Pmm2Edit
PMM2, or phosphomannomutase 2, is a cytosolic enzyme that plays a central role in the early steps of protein glycosylation, a fundamental cellular process that attaches sugar chains to many proteins. The PMM2 gene encodes this enzyme, and mutations in PMM2 cause PMM2-congenital disorder of glycosylation (PMM2-CDG), the most common form of congenital disorders of glycosylation (CDG). The disease is inherited in an autosomal recessive pattern and presents as a multi-systemic condition that can be apparent in infancy and varies widely in severity. Diagnosis primarily relies on biochemical studies of protein glycosylation—often demonstrated by abnormal transferrin glycoforms—followed by confirmation through sequencing of the PMM2 gene. Management is multidisciplinary and focused on treating symptoms and supporting development, nutrition, and organ function as needed.
Function and metabolic role
PMM2 catalyzes the interconversion between mannose-6-phosphate and mannose-1-phosphate, a step that feeds into the production of GDP-mannose. GDP-mannose serves as a donor sugar for the assembly of N-linked glycans, GPI anchors, and other glycosylation pathways. Proper N-glycosylation is essential for the stability, folding, and function of a large proportion of secreted and membrane-bound proteins. When PMM2 function is compromised, the cellular glycosylation machinery is affected broadly, leading to the multi-systemic manifestations seen in PMM2-CDG and related disorders. Related pathways and components include the dolichol-linked oligosaccharide precursor assembly and the broader network of glycosylation that shapes protein maturation and cell signaling. N-glycosylation GDP-mannose GPI-anchor glycosylation transferrin are related terms that provide context for the biochemical underpinnings of PMM2-CDG.
Genetics and epidemiology
PMM2-CDG is caused by biallelic mutations in the PMM2 gene and is inherited in an autosomal recessive pattern. Carriers typically do not have the full-blown disease, though rare milder effects can occur in some contexts. PMM2-CDG is the most frequent subtype among the congenital disorders of glycosylation, a family of rare, inherited metabolic disorders with diverse clinical pictures. The condition is globally rare but can appear with greater frequency in populations where consanguineous marriages are more common, reflecting the autosomal recessive inheritance pattern. For researchers and clinicians, this pattern informs carrier testing, counseling, and considerations around family planning. See also congenital disorders of glycosylation for broader context.
Clinical presentation and diagnosis
Infants with PMM2-CDG typically show multi-systemic involvement that may include developmental delay, hypotonia, failure to thrive, and distinctive patterns of organ involvement such as hepatic dysfunction, coagulation abnormalities, and immune or endocrine issues. The clinical course is highly variable; some individuals experience significant neurologic impairment early on, while others have a comparatively milder trajectory.
A key diagnostic clue is the biochemical signature of defective glycosylation in serum glycoproteins. Transferrin, a major serum glycoprotein, often shows an abnormal glycoform pattern detectable by isoelectric focusing (IEF). This transferrin glycoform pattern points clinicians toward a CDG diagnosis and prompts genetic testing of PMM2. Definitive diagnosis requires sequencing of the PMM2 gene to identify pathogenic variants. In parallel, genetic panels and broader testing for CDG may be used to exclude or confirm related glycosylation disorders. See transferrin and isoelectric focusing for related diagnostic concepts, and PMM2-CDG as the disease-specific designation.
Diagnosis and management
Diagnosis combines biochemical screening (notably abnormal transferrin glycoforms by IEF) with molecular confirmation of PMM2 mutations. Once PMM2-CDG is diagnosed, care is typically coordinated by a multidisciplinary team to address growth, nutrition, neurology, hepatology, hematology (coagulation), immunology, vision, and hearing as needed. Supportive therapies aim to optimize feeding and growth, manage liver and coagulation concerns, provide physical and occupational therapy for motor development, and monitor for organ-specific complications. Vaccination and infection prevention are important, given potential immunologic aspects of the disease. There is no widely available disease-modifying cure, so treatment emphasizes symptom control and quality of life, along with regular surveillance for emerging complications. See multidisciplinary care and coagulopathy for connected clinical concepts.
Research and emerging directions
Research on PMM2-CDG covers natural history, genotype–phenotype correlations, and potential therapeutic strategies. Experimental avenues include approaches to enhance residual PMM2 activity, stabilize the protein with pharmacological chaperones, and explore substrate-level or metabolic interventions that could bolster the glycosylation pathway. Gene therapy and other advanced modalities for glycosylation disorders are areas of ongoing discussion and early-stage development in the broader field of CDG. Readers may explore gene therapy and pharmacological chaperone concepts in relation to PMM2-CDG and similar disorders.