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Specific congenital disorders of glycosylation

Specific congenital disorders of glycosylation
Donna M Krasnewich, MD, PhD
Christina Lam, MD, FAAP, FACMG
Carlos R Ferreira, MD, FACMG
Section Editor:
Sihoun Hahn, MD, PhD
Deputy Editor:
Elizabeth TePas, MD, MS
Literature review current through: Mar 2023. | This topic last updated: Nov 18, 2022.

INTRODUCTION — Congenital disorders of glycosylation (CDGs) comprise a group of over 160 monogenic human diseases with defects in the synthesis of oligosaccharides. Oligosaccharides 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 [1-6].

Different types of glycosylation are defined by the biomolecule, lipid or protein, linked to the oligosaccharide (also called a glycan) and the type of chemical linkage to the oligosaccharide, nitrogen (N-linked) or hydroxyl (O-linked).

In this topic review, we discuss the major groups of human glycosylation disorders (table 1), including disorders of N-linked protein glycosylation, O-linked protein glycosylation, glycosylphosphatidylinositol (GPI) anchor synthesis, lipid glycosylation, and disorders affecting multiple glycosylation pathways, and examples of specific disorders. An overview of the pathogenesis, clinical features, diagnosis, and management of CDGs is presented separately. (See "Overview of congenital disorders of glycosylation".)

N-LINKED CDGs — There are over 30 types of nitrogen (N) linked CDGs, with each type defined by the finding of a deleterious variant in a gene in the N-linked oligosaccharide synthetic pathway.

Epidemiology of N-linked CDGs — While there is no international registry, one report of collective data from European diagnostic labs on 1350 affected persons found that 94 percent had a type 1 CDG (CDG-I), while 6 percent had a type 2 CDG (CDG-II), with 22 different types of CDG-I and 15 types of CDG-II reported [1]. PMM2-CDG (phosphomannomutase 2) was the most frequent CDG by far in this population (62 percent), with ALG6-CDG (ALG6, alpha-1,3-glucosyltransferase) the next most common (8 percent). The rest of the CDG types are rare. The prevalence of PMM2-CDG in Europe is 0.1 to 0.5/100,000, which is 10-fold lower than the expected prevalence based on the carrier frequency of 0.13/10,000 [7] to 0.5/10,000 [8], strongly suggesting that these disorders are underdiagnosed.

Genetics of N-linked CDGs — Most N-linked CDGs are autosomal recessive (AR) disorders. Data gathered from at-risk pregnancies for PMM2-CDG have revealed that the outcome-based risk is closer to 1:3 rather than the predicted risk of 1:4 for AR disorders [9]. This suggests that gametes carrying a deleterious variant in PMM2 have a reproductive advantage at the stage of gametogenesis, fertilization, implantation, or embryogenesis.

Two N-linked CDGs are inherited in an autosomal dominant (AD) pattern: PRKCSH-CDG (protein kinase C substrate heavy chain) [10] and GANAB-CDG (glucosidase II alpha subunit) [11].

N-linked disorders that are X-linked include MAGT1-CDG (mannosyl [alpha-1,3-]-glycoprotein beta-1,2-N-acetylglucosaminyltransferase), ALG13-CDG (ALG13, UDP-N-acetylglucosaminyltransferase subunit), and SSR4-CDG (signal sequence receptor subunit 4) [12].

Pathophysiology of N-linked CDGs — The pathophysiology, while an area of active research, is not well understood. Classical glycobiology has shown that N-linked glycosylation is required for optimal protein folding, trafficking to the correct cellular compartment, turnover of serum glycoproteins, mediation of cell-cell and cell-matrix interactions, and peptide hormone and hormone receptor interactions. The changes are at the subcellular level and affect signaling and metabolic networks. Incorrect glycosylation can also alter the structure and function of glycoproteins, with pathology manifesting when the function falls below the reserve capacity. While the role of protein hypoglycosylation is not completely understood, congenital differences seen in the brain, eye, muscle, kidneys, and bone of affected infants imply an impact of incorrect glycosylation on human embryogenesis [13].

Clinical features of N-linked CDGs — Almost all types of N-linked CDGs present in infancy, although improvements in diagnosis mean affected persons are being identified at all ages. N-linked glycoproteins have many important biologic functions. Incorrect synthesis of these oligosaccharides involves individual or multiple organ systems and may or may not affect neurodevelopment. Presentation in adults may be on the milder end of the spectrum. The phenotypic ranges continue to expand as more affected patients are reported. Several reviews cover published clinical findings of most types of N-linked CDGs and the organ system(s) affected by the disorders [14-16].

Clinical features may include one or more of the following:

Faltering growth in infancy and childhood

Developmental delay



Cardiac issues, including pericardial effusion, cardiomyopathy, structural defects, and arrhythmogenic disorders

Enlarged kidneys, renal cysts, and congenital nephrotic syndrome


Other endocrine disorders including hypogonadotropic hypogonadism and hypothyroidism

Protein-losing enteropathy

Immunologic dysfunction

Congenital eye anomalies as well as strabismus

Skin and skeletal findings

Abnormal brain development (cerebellar atrophy and delayed myelination) detectable on magnetic resonance imaging (MRI)



Stroke-like episodes, typically during late childhood through early adulthood

Clinical presentation in infants and children — The clinical presentation in N-linked CDGs in infants and children is typically multisystemic. Developmental delay is the most common presenting feature, with involvement of other organ systems usually identified during the patient evaluation. Some infants may have a few to many additional presenting features, including neurologic involvement with brain anomalies, hypotonia, and seizures; musculoskeletal and connective tissue features; faltering growth; and immunologic, hepatic, kidney, skin, and eye manifestations.

Clinical features in adults — Clinical features of adults with an N-linked CDG may include a combination of static cognitive impairment, hepatic dysfunction, coagulopathy, retinitis pigmentosa, osteopenia or skeletal involvement, central nervous system involvement, peripheral neuropathy, history of stroke-like episodes or deep vein thrombosis (DVT), and endocrinopathies.

Examples of specific N-linked CDGs — To illustrate the clinical features found in persons affected by N-linked CDGs, three types are discussed in greater detail below. These include PMM2-CDG, the most common N-linked CDG; MPI-CDG (mannose phosphate isomerase), a treatable CDG; and ALG6-CDG, the second most common N-linked CDG. While these descriptions do not fit all affected persons, they will highlight the collective features, leaving rare phenotypic descriptions to available reviews and literature [14,15].

PMM2-CDG – PMM2-CDG (CDG-Ia) was the first described N-linked CDG and is the most common. The phenotypic spectrum ranges from the severely involved fetus with hydrops fetalis to a mild neurologic phenotype in adults with or without multisystemic findings. The clinical course of the most typical cases has been described in three stages: an infantile multisystem stage, late-infantile and childhood ataxia-intellectual disability stage, and adult stable disability stage [17,18].

Infantile multisystem presentation – Infants present with hypotonia, hyporeflexia, esotropia, and developmental delay. Their growth charts reveal faltering growth often accompanied by frequent vomiting. They often have abnormal fat distribution with fat pads over the buttocks and suprapubic areas. Most have elevated liver function tests and decreased pro- and anticoagulation factors including factor IX and XI, antithrombin (AT) III, protein C, and protein S. Rarely, infants may have a complicated early course, sometimes referred to as the infantile catastrophic phase, presenting with infection, seizures, or hypoalbuminemia with accumulation of fluid in interstitial spaces that may progress to anasarca. Some infants are never hospitalized, while others have significant neurologic and multiorgan system involvement, with 20 percent mortality in the first year of life.

