Severe 5,10-methylenetetrahydrofolate reductase deficiency and two MTHFR variants in an adolescent with progressive myoclonic epilepsy.

BACKGROUND: 5,10-Methylenetetrahydrofolate reductase (MTHFR) deficiency is an inborn error of the folate-recycling pathway that affects the remethylation of homocysteine to methionine. The clinical presentation of MTHFR deficiency is highly variable ranging from early neurological deterioration and death in infancy to a mild thrombophilia in adults. PATIENT AND METHODS: We describe an adolescent girl with a history of mild learning disabilities who presented at age 14 years with an epilepsy syndrome initially thought to be juvenile myoclonic epilepsy. She later developed intractable epilepsy with myoclonus, leg weakness, cognitive decline, and ataxia consistent with the syndrome of progressive myoclonic epilepsy. This prompted further evaluation that revealed elevated plasma homocysteine and decreased plasma methionine. The diagnosis of MTHFR deficiency was confirmed based on extremely reduced fibroblast MTHFR activity (0.3 nmol CHO/mg prot/hr) as well as mutation analysis that revealed two variants in the MTHFR gene, a splice site mutation p (IVS5-1G>A), as well as a missense mutation (c.155 G>A; p. Arg52Gln). Therapy with folinic acid, betaine, and methionine has produced significant clinical improvement, including improved strength, less severe ataxia, and decreased seizure frequency, as well as improvements in her electroencephalography and electromyography. CONCLUSION: This patient demonstrates the importance of considering MTHFR deficiency in the differential diagnosis of progressive myoclonic epilepsy because it is one of the few causes for which specific treatment is available.

Clinical neurogenetics: neurologic presentations of metabolic disorders.

This article reviews aspects of the neurologic presentations of selected treatable inborn errors of metabolism within the category of small molecule disorders caused by defects in pathways of intermediary metabolism. Disorders that are particularly likely to be seen by neurologists include those associated with defects in amino acid metabolism (organic acidemias, aminoacidopathies, urea cycle defects). Other disorders of small molecule metabolism are discussed as additional examples in which early treatments have the potential for better outcomes.

Mitochondrial tRNA(Phe) mutation as a cause of end-stage renal disease in childhood.

BACKGROUND: We identified a mitochondrial tRNA mutation (m.586 G > A) in a patient with renal failure and symptoms consistent with a mitochondrial cytopathy. This mutation was of unclear significance due to the absence of consistent reports of linkage to specific disease phenotypes and any data pertaining to its effects on mitochondrial function. CASE-DIAGNOSIS/TREATMENT: A 16-month-old girl with failure-to-thrive, developmental regression, persistent lactic acidosis, hypotonia, gastrointestinal dysmotility, adrenal insufficiency, and hematologic abnormalities developed hypertension and renal impairment with chronic tubulointerstitial fibrosis, progressing to renal failure with the need for peritoneal dialysis. Evaluation of her muscle and blood led to the identification of a mutation of the mitochondrial tRNA for phenylalanine, m.586 G > A. CONCLUSIONS: The m.586 G > A mutation is pathogenic and a cause of end-stage renal disease in childhood. The mutation interferes with the stability of tRNA(Phe) and affects the translation of mitochondrial proteins and the stability of the electron transport chain.