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

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.
AuthorsJose Felix Martí-Massó, Alberto Bergareche, Vladimir Makarov, Javier Ruiz-Martinez, Ana Gorostidi, Adolfo López de Munain, Juan Jose Poza, Pasquale Striano, Joseph D Buxbaum, Coro Paisán-Ruiz
JournalJournal of molecular medicine (Berlin, Germany) (J Mol Med (Berl)) Vol. 91 Issue 12 Pg. 1399-406 (Dec 2013) ISSN: 1432-1440 [Electronic] Germany
PMID23955123 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Tryptophan
  • Carboxy-Lyases
  • aminocarboxymuconate-semialdehyde decarboxylase
  • Quinolinic Acid
  • Adult
  • Aged
  • Amino Acid Sequence
  • Brain (pathology)
  • Carboxy-Lyases (chemistry, genetics, metabolism)
  • DNA Mutational Analysis
  • Electroencephalography
  • Epilepsies, Myoclonic (diagnosis, genetics, metabolism)
  • Exome
  • Female
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Magnetic Resonance Imaging
  • Male
  • Middle Aged
  • Molecular Sequence Data
  • Mutation
  • Neuropsychological Tests
  • Pedigree
  • Quinolinic Acid (metabolism)
  • Sequence Alignment
  • Tryptophan (metabolism)
  • Young Adult

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