Homocystinuria due to methylene tetrahydrofolate reductase deficiency

Homocystinuria due to methylene tetrahydrofolate reductase (MTHFR) deficiency is a rare inherited metabolic disorder caused by mutations in the MTHFR gene, which encodes the enzyme methylenetetrahydrofolate reductase. This enzyme plays a critical role in folate metabolism by converting 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, which is essential for the remethylation of homocysteine to methionine. When MTHFR activity is severely reduced, homocysteine accumulates in the blood and urine (homocystinuria), while methionine levels are typically low. This condition is also known as severe MTHFR deficiency and should be distinguished from the common MTHFR polymorphisms (C677T, A1298C) found in the general population, which cause only mild enzyme reduction. The disease primarily affects the nervous system and vascular system. Clinical severity varies widely depending on residual enzyme activity. The most severe neonatal and infantile forms present with developmental delay, seizures, microcephaly, apnea, feeding difficulties, and hypotonia. Later-onset forms may manifest with gait abnormalities, cognitive decline, psychiatric symptoms, peripheral neuropathy, and thromboembolic events. Some patients develop a clinical picture resembling subacute combined degeneration of the spinal cord. Neuroimaging may reveal white matter abnormalities and cerebral atrophy. Treatment aims to lower homocysteine levels and restore methionine. Therapeutic approaches include oral betaine (trimethylglycine), which provides an alternative pathway for homocysteine remethylation, along with supplementation of folate (particularly 5-methyltetrahydrofolate or folinic acid), methionine, vitamin B12, and pyridoxine. Betaine is considered the mainstay of treatment and has been shown to improve neurological outcomes, particularly when initiated early. Early diagnosis and treatment are critical, as neurological damage may be irreversible once established. Newborn screening programs in some regions can detect this condition through low methionine levels, though this finding is not specific.

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