differentiate these groups in older children and adults. Screening tests for CDGs and the disorders in the differential diagnosis are often performed early in the diagnostic odyssey or in any child with a potential metabolic cause of developmental delay because of the overlapping phenotypes that may include both unexplained neurologic features and involvement of other organ systems. (See "Mitochondrial myopathies: Clinical features and diagnosis" and "Peroxisomal disorders" and "Overview of inherited disorders of glucose and glycogen metabolism".)
MANAGEMENT — Only a few CDGs have a specific treatment available, mainly consisting of supplementation with simple sugars with the goal of improving hypoglycosylation. The treatment and management for other types of CDGs are primarily supportive and palliative.
Specific treatments — Specific treatments are available for the following CDGs:
●MPI-CDG is treated with oral D-mannose at a dose of 1 gram/kg/day divided into four to six doses . This therapy can improve the protein-losing enteropathy but does not halt the progression of the liver disease. Heparin has also been used for protein-losing enteropathy in MPI-CDG . Caution is needed during pregnancy since mannose supplementation in a pregnant murine model of MPI-CDG induced embryonic lethality and blindness in the offspring . In addition, administration of intravenous mannose in one patient was associated with normoglycemia but depressed consciousness and seizures that resolved with glucose administration .
●In SLC35C1-CDG, some, but not all, persons respond to oral fucose supplementation. A decreased incidence of recurrent infections with hyperleukocytosis, without change in the neurodevelopmental issues, is reported [24,25].
●There are ongoing trials to assess the efficacy of D-galactose (1.5 to 2.5 g/kg/day, maximum dose 50 grams) in PGM1-CDG (phosphoglucomutase 1). Preliminary findings show that this therapy can alleviate hypoglycemia, coagulopathy, and endocrinopathy . However, the cardiac and skeletal manifestations of PGM1-CDG are not expected to respond to D-galactose supplementation.
●Galactose has also been shown to correct the N-glycosylation defect in two persons with TMEM165-CDG (transmembrane protein 165), resulting in improved endocrine function and coagulation parameters .
●Extended-release sialic acid and N-acetylmannosamine (ManNAc) are under clinical investigation to treat GNE-CDG (glucosamine [UDP-N-acetyl]-2-epimerase/N-acetylmannosamine kinase), also known as hereditary inclusion body myopathy [28-30].
●In PIGM-CDG (phosphatidylinositol glycan anchor biosynthesis class M), butyrate was shown to resolve intractable seizures in one patient .
●In CAD-CDG (carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase), two persons had cessation of seizures and improvement in development and anemia on uridine supplementation .
Complications and other challenges — Common complications in patients with CDGs include failure to thrive, oral motor dysfunction with persistent vomiting, global developmental delay and intellectual disability, strabismus, myopia, astigmatism, and retinitis pigmentosa, coagulopathy, stroke-like episodes, and orthopedic problems, especially scoliosis and kyphosis. Additional challenges include transitioning to independent living. Management of these issues is most often standard of care and includes the following:
●Failure to thrive – Goals are to maximize caloric intake without any specific type of dietary restriction, employing oral, nasogastric, or gastrostomy techniques as needed. If oral motor dysfunction is identified, thickening of feeds, maintenance of upright position after eating, and/or antacids may help decrease reflux-related symptoms.
●Stroke-like episodes – Supportive therapy includes intravenous hydration and maintenance of normal blood glucose. Patients should also be assessed to ensure that seizures, thrombosis, or bleeding are not ongoing.
●Coagulopathy – Persons with CDG are at higher risk for coagulopathy and deep vein thrombosis (DVT) because of low pro- and anticlotting factors. Clinicians should have a high clinical index of suspicion for evaluation for thrombosis; educate affected patients and their families about their increased risks and presenting symptoms, especially in the setting of an individual with communication disabilities; and consult a hematologist prophylactically prior to surgery or if these complications are identified .
●Ophthalmology – Strabismus, myopia, astigmatism, and retinitis pigmentosa should be managed by a pediatric or adult ophthalmologist.
●Musculoskeletal – Thoracic abnormalities typically do not lead to respiratory compromise and should be followed conservatively. Kyphosis and scoliosis corrective surgeries have been performed in severe cases.
●Rehabilitation – Speech, occupational, physical, and feeding therapies and use of appropriate durable medical equipment with recommendation from rehabilitation medicine will help optimize functional abilities.
●Life skills and vocational training – Some patients may benefit from life skills and vocational training to assure that they live as independently as possible as adults.
●Vaccines – Routine vaccinations are recommended for adults and children affected with CDG, unless otherwise indicated.
Monitoring — The following laboratory tests are recommended at the time of diagnosis, especially for PMM2-CGD , and then annually unless otherwise indicated to establish the extent of disease and patient needs :
●Liver function tests including serum albumin
●Thyroid function tests including free T4 by equilibrium dialysis because thyroid-stimulating hormone (TSH) has been elevated in clinically euthyroid persons with CDG
●Protein C, protein S, antithrombin (AT) III, factor IX
●Serum gonadotropins in adolescent and adult women to evaluate for hypogonadotropic hypogonadism
●Echocardiogram in infants and children for evaluation of pericardial effusion with follow-up as clinically indicated
●Kidney ultrasound to evaluate for microcysts with follow-up as indicated
●Ophthalmologic examination for evaluation of lens, retina, ocular mobility, and intraocular pressure
●Clinical genetics evaluation to discuss the hereditary component of CDGs and updates learned about the disorder
PROGNOSIS — In infancy, evidence of multisystem involvement and the resulting complications must be treated promptly. However, despite all efforts, 25 percent mortality is reported in the first years of life . Morbidity in these infants includes infection, seizure, and hypoalbuminemia with third spacing that may progress to anasarca. Some children are responsive to aggressive albumin replacement with diuresis while others have a more refractory course . Infants who do not have a complicated early medical course may never be hospitalized and can be medically stable throughout their lives. For these patients, care is directed at optimizing growth and development. While the lifespan of affected persons is difficult to predict and is dependent upon their medical issues, adults with PMM2-CDG leading happy lives in their 40s and 50s are reported throughout the world.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Inborn errors of metabolism".)
