Malic Enzyme 2 May Underlie Susceptibility to Adolescent-Onset Idiopathic Generalized Epilepsy

• Published in: American journal of human genetics Vol. 76; no. 1; pp. 139 - 146
• Main Authors: Greenberg, David A., Cayanis, Eftihia, Strug, Lisa, Marathe, Sudhir, Durner, Martina, Pal, Deb K., Alvin, Gabriele B., Klotz, Irene, Dicker, Elisa, Shinnar, Shlomo, Bromfield, Edward B., Resor, Stanley, Cohen, Jeffrey, Moshe, Solomon L., Harden, Cynthia, Kang, Harriet
• Format: Journal Article
• Language: English
• Published: Chicago, IL Elsevier Inc 01.01.2005; University of Chicago Press; Cell Press; The American Society of Human Genetics
• Subjects: Adolescent; Age of Onset; Biological and medical sciences; Chromosome Mapping; Chromosomes; Chromosomes, Human, Pair 18; Enzymes; Epilepsy; Epilepsy, Generalized - genetics; Gene loci; General aspects. Genetic counseling; Genes, Recessive; Genetic linkage; Genetic Predisposition to Disease; Genotype & phenotype; Headache. Facial pains. Syncopes. Epilepsia. Intracranial hypertension. Brain oedema. Cerebral palsy; Humans; Lod Score; Malate Dehydrogenase - genetics; Medical genetics; Medical sciences; Nervous system (semeiology, syndromes); Neurology; Polymorphism, Single Nucleotide; Human; Nervous system diseases; Enzyme; Pathogenesis; Epilepsy; Idiopathic; Malate dehydrogenase; Genetic determinism; Cerebral disorder; Age of onset; Central nervous system disease; Adolescent; Genetic linkage; Predisposition; Genetics; Oxidoreductases
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1086/426735

Idiopathic generalized epilepsy (IGE) is a class of genetically determined, phenotypically related epilepsy syndromes. Linkage analysis identified a chromosome 18 locus predisposing to a number of adolescent-onset IGEs. We report a single-nucleotide polymorphism (SNP) association analysis of the region around the marker locus with the high LOD score. This analysis, which used both case-control and family-based association methods, yielded strong evidence that malic enzyme 2 ( ME2) is the gene predisposing to IGE. We also observed association among subgroups of IGE syndromes. An ME2-centered nine-SNP haplotype, when present homozygously, increases the risk for IGE (odds ratio 6.1; 95% confidence interval 2.9–12.7) compared with any other genotype. Both the linkage analysis and the association analysis support recessive inheritance for the locus, which is compatible with the fact that ME2 is an enzyme. ME2 is a genome-coded mitochondrial enzyme that converts malate to pyruvate and is involved in neuronal synthesis of the neurotransmitter γ-aminobutyric acid (GABA). The results suggest that GABA synthesis disruption predisposes to common IGE and that clinical seizures are triggered when mutations at other genes, or perhaps other insults, are present.