Investigators from the Children's Hospital of Philadelphia, PA, and McGill University, Montreal, Quebec, CA, report an adolescent learning-disabled girl who presented at age 14 years with an epilepsy syndrome initially diagnosed as juvenile myoclonic epilepsy. Her seizures initially resolved while taking valproic acid but later became refractory. At age 15 years she became ataxic and developed leg weakness and cognitive decline. Withdrawal of VPA and substitution of lamotrigine did not halt the mental deterioration, and testing revealed elevated plasma homocysteine and decreased plasma methionine. The diagnosis of 5,10-methylenetetrahydrofolate reductase (MTHFR) deficiency was confirmed by reduced fibroblast MTHFR activity, and mutation analysis revealing 2 variants in the MTHFR gene and splice site and missense mutations. Therapy with folinic acid, betaine, and methionine produced improvements in muscle strength, less severe ataxia, decreased seizures, and improved EEG and EMG. [1]

COMMENTARY. MTHFR deficiency is an autosomal recessive inborn error of folate metabolism with defective remethylation of homocysteine to methionine. Elevated homocysteine and low methionine is a diagnostic marker for MTHFR deficiency. Infants typically present with seizures, microcephaly, neurological deterioration, and coma and death if untreated. Childhood presentation is milder, with developmental delay, and marfanoid appearance, but sometimes more severe with rapid neurological deterioration, seizures, and incoordination. MTHFR may also occur in adults, presenting as hereditary spastic paraplegia. Two unrelated families, each with 2 affected siblings, are reported from Hadassah Medical College, Jerusalem [2]. Treatment aims are normalization of plasma and CSF methionine levels and reduced homocysteinemia.

MTHFR deficiency should be considered in the differential diagnosis of progressive myoclonic epilepsy (PME). The most common causes of PME in a previously healthy adolescent are Unverricht-Lundborg disease, ME with ragged red fibers, neuronal ceroid lipofuscinosis, dentatorubro-pallidoluysian atrophy (DRPLA), and the sialidoses [3]. Investigators from University College, London, UK, and centers in Germany, examine the role of cerebellar pathology and alterations in inhibitory transmission in the pathogenesis of cortical myoclonus and ataxia [4].