PMM2-congenital disorder of glycosylation

PMM2-congenital disorder of glycosylation (PMM2-CDG) is a rare inherited metabolic condition in which the enzyme phosphomannomutase 2 does not work well, so the body cannot attach certain sugar chains called N glycans to proteins. Without these sugar chains, proteins cannot fold or travel correctly, and many organs can be affected, including the brain, liver, heart, kidneys, and digestive system. Symptoms often start in infancy with weak muscle tone, poor growth, and movement problems, but some people are not diagnosed until childhood or adulthood. The severity and specific features can vary considerably from person to person. The exact prevalence is unknown, yet experts agree the disorder is uncommon and probably underdiagnosed worldwide.

Severity and symptoms vary widely between individuals. Three broad clinical patterns are described: an infantile multisystem form, a childhood ataxia-intellectual disability form, and an adult form with stable disability. Neurological features are often the first to draw medical attention. Many babies have low muscle tone (hypotonia) and later develop ataxia, an unsteady, tremor-filled walk that reflects cerebellar hypoplasia or atrophy seen on brain imaging. Global developmental delay is common, and many children have cognitive and speech challenges. Some experience seizures. Eye findings such as strabismus or esodeviation may accompany intention tremor and dysmetria. Extraneurological manifestations remind families and clinicians that this is a truly multi-system condition. In infancy, failure to thrive, feeding difficulties, and enteropathy can be significant. Abnormal fat distribution with inverted nipples and almond-shaped eye openings are characteristic physical clues. Liver involvement may progress to hepatic dysfunction or fibrosis, and coagulation abnormalities can increase bleeding risk. Cardiac and renal findings, including renal cysts, are reported in a subset of individuals. Not all individuals experience all features, and severity varies considerably. Some adults live with stable ataxia and mild intellectual disability, whereas severely affected infants may face life-threatening complications in the first year of life.

PMM2-CDG results from pathogenic variants in the PMM2 gene. Phosphomannomutase 2 converts mannose-6-phosphate to mannose-1-phosphate, a critical early step in N-glycan assembly. When both copies of PMM2 are altered, the body cannot produce enough functional enzyme, leading to structurally abnormal glycoproteins and the wide range of clinical problems described above. The condition is inherited in an autosomal recessive pattern. Typically, each parent carries one altered PMM2 copy but is healthy. When both parents are carriers, each pregnancy carries a 25 percent chance of producing a child who is affected, a 50 percent chance of producing a carrier, and a 25 percent chance of producing a child with two working copies. Because carriers are more likely to share rare variants if they have common ancestors, the condition can be more frequent in families where parents share ancestry. Genetic counseling is recommended for relatives who want to understand their own carrier status or discuss family-planning options.

Currently, management focuses on supportive care and symptom management. Treatment is tailored to the individual and typically involves a multidisciplinary team that may include neurologists, hepatologists, cardiologists, nephrologists, geneticists, physical and occupational therapists, speech-language pathologists, and nutrition specialists. Regular surveillance is an essential part of long-term care, helping to identify potential complications before they become serious. Suggested monitoring includes periodic liver function and coagulation studies, renal and cardiac evaluations, and developmental assessments to guide therapy services. Physical, occupational, and speech therapies address motor coordination, feeding, and communication challenges, while antiepileptic medications are prescribed when seizures occur. Families should work closely with their healthcare providers to create an individualized care plan and revisit it as needs change over time.

Outcomes depend on many factors including the severity of organ involvement, age at diagnosis, and access to specialized care. Some infants with severe multisystem disease face life-threatening complications early in life, while others achieve stable health and live into adulthood with ataxia and varying degrees of intellectual disability. Supportive therapies, early intervention services, and vigilant monitoring can significantly improve quality of life. Outcomes described in medical literature continue to evolve as standards of care improve. Families often find it helpful to connect with expert centers and genetic counselors to understand prognosis in the context of their child’s specific presentation and to plan for future needs.

Several clinical trials are currently investigating new treatments aimed at improving glycosylation efficiency or mitigating organ-specific complications. Individuals interested in clinical trials can search ClinicalTrials.gov or consult their care team about eligibility.