Advertisement

Journal of Molecular Medicine

, Volume 91, Issue 12, pp 1399–1406 | Cite as

The ACMSD gene, involved in tryptophan metabolism, is mutated in a family with cortical myoclonus, epilepsy, and parkinsonism

  • Jose Felix Martí-MassóEmail author
  • Alberto Bergareche
  • Vladimir Makarov
  • Javier Ruiz-Martinez
  • Ana Gorostidi
  • Adolfo López de Munain
  • Juan Jose Poza
  • Pasquale Striano
  • Joseph D. Buxbaum
  • Coro Paisán-RuizEmail author
Original Article

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.

Key message

  • 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.

Keywords

FCMTE Whole exome sequencing ACMSD Kynurenine Pathway 

Notes

Acknowledgments

We thank the patients and their families for participating in this study. This work is supported in part by the “Instituto de Salud Carlos III” (FIS PI10/02714; JFMM) and the National Institute of Neurological Disorders and Stroke of the National Institute of Health under award number R21NS082881 to CPR.

Conflict of interest

All authors declare they have no competing interest.

Supplementary material

109_2013_1075_MOESM1_ESM.pdf (56 kb)
ESM 1 (PDF 56 kb)

References

  1. 1.
    van Rootselaar AF, van Schaik IN, van den Maagdenberg AM, Koelman JH, Callenbach PM, Tijssen MA (2005) Familial cortical myoclonic tremor with epilepsy: a single syndromic classification for a group of pedigrees bearing common features. Mov Disord 20:665–673CrossRefPubMedGoogle Scholar
  2. 2.
    Mikami M, Yasuda T, Terao A, Nakamura M, Ueno S, Tanabe H, Tanaka T, Onuma T, Goto Y, Kaneko S et al (1999) Localization of a gene for benign adult familial myoclonic epilepsy to chromosome 8q23.3-q24.1. Am J Hum Genet 65:745–751CrossRefPubMedGoogle Scholar
  3. 3.
    Depienne C, Magnin E, Bouteiller D, Stevanin G, Saint-Martin C, Vidailhet M, Apartis E, Hirsch E, LeGuern E, Labauge P et al (2010) Familial cortical myoclonic tremor with epilepsy: the third locus (FCMTE3) maps to 5p. Neurology 74:2000–2003CrossRefPubMedGoogle Scholar
  4. 4.
    de Falco FA, Striano P, de Falco A, Striano S, Santangelo R, Perretti A, Balbi P, Cecconi M, Zara F (2003) Benign adult familial myoclonic epilepsy: genetic heterogeneity and allelism with ADCME. Neurology 60:1381–1385CrossRefPubMedGoogle Scholar
  5. 5.
    Striano P, Chifari R, Striano S, de Fusco M, Elia M, Guerrini R, Casari G, Canevini MP (2004) A new benign adult familial myoclonic epilepsy (BAFME) pedigree suggesting linkage to chromosome 2p11.1-q12.2. Epilepsia 45:190–192CrossRefPubMedGoogle Scholar
  6. 6.
    Saint-Martin C, Bouteiller D, Stevanin G, Popescu C, Charon C, Ruberg M, Baulac S, LeGuern E, Labauge P, Depienne C (2008) Refinement of the 2p11.1-q12.2 locus responsible for cortical tremor associated with epilepsy and exclusion of candidate genes. Neurogenetics 9:69–71CrossRefPubMedGoogle Scholar
  7. 7.
    Crompton DE, Sadleir LG, Bromhead CJ, Bahlo M, Bellows ST, Arsov T, Harty R, Lawrence KM, Dunne JW, Berkovic SF et al (2012) Familial adult myoclonic epilepsy: recognition of mild phenotypes and refinement of the 2q locus. Arch Neurol 69:474–481CrossRefPubMedGoogle Scholar
  8. 8.
    Carr JA, van der Walt PE, Nakayama J, Fu YH, Corfield V, Brink P, Ptacek L (2007) FAME 3: a novel form of progressive myoclonus and epilepsy. Neurology 68:1382–1389CrossRefPubMedGoogle Scholar
  9. 9.
    Yeetong P, Ausavarat S, Bhidayasiri R, Piravej K, Pasutharnchat N, Desudchit T, Chunharas C, Loplumlert J, Limotai C, Suphapeetiporn K et al (2013) A newly identified locus for benign adult familial myoclonic epilepsy on chromosome 3q26.32-3q28. Eur J Hum Genet 21:225–228CrossRefPubMedGoogle Scholar
  10. 10.
