General description

Methylenetetrahydrofolate Reductase (MTHFR) Deficiency is the most common genetic cause of elevated homocysteine levels in the blood, known as hyperhomocysteinemia, and is inherited in an autosomal recessive manner with over 50 genetic mutations reported. The MTHFR enzyme plays a crucial role in processing amino acids, especially in converting homocysteine to methionine. Genetic variations can impair or inactivate this enzyme, leading to elevated homocysteine levels, often with low or relatively normal plasma methionine, particularly in individuals who are also folate deficient. Low-dose folic acid supplements can reduce and often normalize homocysteine levels, but this has not been shown to improve health outcomes.

The severity of MTHFR Deficiency correlates with the degree of enzyme impairment. Severe cases, where enzyme activity is below 10% of normal, may present at birth with symptoms like feeding difficulties, apnea, seizures, and rapid deterioration, often leading to death. In cases that develop in early childhood, symptoms include developmental delays, motor and gait abnormalities, and neurological issues such as microcephaly and hydrocephalus. For cases with onset after age 10, where enzyme activity is 10-20% of normal, symptoms may include motor dysfunction, intellectual disability, epilepsy, headaches, and psychiatric symptoms. While most cases manifest in infancy or early childhood, adult-onset is rare.

Radiographic features

MRI shows bilateral and symmetric T2WI and FLAIR hyperintensity in the deep white matter, predominantly in the occipital and parietal lobes. The posterior limb of the internal capsule also exhibits T2WI and FLAIR hyperintensity.