Congenital Disorders of Glycosylation

Congenital disorders of glycosylation (CDG) refers to a group of multisystemic disorders characterized by dysmorphism, coagulation disorders and psychomotor retardation. Multiple subtypes exist, of which type Ia is by far the most common.

Carbohydrate-Deficient Glycoprotein Syndromes (former name).

There are basically two types of protein glycosylation: N-glycosylation and O-glycosylation. N-glycosylation comprises an assembly pathway (in the cytosol and the endoplasmic reticulum) and a processing pathway (in the endoplasmic reticulum and the Golgi complex). O-glycosylation is more complex but lacks a processing pathway. Of the 16 known defects, 12 affect N-glycosylation (eight are assembly defects [CDG Ia-Ih] and four are processing defects [CDG IIa-IId]) and four affect the O-glycosylation.

Approximately 350 patients with CDG type Ia (by far the most common type) have been reported worldwide. Half of these cases are estimated to have occurred in Scandinavia. For the other types of CDG, the number of reported patients varies between one and 30 for each type of CDG type I and II.

Autosomal recessive, except for the multiple exostoses syndrome, which is autosomal dominant inherited.

CDG are due to defects in the synthesis of the glycan moiety of glycoproteins and other glycoconjugates. It results in a defective attachment of carbohydrates to proteins due to mutations affecting the N-glycosylation or O-glycosylation. In CDG type I, lipid-linked oligosaccharide assembly and transfer is affected. In CDG type II, trimming of the protein-bound oligosaccharide or the sugar attachment to it is affected.

Clinical findings and electrophoretic patterns of serum transferrin (serum transferring isoelectrofocusing) is the gold standard for N-glycosylation defects. The lack of negatively charged sialic acid (a component of transferring) results in a cathodal shift in the electrophoresis, which is considered diagnostic, although a normal pattern does not exclude CDG. Multiple subtypes exist (see Table C-1), of which CDG type Ia is the most common. Depending on the subtype, coagulation disorders may result in a prothrombotic or bleeding tendency.

Conditions associated with a defect in N-glycosylation: The clinical features differ between the subtypes. The disorders may affect the head and neck (prominent forehead, large ears, strabismus, nystagmus, myopia, retinopathy pigmentosa, flat nasal bridge, thin upper lip, cleft palate), heart (hypertrophic obstructive cardiomyopathy, cardiac failure, exudative pericarditis, pericardial effusions), blood (prolonged prothrombin time, factor XI deficiency, antithrombin III deficiency, thrombocytosis, platelet hyperaggregability, neutrophil dysfunction, decreased levels of immunoglobulins A and G), central nervous system (psychomotor retardation, generalized hypotonia, cerebral and cerebellar abnormalities, ataxia, hyporeflexia, seizures, stroke-like episodes, olivopontine hypoplasia, Dandy-Walker Syndrome, peripheral neuropathy), skin (orange-peel skin, fat pads, inverted nipples, erythematous changes), endocrine system (hypothyroidism, hypogonadism), liver and gastrointestinal tract (hepatic fibrosis/cirrhosis, hepatomegaly, hypalbuminemia, ascites, failure to thrive, intestinal lymphangiectases, small bowel villous atrophy, abnormal intestinal permeability and enterocyte lipid transport, associated with abnormal glycosylation of intestinal glycoproteins, diarrhea, vomiting), and kidneys (renal cysts, proximal tubulopathy, nephritic syndrome). Other features include pleural effusions, osteopenia, recurrent fractures, kyphosis, dystrophic limbs, weakness, and joint contractures. The clinical picture of CDG type Ib differs markedly from the other forms of CDG, presenting as a protein-losing enteropathy, hyperinsulinemic hypoglycemia, and thrombosis or bleeding disorder. Generalized hypotonia is the only neurologic abnormality in CDG type Ib. Mannose substitution in these patients is an effective treatment. Death in early infancy has been described in a few patients with CDG.