Late-infantile and childhood ataxia-intellectual disability stage – Clinical manifestations in affected children between 3 to 10 years of age include hypotonia, ataxia, delayed language and motor development, cognitive impairment, seizures, retinitis pigmentosa, osteopenia, and joint contractures. Cerebellar hypoplasia on MRI may be seen. Stroke-like episodes or transient unilateral loss of function may occur following seizures, infection, fever, or trauma. Pro- and anticoagulation factors including factor IX and XI, AT-III, protein C, and protein S are decreased.

Adult stable disability stage – In this stage, patients have stable cognitive impairment with ataxia, dysarthria, and dysmetria. Peripheral neuropathy may be present with osteopenia and progressive thoracic and spinal deformities. Females lack secondary sexual development, and males may have decreased testicular volume. Pro- and anticoagulation factors including factor IX and XI, AT-III, protein C, and protein S remain diminished with an increased risk both of bleeding during surgery or trauma as well as DVT. Skeletal manifestations including kyphoscoliosis and osteopenia are common.

MPI-CDG – MPI-CDG (CDG-Ib), while less common than PMM2-CDG or ALG6-CDG, is unique because gastrointestinal symptoms characteristically bring the child to medical attention, the child's development is typically normal, and a therapeutic intervention is available. Children affected with MPI-CDG have cyclic vomiting, protein-losing enteropathy, hypoglycemia, coagulopathy, faltering growth, and progression to liver fibrosis. The liver fibrosis may progress to cirrhosis and require liver transplantation. Affected persons may also have an increased risk of bleeding and thrombosis due to decreased levels of pro- and anticoagulation factors. Affected persons are treated with mannose, a sugar that bypasses the metabolic block, 200 to 400 mg/kg four to six times per day, although treatment may not change the progression of the hepatopathy in all patients [19,20].

ALG6-CDG – ALG6-CDG is also a relatively common N-linked CDG compared with other types where only a few affected persons have been identified. Affected children have hypotonia, developmental delay, ataxia, and seizures [21]. Other reported findings include proximal muscle weakness, brachydactyly and unusual fingers, and low immunoglobulin G (IgG) levels.

Imaging in N-linked CDGs — Persons with defects in the synthesis of N-linked oligosaccharides, depending upon the type, may have brain findings on MRI. Cerebellar atrophy on brain MRI is found in most persons with the most common type of CDG, PMM2-CDG. Some affected persons may have a normal cerebellar MRI early in life, with enlarged hemispheric and vermian fissures seen in later studies. Olivopontocerebellar atrophy is less frequently reported. Rare MRI findings include hypomyelination, agenesis of the corpus callosum, and widening of the lateral ventricles in ALG6-CDG, for example [21]. Cerebral atrophy and delayed myelination have also been reported in ALG9-CDG (ALG9, alpha-1,2-mannosyltransferase) [22].

Bone imaging of persons with N-linked CDG reveals osteopenia, pectus excavatum, scoliosis, and kyphosis. Occasionally, long bone and digital anomalies are reported [23].

Kidney anomalies may include bilateral hyperechoic kidneys seen on ultrasound in children with PMM2-CDG [24].

Cardiac findings may include structural defects, cardiomyopathies, and pericardial effusion seen on ultrasound in children in approximately 20 percent of CDG types including ALG12-CDG (ALG12, alpha-1,6-mannosyltransferase), ALG9-CDG, PMM2-CDG, B3GALTL-CDG (beta 3-glucosyltransferase), B3GAT3-CDG (beta-1,3-glucuronyltransferase 3), POMT1-CDG (protein O-mannosyltransferase 1), and POMT2-CDG (protein O-mannosyltransferase 2) [25].

Laboratory findings in N-linked CDGs — Since N-linked glycosylation is involved in the function of many physiologic systems, abnormal laboratory findings are expected.

Liver – In most types of CDG, liver dysfunction leads to high aspartate aminotransferase (AST) and alanine aminotransferase (ALT) and decreased albumin [26]. AST and ALT can rise to 1000 units/L in infancy and early childhood but typically normalize by five years of age. Decreased albumin typically does not have clinical impact, although it has been reported to cause clinical problems in severe cases, such as anasarca in infants with severe multiorgan system involvement or in children with enteropathy or infections. There are a few CDG types, MPI-CDG, TMEM199-CDG (transmembrane protein 199), CCDC115-CDG (coiled-coil domain containing 115), and ATP6AP1-CDG (ATPase H+ transporting accessory protein 1), where liver involvement is a predominant finding.

Hematology – Glycosylation regulates the turnover of liver-derived proteins, so CDGs lead to low serum levels or activities of both pro- and anticoagulation proteins, such as factor IX, factor XI, protein C, protein S, and AT-III. Prothrombin time (PT) and partial thromboplastin time (PTT) can be normal [27].

Endocrine – Endocrine peptides and their receptors are also glycosylated. Thus, persons with CDG may have decreased peptide levels and limited receptor responsiveness.

Although children with CDG are usually chemically euthyroid [28], thyroid function tests may be abnormal. Thyroid hormone deficiency has been reported, although it is less common than previously thought. Free thyroxine (T4) should be measured by equilibrium dialysis, the most accurate method, to assure that the abnormal glycosylation does not interfere with the measurement.

Hypogonadotrophic hypogonadism is commonly reported in PMM2-CDG, with elevated follicle-stimulating hormone (FSH) and luteinizing hormone (LH) and low estradiol in females and low testosterone with elevated FSH levels in males [28].

Hypoglycemia is commonly seen in many types of CDG. There is some evidence that hyperinsulinemia is the basis of the low blood glucose. The human insulin receptor is heavily N-linked glycosylated and probably functions differently in persons with CDG [28].

Growth axis studies are complicated, and growth problems in these affected children reflect both nutritional factors as well as the function and stability of the components of the growth hormone/insulin-like growth factor (GH/IGF) cascade [28,29].

Immunology – Recurrent infections suggesting immunodeficiency are uncommon in persons with CDG, although there are reported cases of nonresponsiveness to childhood vaccinations [30]. Common vaccine titers are warranted in patients with N-linked CDGs and recurrent infections.

Diagnosis of N-linked CDGs — The diagnosis of N-linked CDG should be considered in any child or adult with multiorgan system involvement, especially those with any of the clinical manifestations described above (see 'Clinical features of N-linked CDGs' above). Serum transferrin isoform analysis is the most readily available 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. Diagnostic testing is reviewed in greater detail separately. (See "Overview of congenital disorders of glycosylation", section on 'Diagnosis'.)

False-positive transferrin isoform analysis results occur in persons with galactosemia, inborn errors of fructose metabolism [31], chronic alcohol consumption, certain bacterial (neuraminidase-producing) infections [32], and pathogenic variants in the transferrin gene [33]. False negatives can occur in the first three weeks of life [34,35]. There are also reported cases where initially abnormal transferrin glycosylation normalized without improvement in symptoms [36]. Certain N-linked defects do not show transferrin isoform abnormalities (MOGS-CDG [mannosyl-oligosaccharide glucosidase], TUSC3-CDG [tumor suppressor candidate 3]).