    Merner ND, Girard SL, Catoire H, Bourassa CV, Belzil VV, Riviere JB, Hince P, Levert A, Dionne-Laporte A, Spiegelman D et al (2012) Exome sequencing identifies FUS mutations as a cause of essential tremor. Am J Hum Genet 91:313–319CrossRefPubMedGoogle Scholar
  11. 11.
    Krebs CE, Paisan-Ruiz C (2012) The use of next-generation sequencing in movement disorders. Front Genet 3:75CrossRefPubMedGoogle Scholar
  12. 12.
    Schwarcz R, Bruno JP, Muchowski PJ, Wu HQ (2012) Kynurenines in the mammalian brain: when physiology meets pathology. Nat Rev Neurosci 13:465–477CrossRefPubMedGoogle Scholar
  13. 13.
    Stone TW, Darlington LG (2002) Endogenous kynurenines as targets for drug discovery and development. Nat Rev Drug Discov 1:609–620CrossRefPubMedGoogle Scholar
  14. 14.
    Karkheiran S, Krebs CE, Makarov V, Nilipour Y, Hubert B, Darvish H, Frucht S, Shahidi GA, Buxbaum JD, Paisan-Ruiz C (2013) Identification of COL6A2 mutations in progressive myoclonus epilepsy syndrome. Hum Genet 132:275–283CrossRefPubMedGoogle Scholar
  15. 15.
    Exome Variant Server (2012) NHLBI Exome Sequencing Project (ESP), Seattle, WA (URL: http://evsgswashingtonedu/EVS/) [06/2013]
  16. 16.
    Thusberg J, Olatubosun A, Vihinen M (2011) Performance of mutation pathogenicity prediction methods on missense variants. Hum Mutat 32:358–368CrossRefPubMedGoogle Scholar
  17. 17.
    Guidetti P, Luthi-Carter RE, Augood SJ, Schwarcz R (2004) Neostriatal and cortical quinolinate levels are increased in early grade Huntington's disease. Neurobiol Dis 17:455–461CrossRefPubMedGoogle Scholar
  18. 18.
    Lapin IP (1978) Stimulant and convulsive effects of kynurenines injected into brain ventricles in mice. J Neural Transm 42:37–43CrossRefPubMedGoogle Scholar
  19. 19.
    Rahman A, Ting K, Cullen KM, Braidy N, Brew BJ, Guillemin GJ (2009) The excitotoxin quinolinic acid induces tau phosphorylation in human neurons. PLoS One 4:e6344CrossRefPubMedGoogle Scholar
  20. 20.
    Wu HQ, Schwarcz R (1996) Seizure activity causes elevation of endogenous extracellular kynurenic acid in the rat brain. Brain Res Bull 39:155–162CrossRefPubMedGoogle Scholar
  21. 21.
    Mori S, Bernardi R, Laurent A, Resnati M, Crippa A, Gabrieli A, Keough R, Gonda TJ, Blasi F (2012) Myb-binding protein 1A (MYBBP1A) is essential for early embryonic development, controls cell cycle and mitosis, and acts as a tumor suppressor. PLoS One 7:e39723CrossRefPubMedGoogle Scholar
  22. 22.
    Lapin IP (1981) Kynurenines and seizures. Epilepsia 22:257–265CrossRefPubMedGoogle Scholar
  23. 23.
    Amaral M, Outeiro TF, Scrutton NS, Giorgini F (2013) The causative role and therapeutic potential of the kynurenine pathway in neurodegenerative disease. J Mol Med (Berl) 91:705–713CrossRefGoogle Scholar
  24. 24.
    Nalls MA, Plagnol V, Hernandez DG, Sharma M, Sheerin UM, Saad M, Simon-Sanchez J, Schulte C, Lesage S, Sveinbjornsdottir S et al (2011) Imputation of sequence variants for identification of genetic risks for Parkinson's disease: a meta-analysis of genome-wide association studies. Lancet 377:641–649CrossRefPubMedGoogle Scholar
  25. 25.
    Magnin E, Vidailhet M, Ryff I, Ferreira S, Labauge P, Rumbach L (2012) Fronto-striatal dysfunction in type 3 familial cortical myoclonic tremor epilepsy occurring during aging. J Neurol 259:2714–2719CrossRefPubMedGoogle Scholar
  26. 26.
    Sharifi S, Aronica E, Koelman JH, Tijssen MA, Van Rootselaar AF (2012) Familial cortical myoclonic tremor with epilepsy and cerebellar changes: description of a new pathology case and review of the literature. Tremor Other Hyperkinet Mov (N Y) 2:472–482Google Scholar
  27. 27.
    Liu X, Cheng R, Verbitsky M, Kisselev S, Browne A, Mejia-Sanatana H, Louis ED, Cote LJ, Andrews H, Waters C et al (2011) Genome-wide association study identifies candidate genes for Parkinson's disease in an Ashkenazi Jewish population. BMC Med Genet 12:104CrossRefPubMedGoogle Scholar
