title: The ACMSD gene, involved in tryptophan metabolism, is mutated in a family with cortical myoclonus, epilepsy, and parkinsonism.
abstract: Familial cortical myoclonic tremor and epilepsy is a phenotypically and genetically heterogeneous autosomal dominant disorder characterized by the presence of cortical myoclonic tremor and epilepsy that is often accompanied by additional neurological features. Despite the numerous familial studies performed and the number of loci identified, there is no gene associated with this syndrome. It is expected that through the application of novel genomic technologies, such as whole exome sequencing and whole genome sequencing, a substantial number of novel genes will come to light in the coming years. In this study, we describe the identification of two disease-segregating mutations in a large family featuring cortical myoclonic tremor with epilepsy and parkinsonism. Due to the previous association of ACMSD deficiency with the development of epileptic seizures, we concluded that the identified nonsense mutation in the ACMSD gene, which encodes for a critical enzyme of the kynurenine pathway of the tryptophan metabolism, is the disease-segregating mutation most likely to be responsible for the phenotype described in our family. This finding not only reveals the identification of the first gene associated with familial cortical myoclonic tremor and epilepsy but also discloses the kynurenine pathway as a potential therapeutic target for the treatment of this devastating syndrome.
  
  
  CONCLUSIONS
  ACMSD is mutated in a family with cortical myoclonus, epilepsy, and parkinsonism. ACMSD mutation contributes to the development of FCMTE QA accumulation is likely to play an important role in the pathogenesis of FCMTE. The kynurenine pathway as a potential drug target for the treatment of epilepsy.
authors: Biodonostia Research Institute, Neurosciences area, University of the Basque Country, EHU-UPV, San Sebastian, Gipuzkoa, Spain, JOSEFELIX.MARTIMASSO@osakidetza.net.
authors: Jose Felix
authors: JF
authors: Martí-Massó
authors: Alberto
authors: A
authors: Bergareche
authors: Vladimir
authors: V
authors: Makarov
authors: Javier
authors: J
authors: Ruiz-Martinez
authors: Ana
authors: A
authors: Gorostidi
authors: Adolfo
authors: A
authors: López de Munain
authors: Juan Jose
authors: JJ
authors: Poza
authors: Pasquale
authors: P
authors: Striano
authors: Joseph D
authors: JD
authors: Buxbaum
authors: Coro
authors: C
authors: Paisán-Ruiz
mesh_terms: D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D001921:Brain / Q000473:pathology; D002262:Carboxy-Lyases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D004252:DNA Mutational Analysis; D004569:Electroencephalography; D004831:Epilepsies, Myoclonic / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D059472:Exome; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D009483:Neuropsychological Tests; D010375:Pedigree; D017378:Quinolinic Acid / Q000378:metabolism; D016415:Sequence Alignment; D014364:Tryptophan / Q000378:metabolism; D055815:Young Adult
chemical_list: D014364:Tryptophan; D002262:Carboxy-Lyases; C024396:aminocarboxymuconate-semialdehyde decarboxylase; D017378:Quinolinic Acid
references: J Neurol. 2012 Dec;259(12):2714-9
references: 22736081
references: Epilepsia. 2004 Feb;45(2):190-2
references: 14738428
references: Lancet. 2011 Feb 19;377(9766):641-9
references: 21292315
references: Epilepsia. 2005;46 Suppl 5:49-51
references: 15987253
references: J Biol Chem. 2002 Sep 20;277(38):35162-7
references: 12140278
references: Neurology. 2003 Apr 22;60(8):1381-5
references: 12707452
references: Neurology. 2007 Apr 24;68(17):1382-9
references: 17452583
references: Neurology. 2010 Jun 15;74(24):2000-3
references: 20548044
references: Neurol Sci. 2010 Feb;31(1):115-6
references: 19953285
references: Hum Genet. 2013 Mar;132(3):275-83
references: 23138527
references: Hum Mutat. 2011 Apr;32(4):358-68
references: 21412949
references: Mov Disord. 2011 Dec;26(14):2573-5
references: 22025266
references: Front Genet. 2012 May 14;3:75
references: 22593763
references: Clin Neurol Neurosurg. 1996 May;98(2):161-4
references: 8836591
references: Tremor Other Hyperkinet Mov (N Y). 2012;2:
references: 23439993
references: Nat Rev Drug Discov. 2002 Aug;1(8):609-20
references: 12402501
references: BMC Med Genet. 2011 Aug 03;12:104
references: 21812969
references: PLoS One. 2009 Jul 22;4(7):e6344
references: 19623258
references: Nat Rev Neurosci. 2012 Jul;13(7):465-77
references: 22678511
references: Mov Disord. 2005 Jun;20(6):665-73
references: 15747356
references: Toxicol Sci. 2004 Oct;81(2):302-8
references: 15229365
references: Am J Hum Genet. 1999 Sep;65(3):745-51
references: 10441581
references: Pol J Pharmacol Pharm. 1987 Sep-Oct;39(5):485-94
references: 2906431
references: J Neural Transm. 1978;42(1):37-43
references: 641543
references: Eur J Hum Genet. 2013 Feb;21(2):225-8
references: 22713812
references: J Mol Med (Berl). 2013 Jun;91(6):705-13
references: 23636512
references: Brain Res Bull. 1996;39(3):155-62
references: 8866691
references: Epilepsia. 1981 Jun;22(3):257-65
references: 6263604
references: Arch Neurol. 2012 Apr;69(4):474-81
references: 22491192
references: PLoS One. 2012;7(10):e39723
references: 23056166
references: Neurogenetics. 2008 Feb;9(1):69-71
references: 17992546
references: Am J Hum Genet. 2012 Aug 10;91(2):313-9
references: 22863194
references: Nat Rev Drug Discov. 2013 Jan;12(1):64-82
references: 23237916
references: Neurobiol Dis. 2004 Dec;17(3):455-61
references: 15571981