Mass spectroscopy analysis of N-glycan profiling is useful in screening of N-linked disorders and may direct the medical team to a gene or set of genes [37].

Molecular testing, in the form of single-gene sequencing if the phenotype is specific for a particular CDG, gene-panel sequencing, or whole exome or whole genome sequencing, can be undertaken to determine the specific defect. The number of diagnosed persons is increasing. In addition, phenotypic findings are expanding as persons are diagnosed when variants in a gene in the N-linked oligosaccharide synthetic pathway are found on whole exome or whole genome sequencing. (See "Next-generation DNA sequencing (NGS): Principles and clinical applications".)

Management of N-linked CDGs — Management for all CDGs can take place in a primary care setting with consultation to a team of specialists.

Highlights of management strategies for N-linked glycosylation and most multiple-pathway disorders except MPI-CDG (see 'CDGs affecting multiple pathways' below) include the following [1-6]:

Faltering growth is managed by optimizing caloric intake without restriction of carbohydrates or lipids that are well tolerated. Early in life, children may do better on elemental formulas. Feeds are advanced based upon oral motor function. A nasogastric tube or gastrostomy tube for nutritional support may be needed until oral motor skills improve. Adults typically eat regular diets.

Oral motor dysfunction with persistent vomiting is addressed by thickening feeds. Maintenance of an upright position after eating and antacids can be helpful for children with gastroesophageal reflux and/or persistent vomiting. Continued speech and oral motor therapy aids transition to oral feeds and encourages speech and communication when the child is developmentally ready.

The diagnosis of developmental delay requires support from occupational therapy, physical therapy, and speech therapy. As the developmental gap widens between children with CDG and their unaffected peers, caregivers may need continued counseling and support.

Some children with severe infantile multiorgan system involvement and anasarca are responsive to aggressive albumin replacement with diuretics while others may have a more refractory course. D-dimer levels, albumin levels, and urinalysis for proteinuria during severe acute illness can help direct management. If any are abnormal, reflex to check protein C activity. If albumin and/or protein C activity are low, infusion with fresh-frozen plasma or activated protein C can reduce endothelial permeability and decrease symptoms of anasarca [38].

Consultation with an ophthalmologist early in life is important so that potential eye abnormalities can be diagnosed and therapies that preserve vision (glasses, patching or surgery for strabismus) can be instituted as needed. Continued follow-up through adulthood with an ophthalmologist for diagnosis of retinitis pigmentosa and counselling about changing vision needs, if present, are important.

Coagulopathy should be assessed in affected persons at diagnosis, routinely every one to two years, and prior to surgical procedures. Low levels of coagulation factors, both pro- and anticoagulant, rarely cause clinical problems in daily activities but must be addressed in a presurgical or trauma setting. Consultation with a hematologist to document and monitor the pro- and anticlotting factor levels and coagulation status, is advised for every patient, especially if deficiencies are identified. If necessary, infusion of fresh-frozen plasma corrects the factor deficiency and clinical bleeding. The potential for imbalance of the level of both pro- and anticoagulant factors may lead to either bleeding or thrombosis. Caregivers, especially of older affected persons, should be taught the signs of DVT, which can occasionally be mistaken for injury from trauma in persons with intellectual and communication disabilities.

Endocrine peptide hormones and biomarkers, including gonadotropins, peptides in the thyroid and growth axis, glucose, insulin, and other hypoglycemia labs as well as calcium, magnesium, and phosphorus, should be monitored at diagnosis, every one to two years thereafter, and as needed based upon clinical symptoms [27,39]. Diagnosis of hypothyroidism and L-thyroxine supplementation is reserved for those children and adults with elevated thyroid-stimulating hormone (TSH) and low free thyroxine measured by equilibrium dialysis, the method unaffected by abnormal glycosylation. Other endocrine issues are addressed by standard of care. The exception is that estrogen supplementation is rarely used in females with hypogonadism because of the risk of coagulopathy and DVT in affected persons.

Baseline kidney ultrasound should be performed on all affected children at the time of diagnosis [17]. While proteinuria in affected children is rare, routine urinalysis to evaluate for proteinuria is recommended after diagnosis. Creatinine should be checked yearly, and follow-up of urinalysis should be performed in the first three years of life or if clinical signs indicate.

Liver function tests should be followed every three to six months until they normalize.

Stroke-like episodes may occur, typically during late childhood through early adulthood. Supportive therapy includes intravenous hydration, maintenance of normal blood glucose, and physical therapy during the recovery period.

Most persons affected with CDGs have functional immune systems. However, children with rare types of N-linked CDG have recurrent or unexpectedly severe infections and should be evaluated by an immunologist. Unless otherwise indicated, full pediatric vaccinations are recommended for affected children and adults. Antibody levels can be measured to evaluate responsiveness to childhood vaccines.

Osteopenia and low bone mineral density are seen in many forms of CDG. In PMM2-CDG, these are typically first seen in adolescence. Encouraging mobility in a safe environment is advised. Successful use of bisphosphonates is also under exploration.

Adults with glycosylation disorders may have additional management needs including:

Care for orthopedic complications including thorax shortening, scoliosis/kyphosis. Management involves appropriate orthopedic and physical therapy, as well as surgery in severe cases [40] .

DVT has been reported in some adults with PMM2-CDG and MPI-CDG and should be kept in mind in the management of all persons with CDG [41,42]. Sedentary affected adults and children are at increased risk for DVT. Rapid diagnosis and treatment of DVT are essential to minimize the risk of pulmonary emboli.

O-LINKED CDGs — There are over 40 types of hydroxyl (O) linked CDGs, with each type defined by the finding of a deleterious variant in a gene in the O-linked oligosaccharide synthetic pathway.

Epidemiology of O-linked CDGs — Dystroglycan is a glycoprotein that connects the intracellular cytoskeleton with the extracellular matrix in skeletal muscle; the glycan chain is attached to dystroglycan via O-mannosylation. Defects in every single step in the biosynthesis of this glycan chain have been described, leading to muscular dystrophies (dystroglycanopathies). The estimated prevalence of congenital muscular dystrophies (CMDs) of the dystroglycanopathy type is 0.226/100,000 (1 in 442,000), accounting for 40 percent of all CMDs [43]. However, this value only accounts for the more severe forms of dystroglycanopathies, not those presenting with limb-girdle muscular dystrophy. In Japan, a form of dystroglycanopathy known as Fukuyama CMD has a prevalence of approximately 1 in 10,000 [44]. Approximately 100 persons have been reported with Peters plus syndrome due to an O-fucosylation defect [45].

Genetics of O-linked CDGs — A founder mutation consisting of a retrotransposal insertion in fukutin (FKTN) explains the high prevalence of Fukuyama CMD in Japan [44]. There is also a founder mutation in fukutin-related protein (FKRP) associated with limb-girdle muscular dystrophy type 2I that is seen in populations of European origin, including Hutterites [46]. Another founder mutation in FKRP exists in the Tunisian population [47], while a founder mutation in protein O-linked mannose N-acetylglucosaminyltransferase 1 (beta 1,2-; POMGNT1) explains the high prevalence of muscle-eye-brain disease (MEB) in Finland [48].

Pathophysiology of O-linked CDGs — There are many different types of O-glycosylation that are based upon which type of sugar is attached to serine or threonine. For example, defects of O-mannosylation lead to an under-glycosylation of alpha-dystroglycan, a protein needed for attachment of the subsarcolemmal cytoskeleton of the skeletal muscle cell to the extracellular matrix (ECM). When alpha-dystroglycan is not glycosylated adequately, its anchoring function is lost, leading to various types of CMDs.

