The ACMSD gene, involved in tryptophan metabolism, is mutated in a family with cortical myoclonus, epilepsy, and parkinsonism
- 628 Downloads
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.
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.
KeywordsFCMTE Whole exome sequencing ACMSD Kynurenine Pathway
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.
- 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
- 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
- 15.Exome Variant Server (2012) NHLBI Exome Sequencing Project (ESP), Seattle, WA (URL: http://evsgswashingtonedu/EVS/) [06/2013]
- 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
- 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
- 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