From the Research
Definition and Classification
- Carbohydrate-Deficient Glycoprotein Syndrome type 1A (CDG type 1A) is an autosomal recessive disorder characterized by defective glycosylation 1.
- It is also known as "Jaeken syndrome" and is linked to chromosome 16p13, with mutations identified in the PMM2 gene in CDG1 patients with a PMM deficiency (CDG1A) 1.
- CDG type 1A is a form of Congenital Disorder of Glycosylation (CDG), a group of inherited multisystemic disorders associated with abnormal glycosylation of serum glycoproteins 2.
Clinical Presentation
- Patients with CDG type 1A usually present with neurologic (hypotonia, strabismus, and cerebellar hypoplasia) and cutaneous (inverted nipples, abnormal distribution of adipose tissue) abnormalities, together with multivisceral involvement (digestive, hepatic, cardiac, renal) 2.
- However, neurologic and cutaneous symptoms may be absent, and CDG must be considered in cases of unexplained organ failure, such as isolated liver insufficiency, cardiomyopathy, pericarditis, tubulopathy, nephrotic syndrome, vascular accident, or retinitis pigmentosa 2.
- The clinical spectrum of symptoms in CDG is variable and may be unspecific, making a generous selective screening for the presence of CDG recommended 3.
Biochemical Abnormalities
- CDG type 1A is characterized by a deficiency of phosphomannomutase (PMM), the enzyme that converts mannose 6-phosphate to mannose 1-phosphate in the synthesis of GDP-mannose 1.
- Biological abnormalities, such as mild hepatic cytolysis, hematologic and hormonal abnormalities, are consistently observed in CDG type 1, as well as renal hyperechogeneity 2.
- The disialo- and tetrasialotransferrin isoforms in CDG type 1 patients have been analyzed, suggesting that disialotransferrin results from underglycosylation, as in PMM-deficient CDG type 1 patients 4.
Genetic Mutations
- Mutations in the PMM2 gene have been identified in CDG type 1A patients, with more than 95% of mutations detectable using a combination of SSCP and sequence analysis 5.
- The most common genotype was 357C>A/422G>A, and no patients homozygous for the most common mutation 422G>A were detected 5.
- The different mutations were clustered, with most located in exon 5 and exon 8, while no mutation was detected in exon 2 5.