Defects in O-xylosylation (or subsequent N-acetylgalactosamine [GalNAc] addition) lead to defective anchoring of glycosaminoglycans (GAGs) to proteins given that a tetrasaccharide composed of Xyl-GalNAc-GalNAc-GlucA acts as a linker between the GAG and protein in proteoglycans. Since many proteoglycans are important components in the skeleton and connective tissue, disorders of GAG synthesis usually lead to skeletal dysplasias or connective tissue disorders.

N-acetylgalactosaminyltransferase 3 (GALNT3) catalyzes the mucin type O-glycosylation of fibroblast growth factor 23 (FGF23). This growth factor acts on the renal tubule to promote renal phosphate excretion, while it acts in the intestines to decrease phosphate absorption. The secretion of FGF23 requires O-galactosylation by GALNT3 [49], and this glycosylation also protects FGF23 from cleavage. A defect in this enzyme thus leads to decreased intact FGF23 with increased serum phosphorus levels, and it account for 75 percent of hyperphosphatemic familial tumoral calcinosis cases [50].

Clinical features of O-linked CDGs — The presentation of CDGs resulting from defective O-linked glycosylation synthesis is variable in both age of diagnosis and clinical manifestations. All affect skeletal and connective tissue in some manner, and involvement of the eye and brain can be seen in some types of O-linked synthetic defects.

Defects in O-mannosylation are associated with muscular dystrophies of different severities, from the more severe muscular dystrophy-dystroglycanopathy with brain and eye anomalies (type A), to the milder congenital muscular dystrophy (CMD) dystroglycanopathy with intellectual impairment (type B), and the even milder limb-girdle muscular dystrophy-dystroglycanopathy (type C) that presents in adulthood. The type A group is historically subdivided into the more severe Walker-Warburg syndrome (WWS) and the slightly less severe MEB. Persons with WWS show severe eye anomalies (such as congenital glaucoma, optic nerve hypoplasia, or retinal hypoplasia) and severe intellectual disability. Persons with MEB commonly show eye anomalies such as microphthalmia, retinal detachment, cataracts, or anterior chamber dysgenesis. Persons with milder forms of the disease can have developmental delay and intellectual disability of variable severity, even in the absence of structural anomalies of the central nervous system. Persons with the milder limb-girdle muscular dystrophy phenotype present with predominant proximal muscle weakness without intellectual disability. Finally, certain pathogenic variants in FKTN are associated with isolated dilated cardiomyopathy without limb-girdle weakness [51].

Defects in O-xylosylation present mainly with skeletal and connective tissue changes. In particular, persons with defects in any of the enzymes adding sugar moieties to create the linker tetrasaccharide present with marked joint laxity and/or subluxations, including a defect in the enzyme adding xylose to the proteoglycan (a form of Desbuquois dysplasia), the second enzyme transferring galactose to xylose (a form of Ehlers-Danlos syndrome), the third enzyme adding another galactose moiety (a form of spondyloepimetaphyseal dysplasia with joint laxity), and the fourth enzyme adding glucuronic acid (a form of Larsen syndrome) to finish the synthesis of the tetrasaccharide upon which GAGs are added. Other enzymes involved in the modification of GAGs also present with skeletal changes and joint laxity.

The most common defect in O-fucosylation presents with Peters plus syndrome, characterized by anterior chamber defects of the eye, variable intellectual disability (in 80 percent of cases), dysmorphic facial features, short stature, and frequently cleft lip and/or palate [45]. The characteristic anterior chamber defect is Peters anomaly, with central corneal clouding, thinned posterior cornea, and iridocorneal adhesions, while the dysmorphic facial features include a prominent forehead, short palpebral fissures, long philtrum, and an exaggerated Cupid's bow. Cleft lip is seen in almost half of all affected persons, cleft palate in approximately a third, heart defects in up to a third, and genitourinary anomalies in up to a fifth of affected persons. Dowling-Degos disease, another defect in O-fucosylation, is an autosomal dominant disorder of reticulate pigmentation mainly affecting the flexural areas. Pathogenic variants in the enzymes transferring xylose and glucose to proteins in the canonical Notch signaling pathway are associated with this phenotype as this pathway is known to participate in the survival of melanoblasts [52].

A defect in O-galactosylation of FGF23 leads to hyperphosphatemic familial tumoral calcinosis (FTC) or the allelic condition hyperostosis-hyperphosphatemia syndrome. A review of 56 affected persons with molecularly confirmed hyperphosphatemic FTC found hyperphosphatemic FTC alone in 54 percent of affected persons, hyperostosis-hyperphosphatemia alone in 11 percent, and combined hyperphosphatemic FTC with hyperostosis in 36 percent of subjects, with females manifesting hyperostosis more commonly [50].

Imaging in O-linked CDGs — Findings on brain magnetic resonance imaging (MRI) in patients with O-linked CDGs include:

Cobblestone lissencephaly, severe cerebellar and brainstem hypoplasia, and hydrocephalus in WWS

Frontoparietal polymicrogyria, cerebellar vermis hypoplasia, and brainstem hypoplasia and commonly also hydrocephalus in MEB

Variable cortical findings in Fukuyama CMD, from normal to only simplified gyri or severe polymicrogyria or pachygyria; the brainstem is usually normal, while the cerebellum can show hypoplasia

The hallmarks for considering a diagnosis of dystroglycanopathy include cobblestone lissencephaly, cerebellar cysts, pontine hypoplasia, and brainstem bowing [53]. There is good correlation between the severity of brain imaging findings and developmental outcomes [53].

Persons with O-xylosylation defects can have various changes on skeletal radiographs including:

Characteristically prominent lesser trochanter, imparting an aspect of "Swedish key" or "monkey wrench" to the proximal femur in Desbuquois dysplasia. Other features include advanced carpal and tarsal ossification, joint subluxations, and, in many cases, an accessory ossification center at the base of the second proximal phalanges and a bifid distal phalanx of the thumbs and first toes [54].

Platyspondyly, trident acetabula, and craniosynostosis in EXTL3-CDG (exostosin-like glycosyltransferase 3) [55].

Preaxial brachydactyly, hyperphalangism, and phalangeal duplication in CHSY1-CDG (chondroitin sulfate synthase 1) [56].

Multiple exostoses in EXT1-CDG (exostosin glycosyltransferase 1) and EXT2-CDG (exostosin glycosyltransferase 2).

Hyperphosphatemic FTC is characterized by the development of calcified masses around one or more large joints, easily seen on skeletal radiographs.

Laboratory findings in O-linked CDGs — A few O-linked CDGs have unique laboratory findings. Persons with EXTL3-CDG have T cell-negative severe combined immunodeficiency, hypereosinophilia, and hyperimmunoglobulin E (IgE) [55,57]. Persons with CHST14-CDG (carbohydrate sulfotransferase 14) can have a prolonged bleeding time and abnormal findings on platelet aggregometry [58].

The laboratory findings of hyperphosphatemic FTC include increased tubular resorption of phosphate for the degree of hyperphosphatemia, elevated or inappropriately normal 1,25-dihydroxyvitamin D, and low intact FGF23 with markedly increased C-terminal FGF23, indicative of increased FGF23 cleavage with normal calcium and parathyroid hormone (PTH) [59].

