Congenital myasthenic syndrome due to a novel missense mutation in the gene encoding choline acetyltransferase.
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.
Schmidt
Carolin
C
Department of Neurology, and Genzentrum, Ludwig-Maximilians-Universität München, Feodor-Lynen-Strasse 25, 81377 Munich, Germany.
Abicht
Angela
A
Krampfl
Klaus
K
Voss
Wolfgang
W
Stucka
Rolf
R
Mildner
Gina
G
Petrova
Sofia
S
Schara
Ulrike
U
Mortier
Wilhelm
W
Bufler
Johannes
J
Huebner
Angela
A
Lochmüller
Hanns
H
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
D007532:Isoleucine; D013912:Threonine; D002795:Choline O-Acetyltransferase