In CDG type IIc, patients present with moderate-to-severe psychomotor retardation, seizures, hypotonia, strabismus, and feeding difficulties. These patients are prone to recurrent infections due to deficient neutrophil motility and can have the so-called Bombay blood phenotype, in which the patient inherits two recessive alleles of the H gene and therefore does not express the “H” protein on the erythrocyte surface. Because the “H” protein is a precursor of the “A” and “B” antigens in the ABO system, patients lack these antigens (they have blood group Oh. These patients can basically receive blood only from another Bombay phenotype person. Because this anomaly is very rare, arrangements for blood transfusions must be made well in advance.

Conditions associated with a defect in O-glycosylation:

Ehlers Danlos Syndrome (EDS): A heterogeneous group (9 types have been described) of inherited connective tissue disorders, characterized by joint hyperlaxity, skin extensibility and tissue fragility. A variant with progeroid features is caused by glucuronyltransferase/N-acetyl-D-hexosaminyltransferase deficiency.

HARD Syndrome (Acronym for: Hydrocephalus, Agyria, Retinal Dysplasia): A very rare and severe autosomal recessive, rapidly lethal syndrome with major neurological impairment. It is characterized by type II lissencephaly in association with retinal dysplasia, obstructive hydrocephalus, and agenesis of the corpus callosum. Affected infants typically have severe growth failure, severe microcephaly, seizures, microphthalmia, and cataracts. In addition, some affected infants have an occipital encephalocele.

Muscle Eye Brain Syndrome: This autosomal recessive inherited syndrome has many features in common with HARD Syndrome. It was first described by the Finnish physician Pirkko Santavuori in 1977. The main findings are congenital brain anomalies (pachygyria, polymicrogyria, hydrocephalus, and lissencephaly) with mental retardation and abnormal electroencephalogram, joint contractures, muscular dystrophy leading to generalized hypotonia and weakness (with increased levels of serum creatinine phosphokinase), and ocular lesions (retinal hypoplasia, glaucoma) resulting in impaired vision.

Multiple Exostoses Syndrome: Hereditary Multiple Exostoses (HME) is the only CDG that is inherited in an autosomal dominant fashion, although sporadic occurrence is responsible for approximately 10% of patients. Three different types of this disorder are known, each one resulting from a different genetic defect. The genetic defects of Type I, II, and III have been mapped to 8q24.11-q24.13, 11p12-p11, and 19p, respectively. The disorder is characterized by multiple epiphyseal exostoses of the long bones and the digits. Most of these exostoses do not grow any further once the patient has reached puberty, and treatment is often not required, however, in severe cases, the tumors may result in deformities of the forearms, spine, pelvis, knees, and ankles, or impose upon blood vessels, nerves, and tendons and, besides the locally destructive effects, also cause severe pain.

Cardiac, renal, thyroid, and hepatic function should be assessed preoperatively. Pericardial and pleural effusions should be sought and drained preoperatively if significant. Obtain a complete coagulation status. Check history for seizures and treatment efficiency. Patients may be severely developmentally delayed, sedative premedication, and/or presence of the primary caregiver for induction of anesthesia may be helpful. Ensure that the patient either does not have the Bombay phenotype or that compatible blood products are available for a procedure with potential blood loss.

In CDG type Ia, there is a prothrombotic tendency, whereas in CDG type IIa there is a bleeding tendency. Impaired cardiac function may occur secondary to cardiomyopathy and pericardial effusions. Kyphosis, recurrent fractures, and contractures can make patient positioning difficult and require special attention.

Chronic use of seizure medications and abnormalities of renal, hepatic, and thyroid function affect the metabolism and excretion of some anesthetic drugs. Drugs that reduce the seizure threshold or interfere with the antiepileptic treatment should be avoided. Avoid succinylcholine because of potentially exaggerated hyperkalemic response.