Diagnosis of O-linked CDGs — The diagnosis of O-linked CDG should be considered in persons with any combination of skeletal, connective tissue, eye involvement, and brain differences. O-glycosylation disorders are not detected by transferrin glycosylation analysis. Thus, other proteins are used for screening for O-glycosylation disorders, such as apolipoprotein CIII (apoCIII) isoelectric focusing or mass spectrometry. Additionally, the analysis of O-glycans chemically released from serum glycoproteins can aid in the diagnosis [60]. Diagnosis of CMDs caused by defective O-mannosylation requires a muscle biopsy with the use of monoclonal antibodies (IIH6 and VIA4-1) directed against the glycan itself. There are also no simple markers for defects in GAG biosynthesis. Diagnostic testing is reviewed in greater detail separately. (See "Overview of congenital disorders of glycosylation", section on 'Diagnosis'.)

Management of O-linked CDGs — Evidence-based guidelines exist for the management of persons with CMDs [61]. Highlights of management strategies for CMDs include the following (see "Oculopharyngeal, distal, and congenital muscular dystrophies", section on 'Congenital muscular dystrophies'):

Consultation with a pediatric neuromuscular specialist for diagnosis and, management, and coordination of multidisciplinary care is advised.

When muscle biopsies are indicated, they should be performed and interpreted at experienced centers.

Clinicians should monitor pulmonary function, with frequency individualized based upon clinical status.

Evaluations by swallow therapists, gastroenterologists, and radiologists are advised if there is evidence of faltering growth or respiratory involvement.

Children should be referred for a baseline cardiac evaluation.

Patients should be monitored as high-risk patients in the postoperative period because of the clinical risk of neuromuscular involvement.

In persons with hyperphosphatemic FTC, treatment modalities consist of decreasing the intestinal absorption of phosphate or increasing the renal excretion of phosphate. Decreased enteral absorption can be achieved by restricting dietary phosphate (with a target range of 400 to 900 mg/day) plus use of phosphate binders, such as aluminum hydroxide or sevelamer. Increased renal excretion of phosphate can be achieved by the use of probenecid or acetazolamide [59,62]. There is variable response to treatment, with some persons demonstrating complete resolution of the calcific lesions, while others show no improvement. Surgical debulking can be performed in affected persons with pain, deformity, or restriction of joint mobility, but unfortunately the calcific masses tend to recur.

GPI ANCHOR CDGs — There are over 20 types of glycosylphosphatidylinositol (GPI) anchor CDGs, with types defined by the finding of a deleterious variant in a gene in the GPI anchor biosynthetic pathway.

Epidemiology of GPI anchor CDGs — There are approximately 100 persons reported with GPI anchoring defects.

Genetics of GPI anchor CDGs — There are over 20 genes associated with GPI biosynthetic defects. Pathogenic variants in six of these genes cause Mabry syndrome (the two most common being phosphatidylinositol glycan anchor biosynthesis class V [PIGV] and post-GPI attachment to proteins 3 [PGAP3]), while pathogenic variants in three other genes cause multiple congenital anomalies-hypotonia-seizures syndrome (MCAHS; the two most common being phosphatidylinositol glycan anchor biosynthesis class A [PIGA] and phosphatidylinositol glycan anchor biosynthesis class N [PIGN]).

A founder mutation in PGAP3 was described in the Egyptian population [63]. PIGM-CDG (phosphatidylinositol glycan anchor biosynthesis class M) is associated with hypomorphic pathogenic variants in the PIGM promoter region [64]. A recurrent nonsense mutation in PIGA is associated with Simpson-Golabi-Behmel syndrome type 2 [65].

Pathophysiology of GPI anchor CDGs — The biosynthesis of GPI requires the addition of sugars to phosphatidylinositol. There are 10 steps required for the synthesis and maturation of GPI, with at least 26 subunits participating in this pathway [66]. GPI is needed for anchoring of approximately 150 different proteins to the cell surface [66]. Thus, a defect in GPI biosynthesis leads to mislocalization of these proteins.

Clinical features of GPI anchor CDGs — There are two main phenotypic groups of GPI biosynthetic defects, MCAHS and Mabry syndrome (hyperphosphatasia with intellectual disability), and a few less common phenotypes. However, overlap exists between these types regardless of the involved gene, and defects in a particular gene can be associated with different phenotypes.

Persons with MCAHS usually present with macrosomia and macrocephaly at birth, followed by profound intellectual disability. Typical dysmorphic features include bitemporal narrowing, large ears with over-folded helices, deep plantar creases, and coarse facies [67]. Multiple congenital anomalies can be seen, but anorectal anomalies are particularly common, such as anal atresia or anal stenosis.

Persons with Mabry syndrome have global developmental delay, large and fleshy earlobes, brachytelephalangy, and frequently also anorectal malformations [68]. However, brachytelephalangy has also been described in patients with MCAHS.

PIGL-CDG (phosphatidylinositol glycan anchor biosynthesis class L), also known as CHIME syndrome, is characterized by coloboma, congenital heart disease, ichthyosiform dermatosis, intellectual disability, ear anomalies with conductive hearing loss, and epilepsy [69]. However, pathogenic variants in this gene have also been described in a patient in with Mabry syndrome [70].

Another recognizable phenotype is that of PIGM-CDG, which leads to portal vein thrombosis and seizures [64].

Pathogenic variants in PIGA are associated with MCAHS, but also with a syndrome of systemic iron overload with epileptic encephalopathy known as ferro-cerebro-cutaneous syndrome [71], with Simpson-Golabi-Behmel syndrome type 2 [65], or with a milder phenotype with intellectual disability and seizures but without dysmorphic features and structural anomalies of the central nervous system [72]. Similarly, pathogenic variants in PIGN are not only associated with MCAHS, but also with Fryns syndrome [73].

Imaging in GPI anchor CDGs — A thin corpus callosum and delayed myelination is seen on brain magnetic resonance imaging (MRI) in some persons with severe PIGA-CDG [72]. Restricted diffusion of myelinated fibers consistent with intramyelin edema has also been described on diffusion-weighted imaging [72].

In persons with PGAP3-CDG, frequently described features include a thin corpus callosum, mild ventriculomegaly, and variable cerebellar vermis hypoplasia [63].

Laboratory findings in GPI anchor CDGs — Alkaline phosphatase is anchored to the plasma membrane through GPI. Thus, many GPI biosynthetic defects, including Mabry syndrome and other forms of GPI anchoring defects such as PIGA-CDG, which is one cause of MCAHS, present with hyperphosphatasemia due to its increased release.

Since lipoprotein lipase is also anchored to the cell surface via GPI, hypertriglyceridemia has also been reported [72].

Diagnosis of GPI anchor CDGs — Defects in GPI synthesis can be identified using flow cytometry of GPI-anchored proteins, such as CD16, CD24, CD55, CD59, and fluorescein-labeled proaerolysin (FLAER) on leukocytes [74]. Diagnostic testing is reviewed in greater detail separately. (See "Overview of congenital disorders of glycosylation", section on 'Diagnosis'.)

Management of GPI anchor CDGs — PIGM-CDG is caused by pathogenic variants leading to hypoacetylation of the promoter region of PIGM. Butyrate is a histone deacetylase inhibitor that results in increased transcription of the gene. It was successfully used in one patient to control seizures [75].

