Methylcobalamin deficiency type cblE

Methylcobalamin deficiency type cblE (also known as methionine synthase reductase deficiency or MTRR deficiency) is a rare inherited disorder of intracellular cobalamin (vitamin B12) metabolism. It is caused by pathogenic variants in the MTRR gene, which encodes methionine synthase reductase, an enzyme essential for maintaining methionine synthase in its active form. When this enzyme is deficient, the body cannot properly convert homocysteine to methionine or produce adequate methylcobalamin, the active cofactor required by methionine synthase. The disorder primarily affects the hematologic and neurological systems. Key clinical features include megaloblastic anemia, which typically presents in infancy or early childhood, along with developmental delay, hypotonia, feeding difficulties, seizures, and failure to thrive. Biochemically, patients characteristically show elevated homocysteine (homocystinuria) and low methionine levels in blood, while methylmalonic acid levels remain normal — a feature that distinguishes cblE from combined deficiency types (such as cblC). Some patients may also present with microcephaly, lethargy, and visual or cognitive impairment. Treatment involves supplementation with intramuscular or oral hydroxocobalamin (a form of vitamin B12), which can improve hematologic abnormalities and, in some cases, neurological outcomes. Betaine supplementation is often added to help lower homocysteine levels by providing an alternative pathway for methionine synthesis. Folate supplementation may also be considered. Early diagnosis and prompt initiation of treatment are critical, as delayed treatment can result in irreversible neurological damage. Long-term outcomes vary, with some patients achieving near-normal development when treated early, while others may have persistent neurodevelopmental deficits despite therapy.

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