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
|CDG type Ia||Phosphomannomutase II deficiency|
|Olivopontocerebellar atrophy of neonatal onset|
|Sialotransferrin development deficiency syndrome|
|CDG type Ib||Phosphomannose isomerase deficiency|
|CDG type IIc||Leukocyte adhesion deficiency syndrome types I and II (II: Rambam-Hasharon syndrome)|
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
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
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.
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|CDG Type||CDG Subtype||Defect||Enzyme Defect||Clinical Presentation|
|I||Ia||N-glycosylation (assembly)||Phosphomannomutase II deficiency||Multisystem disease, hyperglycinemia (see text)|
|Ib||N-glycosylation (assembly)||Phosphomannose isomerase deficiency||Hyperinsulinemic hypoglycemia|
|Ic||N-glycosylation (assembly)||Glycosyltransferase I deficiency ||Hypotonia, strabismus, seizures|
|Id||N-glycosylation (assembly)||Mannosyltransferase VI deficiency ||Severe psychomotor retardation, brain anomalies, microcephaly, hypsarrhythmia|
|Ie||N-glycosylation (assembly)||Dolichylphosphate-mannose synthase I deficiency||Severe psychomotor retardation, seizures, microcephaly|
|If||N-glycosylation (assembly)||Lec35 deficiency ||Severe encephalopathy, dwarfism, erythematous skin disorder|
|Ig||N-glycosylation (assembly)||Mannosyltransferase VIII deficiency||Facial dysmorphism, psychomotor retardation, hypotonia, seizures, microcephaly|
|Ih||N-glycosylation (assembly)||Glycosyltransferase II deficiency||Hepatomegaly, protein-losing enteropathy, ascites, hypalbuminemia|
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