Alkaline phosphatase is needed for absorption of pyridoxine across the blood-brain barrier. A mislocalization of alkaline phosphatase can lead to pyridoxine-responsive seizures. Thus, pyridoxine has been used for treatment of seizures in GPI anchoring defects [76].

Other forms of GPI biosynthetic defects are treated supportively.

LIPID GLYCOSYLATION CDGs — Only three lipid glycosylation disorders have been defined. They are caused by pathogenic variants in genes in the lipid glycosylation synthetic pathway.

Epidemiology of lipid glycosylation CDGs — Approximately 60 persons have been diagnosed with ST3GAL5-CDG (ST3 beta-galactoside alpha-2,3-sialyltransferase 5). Many belong to the Old Order Amish population due to a founder mutation [77], although families from other populations have also been reported [78,79]. There are approximately 50 persons diagnosed with B4GALNT1-CDG (beta-1,4-N-acetylgalactosaminyltransferase 1) in approximately 20 families spread across the globe [80-83].

Genetics of lipid glycosylation CDGs — Both ST3GAL5-CDG and B4GALNT1-CDG are inherited in an autosomal recessive pattern. Pathogenic variants in ST3GAL5 cause loss of function of monosialoganglioside 3 (GM3) synthase. The most commonly reported pathogenic variant is c.862G>T (p.Arg288*), which is a founder variant in the Old Order Amish population. Additional pathogenic variants include the c.994G>A (p.E332K) implicated in salt and pepper syndrome [78], c.694C>T also from the Old Order Amish population, and c.601G>A (p.Gly201Arg) and c.584G>C (p.Cys195Ser) variants found in one Korean family [79]. Similarly, pathogenic variants in B4GALNT1 cause loss of function in GM2/disialoganglioside (GD2) synthase.

Pathophysiology of lipid glycosylation CDGs — Gangliosides are believed to be involved with regulation of receptor-mediated cell-signaling pathways [84] and apoptosis [85]. They are also components of the synaptic plasma membrane involved in synaptic plasticity, signal transduction, and endocytosis [81]. In the brain, they account for more of the total sialic acid content at neural cell surfaces than glycoproteins and contribute to neural cell function through direct interaction with carbohydrate binding proteins and their membrane-partitioning characteristic that indirectly modulates cell signaling [78].

ST3GAL5-CDG is due to deficiency of GM3 synthase, also known as lactosylceramide alpha-2,3 sialyltransferase, which catalyzes the initial step in biosynthesis of complex gangliosides from lactosylceramide [84]. Persons with ST3GAL5-CDG are deficient in GM3 ganglioside and its derivatives and have increased lactosylceramide and its derivatives, although it is not clear if the clinical features are due to the deficiency or excess. Fibroblasts in persons with ST3GAL5-CDG demonstrate almost complete depletion of cellular gangliosides, suppressed epidermal growth factor receptor activation, and defective cell proliferation and migration [86]. Additionally, secondary respiratory chain dysfunction was noted in fibroblasts and the liver of persons with ST3GAL5-CDG [80]. N- and O-linked protein glycosylation profiles are shifted towards increased abundance of complex sialylated structures with decrease high-mannose precursors in ST3GAL5-CDG [78].

B4GALNT1 encodes beta-1,4-N-acetyl-galactosaminyl transferase 1, also known as GM2/GD2 synthase. This enzyme catalyzes the transfer of N-acetyl-galactosamine (GalNAc) into GM3, GD3, and globotriaosylceramide (Gb3) by a beta-1,4 linkage needed for the biosynthesis of the complex gangliosides GM2 and GD2. The clinical phenotype may be due to accumulation of Gb3 and simple gangliosides and/or lack of complex gangliosides [81]. On pathologic examination, spasticity is due to retrograde degeneration of the longest nerve fibers in the corticospinal tracts and posterior columns [82].

Clinical features of lipid glycosylation CDGs — Both ST3GAL5-CDG and B5GALNT1-CDG present with a primarily neurologic phenotype with intellectual disability. However, the specific findings are quite different, with ST3GAL5-CDG exhibiting epilepsy more commonly and B5GALNT1-CDG exhibiting a phenotype of a complex hereditary spastic paraplegia. Common clinical diagnoses attached to ST3GAL5-CDG are Amish infantile epilepsy and salt and pepper developmental regression syndrome.

In ST3GAL5-CDG, prenatal and perinatal histories are typically normal, with first symptoms occurring between ages two weeks and three months and consisting of irritability, poor feeding, vomiting, and faltering growth despite adequate nutrition [77]. Most persons develop intractable seizures in the first year of life, including generalized tonic-clonic seizures, startle myoclonic, tonic spasms, and startle from sleep. Electroencephalograms (EEGs) exhibit multifocal epileptiform discharges superimposed on diffuse slow background. Affected persons also exhibit profound developmental delay. The majority are nonverbal and not being able to sit, reach, or walk [84]. Other reported symptoms include choreoathetosis, hypotonia, cortical visual impairment, optic atrophy, normal retinal function on electroretinography [85], deafness with absent middle-ear muscle reflexes at all frequencies [80], abnormal auditory brainstem responses, absent cochlear microphonics, and abnormal cortical auditory evoked potentials [87]. Later-onset (after age three years) findings include freckle-like hyperpigmented macules, mainly on dorsal aspects of the hands and feet, and hypopigmented macules and patches on face and extremities [86].

In B4GALNT1-CDG, affected persons may develop progressive spastic paraparesis and weakness of variable severity during childhood to early adulthood, with predominant lower limb spasticity. Additional clinical features include dysarthria, distal amyotrophy, facial dyskinesia and dystonia, extrapyramidal signs, cerebellar ataxia, mild-to-moderate intellectual disability, emotional lability and psychiatric illness, infrequent seizures, bladder disturbances, decreased vibration sense, scoliosis, strabismus, low levels of testosterone in males, and pes cavus [81,88]. Electromyography/nerve conduction velocity (EMG/NCV) range from normal to showing peripheral neuropathy, and EEGs are normal [88].

A4GALT-CDG (alpha 1,4-galactosyltransferase) causes NOR polyagglutination syndrome, characterized by red blood cell agglutination to virtually all human sera, with the exception of autologous serum and cord sera (sera from newborns) [89,90].

Imaging in lipid glycosylation CDGs — There are no reports of structural abnormalities in the brain in ST3GAL5-CDG, but progressive diffuse atrophy with rare cases of white-matter hyperintensities have been noted [80]. In B4GALNT1-CDG, brain magnetic resonance imaging (MRI) ranges from normal to having slightly enlarged corpus callosum, white-matter hyperintensities, and cortical or subcortical atrophy [88].

Laboratory studies in lipid glycosylation CDGs — In ST3GAL5-CDG, plasma and fibroblasts show low GM3, GD3, and more complex gangliosides derived from GM3 and GD3 as well as increased lactosylceramide and Gb4 levels. In B4GALNT1-CDG, fibroblasts show decreased GM2 and increased GM3 levels [82]. Unfortunately, these labs are not clinically available. Persons affected with ST3GAL5-CDG also exhibit occasional elevations in serum lactate [80], and some males affected with B4GALNT1-CDG have low testosterone [88].

Diagnosis of lipid glycosylation CDGs — Diagnosis of lipid glycosylation CDGs are typically by whole genome or whole exome sequencing in probands with clinical findings consistent with reported cases or increased familial risk after the diagnosis of a sibling.

