PMM2 – Congenital Disorder of Glycosylation

PMM2 (phosphomannomutase 2) encodes the key enzyme that converts mannose-6-phosphate to mannose-1-phosphate, a precursor for GDP-mannose used in N-glycosylation. Biallelic loss-of-function variants in PMM2 cause congenital disorder of glycosylation (CDG) type Ia, the most common CDG subtype, characterized by multisystemic involvement including neurologic impairment and dysmorphic features (Gene Symbol, Disease Name).

Inheritance is autosomal recessive, with an estimated incidence of 1 in 20 000 to 1 in 40 000 live births and carrier frequencies of ~1% in European populations (PMID:10854097). Typical presentation includes axial hypotonia, developmental delay, failure to thrive, cerebellar hypoplasia, inverted nipples, coagulopathy, and variable cardiac and endocrine involvement.

Genetic evidence is robust: over 800 reported PMM2-CDG patients from more than 100 families harbor >100 distinct pathogenic variants including missense substitutions, nonsense and frameshift mutations, splice defects, and deep-intronic changes. The p.Arg141His (c.422G>A (p.Arg141His)) allele is the most frequent, always observed in compound heterozygosity, consistent with intolerance of homozygosity (PMID:9497260). Case series document recurrent variants across ethnicities without strict genotype–phenotype correlation (PMID:10801058).

Experimental assays demonstrate that most PMM2 mutations reduce enzyme stability or dimerization, yielding residual activities of 0–50% of wild type. Functional studies in patient fibroblasts, yeast models and a Pmm2R137H/F115L mouse replicate hypoglycosylation, impaired growth factor glycoproteins, and neurological phenotypes, and show that restoring PMM2 activity rescues biochemical defects (PMID:27053713). These data support a loss-of-function mechanism via haploinsufficiency.

No major conflicting reports have been published. Mitotic intragenic recombination and modifier alleles such as ALG6:F304S may influence expressivity but do not weaken the core gene–disease link.

In summary, PMM2-CDG is a well-established autosomal recessive inborn error of glycosylation with definitive clinical validity. Genetic testing of PMM2, coupled with transferrin isoform analysis and functional assays, is essential for diagnosis, family counseling, and emerging precision therapies targeting enzyme stabilization.

Key Take-home: PMM2 testing is critical in infants with multisystem dysfunction, and functional rescue strategies hold promise for this definitive AR disorder.

References

• American journal of medical genetics • 2002 • A deletion-insertion mutation in the phosphomannomutase 2 gene in an African American patient with congenital disorders of glycosylation-Ia. PMID:11891694
• Journal of inherited metabolic disease • 2000 • Genotypes and phenotypes of patients in the UK with carbohydrate-deficient glycoprotein syndrome type 1. PMID:10801058
• Human molecular genetics • 2016 • A mouse model of a human congenital disorder of glycosylation caused by loss of PMM2. PMID:27053713

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