Methylcobalamin deficiency type cblG

Methylcobalamin deficiency type cblG (also known as methionine synthase deficiency or functional methionine synthase deficiency) is a rare inborn error of cobalamin (vitamin B12) metabolism caused by pathogenic variants in the MTR gene, which encodes the enzyme methionine synthase. This enzyme is essential for converting homocysteine to methionine using methylcobalamin as a cofactor. When methionine synthase is deficient or dysfunctional, the body accumulates homocysteine (homocysteinemia and homocystinuria) and develops low methionine levels, along with megaloblastic anemia due to impaired folate metabolism. The condition primarily affects the hematologic and neurological systems. Key clinical features include megaloblastic anemia, developmental delay, intellectual disability, seizures, feeding difficulties, hypotonia, and failure to thrive. Neurological deterioration can be progressive if untreated. Onset is typically in infancy or early childhood, though some patients may present later. Laboratory findings characteristically show elevated homocysteine in blood and urine, low to normal methionine levels, and megaloblastic anemia without methylmalonic aciduria, which helps distinguish cblG from combined deficiency types (such as cblC). Treatment involves supplementation with hydroxocobalamin (often given by intramuscular injection), betaine to promote alternative remethylation of homocysteine, folate (or folinic acid), and methionine supplementation. Early diagnosis and treatment are critical to improving neurological outcomes, though some degree of developmental impairment may persist despite therapy. Long-term management requires regular monitoring of metabolic markers and clinical status. The prognosis varies depending on the severity of the defect and the timing of treatment initiation.

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