Management of lipid glycosylation CDGs — Management of patients with ST3GAL5-CDG and B4GALNT1-CDG is mainly supportive, with standard of care for the clinical manifestations they develop. In ST3GAL5-CDG, oral ganglioside supplementation leads to transient improvements in growth and development that unfortunately disappear after 12 months of supplementation [91].

CDGs AFFECTING MULTIPLE PATHWAYS — There are over 60 types of CDGs affecting multiple pathways (mixed nitrogen [N] and hydroxyl [O] linked CDGs), with each type defined by the finding of a pathogenic variant in a gene with the potential to disrupt pathways common to both N-linked and O-linked glycan synthesis.

Epidemiology of CDGs affecting multiple pathways — Only a handful of persons have been identified with each of the numerous disorders of glycosylation affecting multiple pathways. As an example, only 33 affected persons have been described with a defect in any of the seven subunits of the component of oligomeric Golgi (COG) complex [92].

Genetics of CDGs affecting multiple pathways — Given the small number of persons with each genetic defect, there are no known genotype-phenotype correlations, although, in the case of COG defects, it is suspected that variants in genes encoding for the subunits of lobe A lead to a more severe phenotype than that associated with variants in genes encoding subunits of lobe B [92].

Specific conditions are common in certain populations, with a founder mutation in solute carrier family 39 member 8 (SLC39A8) in the Hutterite population [93], in phosphoglucomutase 3 (PGM3) in the Tunisian population [94], and in solute carrier family 35 member C1 (SLC35C1) in Arab Israelis [95].

A common recurrent intronic splice site mutation in COG7 has been described [96].

Pathophysiology of CDGs affecting multiple pathways — Examples of the pathophysiology of several pathways involved in these CDGs include the following:

Dolichol is the lipid anchor upon which the lipid-linked oligosaccharide is built during the N-glycosylation assembly process. In addition, dolichol is needed as a sugar donor in the form of Dol-P-Man, which donates mannoses for O-glycosylation of dystroglycan and for glycosylphosphatidylinositol (GPI) biosynthesis. Thus, a defect in the synthesis or utilization of dolichol affects multiple pathways.

CAD is a trifunctional enzyme composed of carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase, the first three enzymes in the biosynthetic pathway of pyrimidines. These pyrimidines are needed in order to activate the sugars, so they can act as sugar donors [97].

In persons with SLC39A8-CDG due to a defect in the manganese transporter, the low availability of manganese leads to a deficient activity of manganese-dependent enzymes such as beta-1,4-galactosyltransferase [98].

A defect in the Golgi transport of both uridine diphosphate-glucuronic acid (UDP-GlcA) and uridine diphosphate-N-acetylgalactosamine (UDP-GalNAc) leads to disturbed glycosaminoglycan synthesis and a severe and lethal skeletal dysplasia known as Schneckenbecken dysplasia.

The COG complex, which is composed of eight subunits with four subunits forming each of its two lobes, mediates retrograde vesicular trafficking from the Golgi to the endoplasmic reticulum (ER). COG defects thus lead to mislocalization of the glycosylation machinery.

The vacuolar ATPase is an enzymatic complex that couples the energy from adenosine triphosphate (ATP) hydrolysis into pumping protons across membranes. Defects in the subunits or assembly of this vacuolar ATPase lead to abnormal Golgi pH, and thus altered Golgi homeostasis leads to disruptions in glycosylation.

Clinical features of CDGs affecting multiple pathways — Clinical manifestations in persons with CDGs involving multiple pathways typically affect multiple organ systems and may present from infancy to early childhood. These include neurologic, bone marrow, skin, cardiac, and skeletal features, reflecting the importance of glycosylation in human embryology and physiology. Examples of manifestations of CDGs due to defects affecting multiple glycosylation pathways include the following:

Defects in one of the subunits of the Dol-P-Man synthase (DPM1, DPM2, or DPM3) cause a muscular dystrophy with hypoglycosylation of alpha-dystroglycan, like that caused by specific defects in the O-mannosylation defects described previously (see 'Clinical features of O-linked CDGs' above). Patients with a deficiency of dolichol kinase present with dilated cardiomyopathy, also related to hypoglysylation of alpha-dystroglycan [99].

CAD deficiency in CAD-CDG leads to epileptic encephalopathy and dyserythropoietic anemia [100].

Persons with SLC39A8-CDG have variable short stature and neurologic symptoms, such as intellectual disability, infantile spasms, hypotonia, and cerebellar atrophy [93,98].

A defect in the transport of both UDP-GlcA and UDP-GalNAc across the Golgi presents with Schneckenbecken dysplasia, meaning "snail pelvis" in German. This lethal skeletal dysplasia receives its name from the medial bone excrescence protruding from the inner iliac margin, which resembles the head of a snail, and thus gives the whole pelvis the aspect of this mollusk.

COG7-CDG is associated with a characteristic phenotype of severe microcephaly and intellectual disability, ventricular septal defect, adducted thumbs, and episodes of extreme hyperthermia [96], while patients with COG6-CDG frequently exhibit hypohidrosis.

Persons with ATP6V0A2-CDG (ATPase H+ transporting V0 subunit a2) have generalized cutis laxa, motor developmental delay, short stature, marked joint laxity, and commonly also seizures. Persons with ATP6V1E1-CDG (ATPase H+ transporting V1 subunit E1) have generalized cutis laxa, while persons with ATP6V1A-CDG (ATPase H+ transporting V1 subunit A) have large skin folds. The last two can be associated with severe cardiorespiratory complications, including pneumothorax, congenital heart defects, aortic root dilatation, and hypertrophic cardiomyopathy, which distinguishes these two entities from ATP6V0A2-CDG [101].

Imaging in CDGs affecting multiple pathways — In persons with SLC39A8-CDG, the brain magnetic resonance imaging (MRI) not only shows cerebral and cerebellar atrophy but also restricted diffusion and T2-weighted hyperintensities of the basal ganglia [102].

Aside from the characteristic snail pelvis (see 'Clinical features of CDGs affecting multiple pathways' above), persons with Schneckenbecken dysplasia present a bell-shaped thorax, handlebar clavicles, hypomineralization of the vertebral bodies, interpedicular narrowing, and metaphyseal flaring on radiographs [103].

TMEM165-CDG (transmembrane protein 165) causes a spondyloepimetaphyseal skeletal dysplasia with marked osteopenia [104].

Laboratory findings in CDGs affecting multiple pathways — Several CDGs affecting multiple pathways have unique laboratory findings. They are reviewed below.

Diagnosis of CDGs affecting multiple pathways — The diagnosis of a CDG that affects multiple glycosylation pathways should be considered in persons with multiple organ system involvement including brain, bone marrow, skin, heart, kidney, and skeleton/connective tissue. Diagnostic testing for CDGs is reviewed in greater detail separately. (See "Overview of congenital disorders of glycosylation", section on 'Diagnosis'.)

The diagnosis of a multiple-pathway CDG is typically made through molecular testing using whole exome or whole genome sequencing of a child or adult with clinical features of CDG. In addition, specific multiple-pathway CDGs show the laboratory features noted below:

SLC39A8-CDG – Variably low concentrations of manganese and zinc in blood, with elevated concentrations in the urine, indicative of renal wasting [93]. A type II glycosylation pattern is found on transferrin analysis.

