title: Congenital myasthenic syndrome due to a novel missense mutation in the gene encoding choline acetyltransferase.
abstract: Congenital myasthenic syndromes are caused by different genetic defects affecting proteins expressed at the neuromuscular junction. Recently, the first molecular genetic defect resulting in a presynaptic congenital myasthenic syndrome has been reported: Recessive loss-of-function mutations in CHAT, the gene encoding choline acetyltransferase, were described in five congenital myasthenic syndrome families. In this study, we investigated three patients from two independent Turkish kinships. Clinically, all patients presented with moderate myasthenic symptoms including ptosis and muscle weakness with increased fatigability. Multiple episodes of sudden apnea were reported for all patients. One child suffering from a second, unrelated disorder, i.e. hepatocellular carcinoma, showed a severe myasthenic phenotype, requiring permanent ventilation. Genetically, we identified a novel missense mutation (I336T) in the CHAT gene homozygously in all three patients. Haplotype analysis revealed that the mutant allele cosegregates with the clinical phenotype in both families (maximum combined two-point LOD-score of 2.46 for D10S1793). In summary, we confirm that CHAT mutations are responsible for a clinically distinct form of congenital myasthenic syndrome, characterized by episodic apnea. Infections and stress may lead to a life-threatening failure of neuromuscular transmission in congenital myasthenic syndrome with episodic apnea. The observation of the same mutation (I336T) in two independent Turkish kinships may suggest a common origin, i.e. founder.
authors.affiliation: Department of Neurology, and Genzentrum, Ludwig-Maximilians-Universität München, Feodor-Lynen-Strasse 25, 81377 Munich, Germany.
authors.forename: Carolin
authors.initials: C
authors.lastname: Schmidt
authors.forename: Angela
authors.initials: A
authors.lastname: Abicht
authors.forename: Klaus
authors.initials: K
authors.lastname: Krampfl
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Voss
authors.forename: Rolf
authors.initials: R
authors.lastname: Stucka
authors.forename: Gina
authors.initials: G
authors.lastname: Mildner
authors.forename: Sofia
authors.initials: S
authors.lastname: Petrova
authors.forename: Ulrike
authors.initials: U
authors.lastname: Schara
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Mortier
authors.forename: Johannes
authors.initials: J
authors.lastname: Bufler
authors.forename: Angela
authors.initials: A
authors.lastname: Huebner
authors.forename: Hanns
authors.initials: H
authors.lastname: Lochmüller
mesh_terms: D000293:Adolescent; D001049:Apnea / Q000150:complications / Q000235:genetics; D002648:Child; D002795:Choline O-Acetyltransferase / Q000235:genetics* / Q000378:metabolism; D004252:DNA Mutational Analysis / Q000379:methods; D005260:Female; D008040:Genetic Linkage; D006239:Haplotypes; D006720:Homozygote; D006801:Humans; D007532:Isoleucine / Q000235:genetics; D008126:Lod Score; D020125:Mutation, Missense; D020294:Myasthenic Syndromes, Congenital / Q000209:etiology* / Q000235:genetics*; D010375:Pedigree; D015183:Restriction Mapping / Q000379:methods; D016415:Sequence Alignment / Q000379:methods; D013912:Threonine / Q000235:genetics
chemical_list: D007532:Isoleucine; D013912:Threonine; D002795:Choline O-Acetyltransferase