title: Severe 5,10-methylenetetrahydrofolate reductase deficiency and two MTHFR variants in an adolescent with progressive myoclonic epilepsy.
abstract: 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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors: Department of Pediatrics, Division of Metabolism, The Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors: Kristin E
authors: KE
authors: D'Aco
authors: Department of Pedatrics, Division of Neurology, The Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors: David
authors: D
authors: Bearden
authors: Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
authors: David
authors: D
authors: Watkins
authors: Medical Neurogenetics, Atlanta, Georgia.
authors: Keith
authors: K
authors: Hyland
authors: Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
authors: David S
authors: DS
authors: Rosenblatt
authors: Department of Pediatrics, Division of Metabolism, The Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address: Ficicioglu@email.chop.edu.
authors: Can
authors: C
authors: Ficicioglu
mesh_terms: D000293:Adolescent; D001622:Betaine / Q000008:administration & dosage; D005260:Female; D005492:Folic Acid / Q000008:administration & dosage; D006712:Homocystinuria / Q000175:diagnosis* / Q000188:drug therapy / Q000235:genetics*; D006801:Humans; D008082:Lipotropic Agents / Q000008:administration & dosage; D008715:Methionine / Q000008:administration & dosage; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000172:deficiency* / Q000235:genetics; D009128:Muscle Spasticity / Q000175:diagnosis* / Q000188:drug therapy / Q000235:genetics*; D009154:Mutation; D020191:Myoclonic Epilepsies, Progressive / Q000188:drug therapy / Q000235:genetics*; D011618:Psychotic Disorders / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics; D014803:Vitamin B Complex / Q000008:administration & dosage
chemical_list: D008082:Lipotropic Agents; D014803:Vitamin B Complex; D001622:Betaine; D005492:Folic Acid; D008715:Methionine; C573423:MTHFR protein, human; D042965:Methylenetetrahydrofolate Reductase (NADPH2)
keywords: MTHFR; betaine; folate; homocysteine; progressive myoclonic epilepsy