Pearls & oy-sters: familial epileptic encephalopathy due to methylenetetrahydrofolate reductase deficiency.

Methylenetetrahydrofolate reductase (MTHFR) deficiency is a rare autosomal recessive disease included in the group of homocysteine remethylation disorders. The MTHFR catalyzes the irreversible conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate. Besides the well-known association of thrombophilic defects with MTHFR variants and elevated homocysteine, few patients with MTHFR mutations have been described, all presenting with neurologic defects, including developmental delay, seizures, progressive neurologic deterioration, and central respiratory failure, eventually evolving into coma. How the enzyme deficiency results in the development of the seizure disorder is unclear. We describe 3 patients, 2 siblings and their firstdegree cousin, who presented with neurologic symptoms of variable severity leading to the suspicion of MTHFR deficiency. The diagnosis was hypothesized after the detection of increased plasma and urine homocysteine and was confirmed in 2 patients by MTHFR gene sequencing. Notwithstanding the same MTHFR gene mutations, the severity of manifestations and age at onset of epileptic encephalopathy varied greatly.