Abstract：
BACKGROUND: The causative genes for over 60% of inherited peripheral neuropathy (IPN) remain unidentified. This study endeavours to enhance the genetic diagnostic rate in IPN cases by conducting screenings focused on non-coding repeat expansions.
METHODS: We gathered data from 2424 unrelated Japanese patients diagnosed with IPN, among whom 1555 cases with unidentified genetic causes, as determined through comprehensive prescreening analyses, were selected for the study. Screening for CGG non-coding repeat expansions in LRP12, GIPC1 and RILPL1 genes was conducted using PCR and long-read sequencing technologies.
RESULTS: We identified CGG repeat expansions in LRP12 from 44 cases, establishing it as the fourth most common aetiology in Japanese IPN. Most cases (29/37) exhibited distal limb weakness, without ptosis, ophthalmoplegia, facial muscle weakness or bulbar palsy. Neurogenic changes were frequently observed in both needle electromyography (97%) and skeletal muscle tissue (100%). In nerve conduction studies, 28 cases primarily showed impairment in motor nerves without concurrent involvement of sensory nerves, consistent with the phenotype of hereditary motor neuropathy. In seven cases, both motor and sensory nerves were affected, resembling the Charcot-Marie-Tooth (CMT) phenotype. Importantly, the mean CGG repeat number detected in the present patients was significantly shorter than that of patients with LRP12-oculopharyngodistal myopathy (p<0.0001). Additionally, GIPC1 and RILPL1 repeat expansions were absent in our IPN cases.
CONCLUSIONS: We initially elucidate LRP12 repeat expansions as a prevalent cause of CMT, highlighting the necessity for an adapted screening strategy in clinical practice, particularly when addressing patients with IPN.
METHODS: We gathered data from 2424 unrelated Japanese patients diagnosed with IPN, among whom 1555 cases with unidentified genetic causes, as determined through comprehensive prescreening analyses, were selected for the study. Screening for CGG non-coding repeat expansions in LRP12, GIPC1 and RILPL1 genes was conducted using PCR and long-read sequencing technologies.
RESULTS: We identified CGG repeat expansions in LRP12 from 44 cases, establishing it as the fourth most common aetiology in Japanese IPN. Most cases (29/37) exhibited distal limb weakness, without ptosis, ophthalmoplegia, facial muscle weakness or bulbar palsy. Neurogenic changes were frequently observed in both needle electromyography (97%) and skeletal muscle tissue (100%). In nerve conduction studies, 28 cases primarily showed impairment in motor nerves without concurrent involvement of sensory nerves, consistent with the phenotype of hereditary motor neuropathy. In seven cases, both motor and sensory nerves were affected, resembling the Charcot-Marie-Tooth (CMT) phenotype. Importantly, the mean CGG repeat number detected in the present patients was significantly shorter than that of patients with LRP12-oculopharyngodistal myopathy (p<0.0001). Additionally, GIPC1 and RILPL1 repeat expansions were absent in our IPN cases.
CONCLUSIONS: We initially elucidate LRP12 repeat expansions as a prevalent cause of CMT, highlighting the necessity for an adapted screening strategy in clinical practice, particularly when addressing patients with IPN.
摘要：
背景：超过60％的遗传性周围神经病（IPN）的致病基因仍未鉴定。本研究通过进行针对非编码重复扩增的筛查，努力提高IPN病例的遗传诊断率。
方法：我们收集了2424名诊断为IPN的无关日本患者的数据，其中1555例遗传原因不明，通过全面的预筛选分析确定，被选中进行研究。使用PCR和长读取测序技术进行LRP12、GIPC1和RILPL1基因中CGG非编码重复扩增的筛选。
结果：我们从44例LRP12中发现CGG重复扩增，将其确立为日本IPN中第四大最常见的病因。大多数病例（29/37）表现为远端肢体无力，没有上睑下垂，眼肌麻痹,面部肌肉无力或球麻痹。在针肌电图（97％）和骨骼肌组织（100％）中经常观察到神经源性变化。在神经传导研究中,28例主要表现为运动神经损害，未同时累及感觉神经，与遗传性运动神经病的表型一致。在七个案例中，运动神经和感觉神经都受到影响，类似于Charcot-Marie-Tooth（CMT）表型。重要的是,与LRP12-眼咽远端肌病患者相比,本患者检测到的平均CGG重复数显著缩短(p<0.0001).此外,在我们的IPN病例中没有GIPC1和RILPL1重复扩增。
结论：我们最初阐明LRP12重复扩增是CMT的普遍原因，强调在临床实践中采用适应性筛查策略的必要性，特别是在处理IPN患者时。
方法：我们收集了2424名诊断为IPN的无关日本患者的数据，其中1555例遗传原因不明，通过全面的预筛选分析确定，被选中进行研究。使用PCR和长读取测序技术进行LRP12、GIPC1和RILPL1基因中CGG非编码重复扩增的筛选。
结果：我们从44例LRP12中发现CGG重复扩增，将其确立为日本IPN中第四大最常见的病因。大多数病例（29/37）表现为远端肢体无力，没有上睑下垂，眼肌麻痹,面部肌肉无力或球麻痹。在针肌电图（97％）和骨骼肌组织（100％）中经常观察到神经源性变化。在神经传导研究中,28例主要表现为运动神经损害，未同时累及感觉神经，与遗传性运动神经病的表型一致。在七个案例中，运动神经和感觉神经都受到影响，类似于Charcot-Marie-Tooth（CMT）表型。重要的是,与LRP12-眼咽远端肌病患者相比,本患者检测到的平均CGG重复数显著缩短(p<0.0001).此外,在我们的IPN病例中没有GIPC1和RILPL1重复扩增。
结论：我们最初阐明LRP12重复扩增是CMT的普遍原因，强调在临床实践中采用适应性筛查策略的必要性，特别是在处理IPN患者时。
