CDGIa

CDG-Ia, also known as PMM2-CDG, is a rare inherited metabolic disorder in the group of congenital disorders of glycosylation (CDG). It results from bi-allelic pathogenic variants in PMM2, which encodes phosphomannomutase 2, a key enzyme in the early steps of N-glycosylation.

Genetics and mechanism: The condition is autosomal recessive. The PMM2 gene is located on chromosome 16p13.2; affected individuals have two pathogenic PMM2 variants, one inherited from each parent. The enzyme deficiency disrupts synthesis of dolichol-linked oligosaccharides, leading to impaired N-glycosylation of numerous glycoproteins and widespread multisystem effects.

Clinical presentation: Symptoms typically begin in infancy with hypotonia, feeding difficulties, and developmental delay. As children age, they may develop ataxia, skeletal and musculoskeletal abnormalities, liver dysfunction, and coagulation abnormalities. Ocular and hearing problems are common, and distinctive features such as inverted nipples and abnormal fat distribution are frequently reported.

Diagnosis: Screening uses serum transferrin glycoform analysis, which shows an abnormal pattern consistent with CDG-I. Definitive diagnosis is by sequencing of PMM2 to identify bi-allelic pathogenic variants. Brain MRI can reveal cerebellar hypoplasia or atrophy; a comprehensive multisystem assessment is standard.

Management and prognosis: There is no disease-modifying cure; management is multidisciplinary and supportive, addressing nutrition, motor and developmental therapies, liver and coagulation monitoring, and infection prevention. Prognosis varies and depends on the extent of multisystem involvement.

Research and context: PMM2-CDG is the most common form of CDG. Ongoing research explores experimental therapies, potential enzyme- or substrate-targeted approaches, and natural-history studies through patient registries.