PMM2-CDG (CDG-1a) (previously known as congenital disorder of glycosylation type 1a), the most common of a group of disorders of abnormal glycosylation of N-linked oligosaccharides, is divided into three stages: infantile multisystem, late-infantile and childhood ataxia-intellectual disability, and adult stable disability. The three stages notwithstanding, clinical presentation and course are highly variable, ranging from infants who die in the first year of life to mildly involved adults. Clinical presentations tend to be similar in siblings. In the infantile multisystem stage, infants show axial hypotonia, hyporeflexia, esotropia, and developmental delay; feeding problems, vomiting, and diarrhea with failure to thrive; and impaired growth. Subcutaneous fat may be excessive over the buttocks and suprapubic region. Two distinct clinical presentations are observed: (1) a non-fatal neurologic form with strabismus, psychomotor retardation, and cerebellar hypoplasia in infancy followed by neuropathy and retinitis pigmentosa in the first or second decade and (2) a neurologic-multivisceral form with approximately 20% mortality in the first year of life. The late-infantile and childhood ataxia-intellectual disability stage, with onset between age three and ten years, is characterized by hypotonia, ataxia, severely delayed language and motor development, inability to walk, and IQ of 40 to 70; other findings include stroke-like episodes or transient unilateral loss of function, retinitis pigmentosa, joint contractures, and skeletal deformities. In the adult stable disability stage, intellectual ability is stable; peripheral neuropathy is variable, thoracic and spinal deformities progress, and premature aging is observed; females lack secondary sexual development and males may exhibit decreased testicular volume. Hyperglycemia-induced growth hormone release, hyperprolactinemia, insulin resistance, and coagulopathy may occur. An increased risk of deep venous thrombosis is present.
PMM2-CDG (CDG-Ia) is diagnosed by clinical features, neuroimaging, and transferrin isoform analysis to determine the number of sialylated N-linked oligosaccharide residues linked to serum transferrin. Characteristic findings are decreased tetrasialotransferrin and increased asialotransferrin and disialotransferrin. PMM2 is the only gene associated with PMM2-CDG (CDG-Ia). Sequence analysis of PMM2 detects mutations in up to 100% of individuals in whom PMM2-CDG (CDG-Ia) has been enzymatically confirmed in research studies.
PMM2-CDG (CDG-Ia) is inherited in an autosomal recessive manner. At conception, the theoretic risks to sibs of an affected individual are a 25% risk of being affected, a 50% risk of being an asymptomatic carrier, and a 25% risk of being unaffected and not a carrier; however, based on outcomes of at-risk pregnancies, the risk of having an affected child is closer to 1/3 than to the expected 1/4. Carrier testing for at-risk family members and prenatal diagnosis for pregnancies at increased risk for PMM2-CDG (CDG-Ia) is possible when both disease-causing mutations in the family have been identified.