title: Severe methylenetetrahydrofolate reductase deficiency: clinical clues to a potentially treatable cause of adult-onset hereditary spastic paraplegia.
abstract: OBJECTIVE
  Hereditary spastic paraplegia is a highly heterogeneous group of neurogenetic disorders with pure and complicated clinical phenotypes. No treatment is available for these disorders. We identified 2 unrelated families, each with 2 siblings with severe methylenetetrahydrofolate reductase (MTHFR) deficiency manifesting a complicated form of adult-onset hereditary spastic paraparesis partially responsive to betaine therapy.
  
  
  METHODS
  Both pairs of siblings presented with a similar combination of progressive spastic paraparesis and polyneuropathy, variably associated with behavioral changes, cognitive impairment, psychosis, seizures, and leukoencephalopathy, beginning between the ages of 29 and 50 years. By the time of diagnosis a decade later, 3 patients were ambulatory and 1 was bedridden. Investigations have revealed severe hyperhomocysteinemia and hypomethioninemia, reduced fibroblast MTHFR enzymatic activity (18%-52% of control participants), and 3 novel pathogenic MTHFR mutations, 2 as compound heterozygotes in one family and 1 as a homozygous mutation in the other family. Treatment with betaine produced a rapid decline of homocysteine by 50% to 70% in all 4 patients and, over 9 to 15 years, improved the conditions of the 3 ambulatory patients.
  
  
  CONCLUSIONS
  Although severe MTHFR deficiency is a rare cause of complicated spastic paraparesis in adults, it should be considered in select patients because of the potential therapeutic benefit of betaine supplementation.
authors.affiliation: Center for Human Neurogenetics, Department of Neurology and Agnes Ginges, Hebrew University-Hadassah Medical Center, Jerusalem, Israel.
authors.forename: Alexander
authors.initials: A
authors.lastname: Lossos
authors.affiliation: Hebrew University-Hadassah School of Medicine, Jerusalem, Israel3National Institute for Biotechnology in the Negev, Ben Gurion University, Beer Sheva, Israel.
authors.forename: Omri
authors.initials: O
authors.lastname: Teltsh
authors.affiliation: Hebrew University-Hadassah School of Medicine, Jerusalem, Israel.
authors.forename: Tsipi
authors.initials: T
authors.lastname: Milman
authors.affiliation: Department of Genetics, Hebrew University-Hadassah Medical Center, Jerusalem, Israel5Department of Metabolic Diseases, Hebrew University-Hadassah Medical Center, Jerusalem, Israel.
authors.forename: Vardiella
authors.initials: V
authors.lastname: Meiner
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Quebec, Canada7Department of Pediatrics, McGill University, Montreal, Quebec, Canada.
authors.forename: Rima
authors.initials: R
authors.lastname: Rozen
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Quebec, Canada7Department of Pediatrics, McGill University, Montreal, Quebec, Canada.
authors.forename: Daniel
authors.initials: D
authors.lastname: Leclerc
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Quebec, Canada7Department of Pediatrics, McGill University, Montreal, Quebec, Canada.
authors.forename: Bernd C
authors.initials: BC
authors.lastname: Schwahn
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Quebec, Canada7Department of Pediatrics, McGill University, Montreal, Quebec, Canada.
authors.forename: Natalya
authors.initials: N
authors.lastname: Karp
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Quebec, Canada7Department of Pediatrics, McGill University, Montreal, Quebec, Canada8Department of Medicine, McGill University, Montreal, Quebec, Canada9Department of Biology, McGill University, M.
authors.forename: David S
authors.initials: DS
authors.lastname: Rosenblatt
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Watkins
authors.affiliation: Department of Genetics, Hebrew University-Hadassah Medical Center, Jerusalem, Israel5Department of Metabolic Diseases, Hebrew University-Hadassah Medical Center, Jerusalem, Israel.
authors.forename: Avraham
authors.initials: A
authors.lastname: Shaag
authors.affiliation: Department of Genetics, Hebrew University-Hadassah Medical Center, Jerusalem, Israel5Department of Metabolic Diseases, Hebrew University-Hadassah Medical Center, Jerusalem, Israel.
authors.forename: Stanley H
authors.initials: SH
authors.lastname: Korman
authors.affiliation: Department of Internal Medicine, Hebrew University-Hadassah Medical Center, Jerusalem, Israel.
authors.forename: Samuel N
authors.initials: SN
authors.lastname: Heyman
authors.affiliation: Center for Human Neurogenetics, Department of Neurology and Agnes Ginges, Hebrew University-Hadassah Medical Center, Jerusalem, Israel.
authors.forename: Aya
authors.initials: A
authors.lastname: Gal
authors.affiliation: Center for Human Neurogenetics, Department of Neurology and Agnes Ginges, Hebrew University-Hadassah Medical Center, Jerusalem, Israel.
authors.forename: J P
authors.initials: JP
authors.lastname: Newman
authors.affiliation: Department of Neurology, Shaare Zedek Medical Center, Jerusalem, Israel.
authors.forename: Bettina
authors.initials: B
authors.lastname: Steiner-Birmanns
authors.affiliation: Center for Human Neurogenetics, Department of Neurology and Agnes Ginges, Hebrew University-Hadassah Medical Center, Jerusalem, Israel.
authors.forename: Oded
authors.initials: O
authors.lastname: Abramsky
authors.affiliation: Hebrew University-Hadassah School of Medicine, Jerusalem, Israel12Department of Child and Adolescent Psychiatry, Jerusalem Mental Health Center, Eitanim Psychiatric Hospital, Jerusalem, Israel.
authors.forename: Yoav
authors.initials: Y
authors.lastname: Kohn
mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D001622:Betaine / Q000494:pharmacology*; D005260:Female; D006712:Homocystinuria / Q000145:classification / Q000235:genetics*; D006801:Humans; D008082:Lipotropic Agents / Q000494:pharmacology*; D008279:Magnetic Resonance Imaging; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000145:classification / Q000172:deficiency* / Q000187:drug effects / Q000235:genetics; D008875:Middle Aged; D009128:Muscle Spasticity / Q000145:classification / Q000235:genetics*; D011446:Prospective Studies; D011618:Psychotic Disorders / Q000145:classification / Q000235:genetics; D012720:Severity of Illness Index; D015419:Spastic Paraplegia, Hereditary / Q000188:drug therapy / Q000209:etiology* / Q000235:genetics*; D016896:Treatment Outcome
chemical_list: D008082:Lipotropic Agents; D001622:Betaine; D042965:Methylenetetrahydrofolate Reductase (NADPH2)