Schmidt Carolin, Abicht Angela, Krampfl Klaus, Voss Wolfgang, Stucka Rolf, Mildner Gina, Petrova Sofia, Schara Ulrike, Mortier Wilhelm, Bufler Johannes, Huebner Angela, Lochmüller Hanns
Department of Neurology, and Genzentrum, Ludwig-Maximilians-Universität München, Feodor-Lynen-Strasse 25, 81377 Munich, Germany.
Neuromuscul Disord. 2003 Mar;13(3):245-51. doi: 10.1016/s0960-8966(02)00273-0.
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.
先天性肌无力综合征由影响神经肌肉接头处表达的蛋白质的不同基因缺陷引起。最近，已报道了首例导致突触前先天性肌无力综合征的分子遗传缺陷：五个先天性肌无力综合征家族中描述了编码胆碱乙酰转移酶的基因CHAT中的隐性功能丧失突变。在本研究中，我们调查了来自两个独立土耳其家族的三名患者。临床上，所有患者均表现出中度肌无力症状，包括上睑下垂和肌肉无力且疲劳感增加。所有患者均报告有多次突发性呼吸暂停发作。一名患有第二种无关疾病即肝细胞癌的儿童表现出严重的肌无力表型，需要长期通气。基因分析方面，我们在所有三名患者中均发现了CHAT基因中的一种新型错义突变（I336T），且为纯合子。单倍型分析显示，在两个家族中突变等位基因均与临床表型共分离（D10S1793的最大联合两点LOD分数为2.46）。总之，我们证实CHAT突变是导致一种临床上独特的先天性肌无力综合征的原因，其特征为发作性呼吸暂停。感染和应激可能导致伴有发作性呼吸暂停的先天性肌无力综合征患者出现危及生命的神经肌肉传递衰竭。在两个独立的土耳其家族中观察到相同的突变（I336T）可能提示存在共同起源，即奠基者效应。
