The CDG syndrome

Author: Doctor Nathalie Seta
Scientific Editor: Professor Jean-Marie Saudubray

Date of creation: February 2001
Up date : February 2003

Name of the disease and synonyms
CDG syndrome
Congenital disorders of glycosylation
Previously Carbohydrate-deficient glycosylation syndrome

Definition/Classification
CDG syndrome represents a group of innate diseases affecting the synthesis of glycoproteins; their classification is based on the level of the limiting step of glycosylation.

CDG I (upstream from the transfer of oligosaccharide onto the peptide chain) is the most common, with more than 300 cases described world-wide, and corresponds to the partial-to-total absence of the glycan chains of serum N-glycoproteins.
CDG Ia is an autosomal recessive disease characterized by a deficit in phosphomannomutase (PMM) activity and mutations in the PMM2 gene located on chromosome 16p13.
Only a limited number of cases of the other CDG I have been reported:
CDG Ib is associated with a deficit in phosphomannose isomerase (PMI gene); it can be treated with mannose per os.
CDG Ic presents a deficit in one of the glucosyltransferases of the endoplasmic reticulum (dolichyl-P-Glc:Man9GlcNAc2-PP-dolichyl alpha1,3 glucosyltransferase); it is characterized by a mutation in the apoptosis-linked gene hALG6.
CDG Id is deficient in one of the mannosyltransferases of the endoplasmic reticulum (dolichyl-P-Man:Man5GlcNAc2-PP-dolichyl alpha1,3 mannosyltransferase); it is characterized by a mutation in the hALG3 gene.
CDG Ie has a deficit in dolichyl-phosphate-mannose (Dol-P-Man) synthase of the endoplasmic reticulum; it is characterized by a mutation in the DPM1gene.
CDG If is associated with a deficit in Lec35, a protein whose role is not totally clear; it is characterized by a mutation in the Lec35 gene.
CDG Ig presents a deficit in one of the mannosyltransferases of the endoplasmic reticulum (dolichyl-P-Man:Man7GlcNAc2-PP-dolichyl alpha1,6 mannosyltransferase); it is characterized by a mutation in the hALG12 gene.

CDG II (downstream from the transfer of the oligosaccharide onto the peptide chain) is currently comprised of:
CDG II a is attributable to a deficit in UDP-GlcNAc:alpha-6-Dmannoside beta 1,2-N-Acetyl glucosaminyltransferase II (GnT II) of the median compartment of the Golgi apparatus and mutations in the MGAT2 gene.
CDG IIb is attributable to a deficit in glucosidase I of the endoplasmic reticulum and mutations in the corresponding gene.
CDG IIc (formerly called Leucocyte Adhesion Deficiency II; LAD II) is a deficit in the fucose transporter from the cytosolic compartment to the lumen of the Golgi apparatus; it is characterized by a mutation in the corresponding gene. It can be treated with fucose per os.

CDGx corresponds to patients whose deficit is unknown.
 

Clinical description
The clinical picture varies according to the type and is heterogeneous.
CDG Ia in its usual form is very characteristic and associated as of birth with an internal strabismus, marked hypotonia, inverted nipples and a very characteristic dysmorphism (almond-shaped eyes and large forehead). Atrophied cerebellum and/or cerebral trunk (olivopontocerebellar atrophy) are present. The first months of life see the appearance of lipocutaneous anomalies (peau d’orange, infiltration of the external face of the thighs and buttocks) that can already be present at birth, very frequently pigmentary retinitis and moderate hepatomegaly with cytolysis in association with quasi-constant hepatic fibrosis. Cardiac involvement (pericarditis, cardiomyopathy) is common and often responsible for death in the first or second year of life. Other manifestations can also be seen: renal, diverse endocrine (hypoglycemia due to hyperinsulinemia, hypogonadism, electrolyte loss), coagulation disorders. Sometimes, the disease can apparently start with one symptom or another. When seen late, the cutaneous signs have a tendency to disappear and the neurolgical manifestations to predominate (psychomotor retardation, peripheral neuropathy, ataxia).
CDG Ib has no neurological manifestations but hepatodigestive symptoms predominate (hepatic fibrosis, exsudative enteropathy, recurrent episodes of angiocolitis, hepatic cytolysis, coagulation disorders) and short-term fasting hypoglycemia that stimulates hyperinsulinism and can reveal the disease.
The other types (c, d and e) are too rare to describe the symptomatology, which seems to be primarily neurological (mental retardation, convulsions or grand-mal epilepsy).

Diagnostic criteria
The association of neurological signs, pigmentary retinitis, cutaneous signs and hepatodigestive signs (cytolysis, fibrosis) is highly suggestive of a CDG syndrome.
The diagnosis is based on the demonstration of serum N-glycoprotein glycosylation anomalies (isoelectrofocalization of serum transferrin or Western blot of different serum glycoproteins) and dosage of the responsible cellular (leukocytes or fibroblasts) enzymes, and the search for the corresponding mutations. Congenital galactosemia and fructose intolerance are considered to be secondary CDG syndromes since the serum glycoproteins present the same glycosylation anomalies.

Prenatal diagnosis
Type Ia can be diagnosed prenatally by enzyme dosage in cultured amniotic cells and trophobasts, and search for mutations in the corresponding gene.

Management
CDG Ib can be treated with mannose.
 

References
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2. Seta N, Dupré T, Cormier-Daire V, de Lonlay P, Durand G, Moore S, Codogno P. Le "Carbohydrate-Deficient Glycoprotéin syndrome" type I : un nouvel éclairage sur le métabolisme du mannose et la synthèse des N-glycosylprotéines. Médecine-Sciences, 1999, 15: 1202-10.

3. Van Schaftingen E, and Jaeken J. Phosphomannomutase deficiency is a cause of carbohydrate-deficiency glycoprotein syndrome type I. FEBS 1995 Lett; 377: 318-20.

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