PMM2

PMM2 refers to the human gene that encodes the enzyme phosphomannomutase 2, a cytosolic enzyme that participates in the N-glycosylation pathway by converting mannose-6-phosphate to mannose-1-phosphate, a precursor used for the synthesis of GDP-mannose and the assembly of N-linked glycans. When PMM2 function is defective, glycosylation of many glycoproteins is impaired.

The PMM2 gene is located on chromosome 16p13.3 and is inherited in an autosomal recessive manner. Biallelic pathogenic variants in PMM2 cause PMM2-CDG, also known as CDG-Ia, which is the most common form of congenital disorder of glycosylation.

Clinical features typically begin in infancy or early childhood and reflect multisystem involvement. Features can include developmental delay, hypotonia, feeding difficulties, growth failure, skeletal anomalies, and dysmorphic traits such as inverted nipples. Neurologic signs may include cerebellar hypoplasia or ataxia. Hepatic dysfunction, coagulopathy, and susceptibility to infections are also reported, with severity varying among individuals.

Diagnosis is supported by laboratory evidence of hypoglycosylation, most commonly abnormal serum transferrin glycoforms detected by isoelectric focusing or mass spectrometry, followed by molecular genetic testing that identifies biallelic PMM2 variants. Prenatal testing may be available in some clinical settings.

There is currently no cure for PMM2-CDG; management is supportive and multidisciplinary, focusing on nutrition, physical and developmental therapies, and monitoring and treatment of organ-specific complications. The prognosis is variable and largely depends on the extent of glycosylation impairment and subsequent organ involvement.