SUMMARY AND RECOMMENDATIONS
●Overview – Congenital disorders of glycosylation (CDGs) are a large group of disorders resulting from defects in the synthesis of oligosaccharides, which are involved in many physiologic and embryologic systems. Perturbed glycosylation impacts multiple organs, most commonly neurologic, hepatic, musculoskeletal, and coagulation and endocrine pathways, with less frequent involvement of the kidneys and heart. (See 'Introduction' above and 'Pathogenesis' above.)
•Infants – Clinical presentation for all types is typically in infancy, although some patients are identified in adulthood. Infantile presentation includes developmental delay, failure to thrive, hepatopathy, hypotonia, hypoglycemia, protein-losing enteropathy, immunologic findings, and skin, eye, and skeletal findings. Most infants do not require hospitalization. However, an affected infant rarely may suffer an intractable course of infection or third spacing with anasarca leading to multiorgan system failure. Some affected infants are medically stable and never hospitalized, with their care directed at optimizing growth and development.
•Children – In childhood, developmental issues continue with neurologic signs of cognitive impairment, hypotonia, seizures, ataxia, dysarthria, and dysmetria. Hepatopathy stabilizes, although coagulopathy continues. Osteopenia is present, with kyphoscoliosis seen. Stroke-like episodes may occur. Retinitis pigmentosa may begin in childhood.
•Adults – Adults may have a milder presentation, or the diagnosis may have been missed in childhood. Clinical features may include nonprogressive cognitive impairment, cerebellar symptoms, skeletal findings including kyphoscoliosis and truncal shortening, stroke-like episodes, coagulopathy, or deep vein thrombosis (DVT). (See 'Clinical features' above and "Specific congenital disorders of glycosylation".)
●Diagnosis – CDGs should be considered in any child or adult with unexplained multiorgan system involvement. Diagnostic testing depends upon the suspected clinical type (table 2 and algorithm 1). (See 'Diagnosis' above.)
●Differential diagnosis – The differential diagnosis in patients with multiorgan system involvement includes mitochondrial diseases, peroxisomal diseases, and lysosomal storage diseases. Screening tests for CDGs and the disorders in the differential diagnosis are often performed early in the diagnostic odyssey or in any child with a potential metabolic cause of developmental delay because of the overlapping phenotypes that may include both neurologic features and involvement of other organ systems. (See 'Differential diagnosis' above.)
●Management – Management strategies for the many different types of CDG are mainly supportive. Clinical management areas include (see 'Management' above):
•Physical, occupational, and speech therapy to support development and function in infancy through adulthood
•Elemental formulas and possible gastrostomy tube for nutritional improvement in infants
•Consultation with ophthalmology to optimize vision in all ages and assess for retinitis pigmentosa
•Endocrinology assessment of thyroid, reproductive, glycemic, and growth axes
•Assessment by hematology, especially prior to surgery, of coagulation cascade (factors IX and XI, as well as protein C, protein S, and antithrombin [AT] III)
•Education of the affected person and/or their caregivers about clinical signs and increased risk of DVT
•Orthopedic management of kyphoscoliosis by standard measures to optimize function
•Administration of full course of immunizations, unless otherwise indicated
1 : Henrissat B, Surolia A, Stanley P. A genomic view of glycobiology. In: Essentials of Glycobiology [Internet], 3rd ed, Varki A, Cummings RD, Esko JD, et al (Eds), Cold Spring Harbor Laboratory Press, Cold Spring Harbor 2015.
3 : Lack of Hardy-Weinberg equilibrium for the most prevalent PMM2 mutation in CDG-Ia (congenital disorders of glycosylation type Ia).
4 : The Prevalence of PMM2-CDG in Estonia Based on Population Carrier Frequencies and Diagnosed Patients.
10 : Stroke-Like Episodes and Cerebellar Syndrome in Phosphomannomutase Deficiency (PMM2-CDG): Evidence for Hypoglycosylation-Driven Channelopathy.
11 : Stroke-Like Episodes and Cerebellar Syndrome in Phosphomannomutase Deficiency (PMM2-CDG): Evidence for Hypoglycosylation-Driven Channelopathy.
12 : Clinical, laboratory and molecular findings and long-term follow-up data in 96 French patients with PMM2-CDG (phosphomannomutase 2-congenital disorder of glycosylation) and review of the literature.
13 : International clinical guidelines for the management of phosphomannomutase 2-congenital disorders of glycosylation: Diagnosis, treatment and follow up.
19 : Gene identification in the congenital disorders of glycosylation type I by whole-exome sequencing.
22 : The clinical spectrum of phosphomannose isomerase deficiency, with an evaluation of mannose treatment for CDG-Ib.
23 : Seizures and stupor during intravenous mannose therapy in a patient with CDG syndrome type 1b (MPI-CDG).
29 : Aceneuramic Acid Extended Release Administration Maintains Upper Limb Muscle Strength in a 48-week Study of Subjects with GNE Myopathy: Results from a Phase 2, Randomized, Controlled Study.
30 : Safety, pharmacokinetics and sialic acid production after oral administration of N-acetylmannosamine (ManNAc) to subjects with GNE myopathy.
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