背景:先天性肌无力综合征(CMSs)是罕见的遗传性疾病,由于神经肌肉接头异常导致永久性或暂时性肌肉疲劳和无力。迄今为止,发现32个基因参与具有常染色体显性和/或隐性遗传模式的CMS。CMS与乙酰胆碱酯酶缺乏症,特别是,被确定是由于具有早发性临床症状的COLQ基因的双等位基因突变。这里,我们报告了1例摩洛哥患者的COLQ相关CMS的临床特征和新的分子发现,并回顾了这种罕见形式的文献.
方法:在本研究中,我们报道了一名28个月大的摩洛哥女性张力减退患者的病例,与轴性肌无力有关,全球电机延迟,双侧下垂,单侧部分视野缺损伴正常眼运动,和疲劳的肌肉无力。临床外显子组测序揭示了COLQ基因中外显子13的新纯合缺失,NM_005677.4(COLQ):c。(814+1_815-1)_(954+1_955-1)delp.(Gly272Aspfs*11)。这一发现随后在先证者及其父母中通过定量实时PCR(qPCR)得到证实。STRING工具对蛋白质-蛋白质相互作用网络的计算机模拟分析显示,12种蛋白质与COLQ高度相关,置信度得分提高。用沙丁胺醇治疗产生明显的益处和恢复。
结论:这项临床观察说明了下一代测序在异质性CMS的精确分子诊断中的重要地位。适当的管理和有针对性的治疗,和家庭遗传咨询,更好地表征了摩洛哥人群中这种罕见疾病的突变特征。
BACKGROUND: Congenital myasthenic syndromes (CMSs) are rare genetic diseases due to abnormalities of the neuromuscular junction leading to permanent or transient muscle fatigability and weakness. To date, 32 genes were found to be involved in CMSs with autosomal dominant and/or recessive inheritance patterns. CMS with acetylcholinesterase deficiency, in particular, was determined to be due to biallelic mutations of COLQ gene with early-onset clinical signs. Here, we report clinical features and novel molecular findings of COLQ-related CMS in a Moroccan patient with a
review of the literature for this rare form.
METHODS: In this study, we report the case of a 28-month-old Moroccan female patient with hypotonia, associated to axial muscle weakness, global motor delay, bilateral ptosis, unilateral partial visual field deficiency with normal ocular motility, and fatigable muscle weakness. Clinical exome sequencing revealed a novel homozygous deletion of exon 13 in COLQ gene, NM_005677.4(COLQ):c.(814+1_815-1)_(954+1_955-1) del p.(Gly272Aspfs*11). This finding was subsequently confirmed by quantitative real-time PCR (qPCR) in the proband and her parents. In silico analysis of protein-protein interaction network by STRING tool revealed that 12 proteins are highly associated to COLQ with an elevated confidence score. Treatment with Salbutamol resulted in clear benefits and recovery.
CONCLUSIONS: This clinical observation illustrates the important place of next-generation sequencing in the precise molecular diagnosis of heterogeneous forms of CMS, the appropriate management and targeted treatment, and genetic counseling of families, with a better characterization of the mutational profile of this rare disease in the Moroccan population.