PGM3-CDG – Increased IgE levels, eosinophilia, impaired T cell proliferation, and a reversed CD4/CD8 ratio [105].

CDGs caused by defects in vacuolar ATPase subunits - A type 2 pattern on transferrin analysis plus abnormalities on O-glycosylation analysis.

TMEM199-CDG and CCDC115-CDG – Elevated transaminases, elevated alkaline phosphatase, hypercholesterolemia, and low serum ceruloplasmin and have thus been known to be confused with Wilson disease [106,107].

Disorders of vesicular trafficking due to COG defects and due to TMEM165 deficiency – Abnormalities in screening tests for both N- and O-glycosylation.

Defects in transport through SLC35A1 and SLC35C1 – Associated with a normal transferrin analysis [108], but an SLC35C1 defect can be associated with leukocytosis and an abnormal N-glycan profile, while a defect in SLC35A1 has a normal N-glycan profiling [109].

Management of CDGs affecting multiple pathways — Highlights of management strategies for most multiple-pathway disorders except MPI-CDG are reviewed above (see 'Management of N-linked CDGs' above). Examples of additional management approaches for specific disorders include the following:

The dilated cardiomyopathy associated with dolichol kinase deficiency has been successfully treated with cardiac transplantation [110].

Since persons with CAD-CDG (carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase) cannot synthesize uridine needed for activation of sugars to act as donors, supplementation of uridine has been tried in affected persons, leading to neurodevelopmental progress and resolution of anemia [100].

In persons with SLC39A8-CDG, supplementation with galactose and uridine led to a normalization of glycosylation on transferrin analysis [98]. Treatment with manganese supplementation was attempted in two persons with SLC39A8-CDG, with improvement of neurologic symptoms, although patients receiving this treatment should be carefully monitored for findings of manganism that resemble Parkinson disease and may include irritability, aggressiveness, hallucinations, tremors, difficulty walking, and facial muscle spasms [111].

In TMEM165-CDG, supplementation with D-galactose at a dose of 1 g/kg/day led to normalization of the glycosylation abnormalities [112].

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".)


Classification of CDGs – 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. CDGs are classified according to the incorrectly glycosylated biomolecule, which can include proteins, lipids, or glycosylphosphatidylinositol. The types of glycosylation include nitrogen (N) linked protein glycosylation, hydroxyl (O) linked protein glycosylation, combined N- and O-linked protein glycosylation, glycophosphotidylinositol (GPI) anchor synthesis, and lipid glycosylation. (See 'Introduction' above and "Overview of congenital disorders of glycosylation", section on 'Classification'.)

Clinical features – The phenotypic spectrum of CDGs is broad, both within and between types. Most patients present with neurologic findings. Clinical presentations range from isolated developmental delay to multisystem manifestations (table 1) (see "Overview of congenital disorders of glycosylation", section on 'Clinical features'). Some features are more common or unique to certain CDGs types or defects:

N-linked CDGs – Almost all types of N-linked CDGs present in infancy with multisystem disease that often includes neurodevelopmental defects. Presenting features may include neurologic involvement with brain anomalies, hypotonia, and seizures; musculoskeletal and connective tissue features; faltering growth; and immunologic, hepatic, kidney, skin, and eye manifestations. Presentation in adults is typically on the milder end of the spectrum and may include a combination of static cognitive impairment, hepatic dysfunction, coagulopathy, retinitis pigmentosa, osteopenia or skeletal involvement, central nervous system involvement, peripheral neuropathy, history of stroke-like episodes or deep vein thrombosis (DVT), and endocrinopathies. (See 'Clinical features of N-linked CDGs' above.)

O-linked CDGs – The presentation of CDGs resulting from defective O-linked glycosylation synthesis is variable in both age of diagnosis and clinical manifestations. Presenting features may include congenital hypotonia, muscular dystrophy, eye anomalies, anatomic brain anomalies, and skeletal and connective tissue changes. (See 'Clinical features of O-linked CDGs' above.)

Glycosylphosphatidylinositol (GPI) anchor CDGs – The two main phenotypic groups of GPI biosynthetic defects are multiple congenital anomalies-hypotonia-seizures syndrome (MCAHS) and Mabry syndrome. Persons with MCAHS usually present with macrosomia and macrocephaly at birth, followed by profound intellectual disability. They also have dysmorphic features and may have multiple congenital anomalies. Persons with Mabry syndrome have global developmental delay; large, fleshy earlobes; brachytelephalangy; and often also anorectal malformations. (See 'Clinical features of GPI anchor CDGs' above.)

Lipid glycosylation CDGs – These CDGs present with a primarily neurologic phenotype with intellectual disability. Epilepsy is seen more commonly in one form and, in another, complex hereditary spastic paraplegia. (See 'Clinical features of lipid glycosylation CDGs' above.)

CDGs affecting multiple pathways – Clinical manifestations in persons with CDGs involving multiple pathways typically affect multiple organ systems. These include neurologic, bone marrow, skin, cardiac, and skeletal features. (See 'Clinical features of CDGs affecting multiple pathways' above.)

Diagnostic testing – Diagnostic testing depends upon the suspected clinical type (table 2 and algorithm 1) (see "Overview of congenital disorders of glycosylation" and 'Diagnosis of N-linked CDGs' above and 'Diagnosis of O-linked CDGs' above and 'Diagnosis of GPI anchor CDGs' above and 'Diagnosis of lipid glycosylation CDGs' above and 'Diagnosis of CDGs affecting multiple pathways' above):

Serum transferrin glycosylation isoform analysis is useful in screening of N-linked glycosylation disorders.

N-glycan profiling is useful in screening of N-linked and mixed N- and O-linked glycosylation disorders.

Apolipoprotein CIII isoform analysis can be used to screen some mixed N- and O-linked and O-glycosylation disorders.

Muscle biopsy in an expert lab is the gold standard for diagnosis of O-linked glycosylation disorders, particularly the congenital muscular dystrophies.

O-glycan profiling is useful in screening a subset of mixed N- and O-linked glycosylation disorders.

Urine oligosaccharide analysis by mass spectrometry is useful in detecting MOGS-CDG (mannosyl-oligosaccharide glucosidase).

Phosphomannomutase 2 (PMM2) or mannose phosphate isomerase (MPI) enzymatic analysis in leukocytes or fibroblasts is clinically available for diagnosis of PMM2-CDG and MPI-CDG, especially if needed to clarify variants of uncertain significance in PMM2 or MPI.

The choice of single gene, gene panel, whole exome, or whole genome sequencing for initial or confirmatory testing depends upon the specificity of the clinical presentation and biochemical marker analysis, if performed. More affected persons are being identified by deoxyribonucleic acid (DNA) sequence analysis. Often, whole genome or whole exome sequencing reveals a pathogenic variant in one of the glycosylation synthetic pathways before a CDG is even considered.

Management – Management strategies for the many different types of CDG are mainly supportive. There are few therapeutic interventions for different types of CDG, with evidence-based practice dependent upon small clinical populations in these rare diseases. (See "Overview of congenital disorders of glycosylation", section on 'Management' and 'Management of N-linked CDGs' above and 'Management of O-linked CDGs' above and 'Management of GPI anchor CDGs' above and 'Management of lipid glycosylation CDGs' above and 'Management of CDGs affecting multiple pathways' above.)

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Topic 126336 Version 2.0


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