  28. 28.
    Fukuoka S, Ishiguro K, Yanagihara K, Tanabe A, Egashira Y, Sanada H, Shibata K (2002) Identification and expression of a cDNA encoding human alpha-amino-beta-carboxymuconate-epsilon-semialdehyde decarboxylase (ACMSD). A key enzyme for the tryptophan-niacine pathway and “quinolinate hypothesis”. J Biol Chem 277:35162–35167CrossRefPubMedGoogle Scholar
  29. 29.
    Fukuwatari T, Ohsaki S, Fukuoka S, Sasaki R, Shibata K (2004) Phthalate esters enhance quinolinate production by inhibiting alpha-amino-beta-carboxymuconate-epsilon-semialdehyde decarboxylase (ACMSD), a key enzyme of the tryptophan pathway. Toxicol Sci 81:302–308CrossRefPubMedGoogle Scholar
  30. 30.
    Schwarcz R, Speciale C, French ED (1987) Hippocampal kynurenines as etiological factors in seizure disorders. Pol J Pharmacol Pharm 39:485–494CrossRefPubMedGoogle Scholar
  31. 31.
    Arbatova J, D’Amato E, Vaarmann A, Zharkovsky A, Reeben M (2005) Reduced serotonin and 3-hydroxyanthranilic acid levels in serum of cystatin B-deficient mice: a model system for progressive myoclonus epilepsy. Epilepsia 46(Suppl 5):49–51CrossRefPubMedGoogle Scholar
  32. 32.
    Striano P, D’Amato E, Pezzella M, Mainardi P, Zara F, Striano S (2010) Sudden death in Unverricht–Lundborg patients: is serotonin the key? Neurol Sci 31:115–116CrossRefPubMedGoogle Scholar
  33. 33.
    Errichiello L, Pezzella M, Santulli L, Striano S, Zara F, Minetti C, Mainardi P, Striano P (2011) A proof-of-concept trial of the whey protein alfa-lactalbumin in chronic cortical myoclonus. Mov Disord 26:2573–2575CrossRefPubMedGoogle Scholar
  34. 34.
    Pranzatelli MR, Tate E, Galvan I, Wheeler A (1996) A controlled trial of 5-hydroxy-L-tryptophan for ataxia in progressive myoclonus epilepsy. Clin Neurol Neurosurg 98:161–164CrossRefPubMedGoogle Scholar
  35. 35.
    Vecsei L, Szalardy L, Fulop F, Toldi J (2013) Kynurenines in the CNS: recent advances and new questions. Nat Rev Drug Discov 12:64–82CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Jose Felix Martí-Massó
    • 1
    • 2
    • 3
    • 4
    • 12
    Email author
  • Alberto Bergareche
    • 1
    • 2
    • 3
  • Vladimir Makarov
    • 5
  • Javier Ruiz-Martinez
    • 1
    • 2
    • 3
  • Ana Gorostidi
    • 1
    • 2
    • 3
  • Adolfo López de Munain
    • 1
    • 2
    • 3
    • 4
  • Juan Jose Poza
    • 1
    • 2
    • 3
  • Pasquale Striano
    • 6
  • Joseph D. Buxbaum
    • 7
    • 8
    • 9
    • 10
  • Coro Paisán-Ruiz
    • 7
    • 8
    • 10
    • 11
    Email author
  1. 1.Biodonostia Research Institute, Neurosciences areaUniversity of the Basque Country, EHU-UPVSan SebastianSpain
  2. 2.Hospital Universitario Donostia, Department of Neurology, Movement Disorders UnitSan SebastianSpain
  3. 3.Centro de investigación biomédica en Red para enfermedades Neurodegenerativas (CIBERNED), Carlos III Health InstituteMadridSpain
  4. 4.Department of NeurosciencesUniversity of the Basque Country, EHU-UPVSan SebastianSpain
  5. 5.Department of BiostatisticsColumbia University, Mailman School of Public HealthNew YorkUSA
  6. 6.Pediatric Neurology and Muscular Diseases Unit, Department of Neurosciences-DINOGMI, Gaslini InstituteGenoaItaly
  7. 7.Department of PsychiatryIcahn School of Medicine at Mount SinaiNew YorkUSA
  8. 8.Department of Genetics and Genomic SciencesIcahn School of Medicine at Mount SinaiNew YorkUSA
  9. 9.Department of NeurosciencesIcahn School of Medicine at Mount SinaiNew YorkUSA
  10. 10.Friedman Brain and Mindich Child Health and Development Institutes, Icahn School of Medicine at Mount SinaiNew YorkUSA
  11. 11.Department of NeurologyIcahn School of Medicine at Mount SinaiNew YorkUSA
  12. 12.Department of Neurology, Hospital DonostiaSan SebastianSpain

Personalised recommendations