HINT1基因变异致常染色体隐性遗传轴索型神经病伴神经性肌强直藏族家系及文献复习

Autosomal recessive axonal neuropathy with neuromyotonia in a Tibetan family caused by HINT1 gene variation and literature review

目的分析HINT1基因变异致常染色体隐性遗传轴索型神经病伴神经性肌强直(ARAN-NM)的特点。方法回顾性病例总结。分析2023年8月在北京大学第一医院儿科确诊为ARAN-NM的2例藏族兄妹的临床资料。检索各个数据库收录的相关中国病例的文献并进行分析。结果先证者及其兄分别为13岁和19岁,均于11岁出现步态异常,其后出现足内翻及跛行、拇指力弱,先证者合并神经性肌强直。查体先证者及其兄均四肢肌力下降,拇指和下肢远端为著,先证者下肢远端肌肉萎缩,先证者兄双手肌肉萎缩,二人双足均马蹄内翻畸形。先证者肌电图(EMG)检查示周围神经病损(运动和感觉纤维轴索受累,远端受累为重)和肌强直电位。家系全外显子组测序检测到二人HINT1基因纯合致病性变异[c.169A>G(p.K57E)],确诊ARAN-NM。先证者口服卡马西平后神经性肌强直症状缓解,麻木、无力症状明显改善。先证者和其兄行骨科手术治疗和康复治疗后足部畸形及步态明显改善。检索到符合条件的中文文献2篇(2例),英文文献4篇(8例)。加上本例先证者及其兄共12例,10例有临床资料,起病年龄为2~16岁(1例未知),诊断年龄为13~33岁,9例有肌无力,肌无力以远端为著,8例伴神经性肌强直,9例出现肌肉萎缩,7例合并足畸形,2例合并感觉障碍,9例检测肌酸激酶的患者均有升高,EMG均提示神经源性损伤,6例可见神经性肌强直放电,3例接受卡马西平治疗,部分症状缓解。12例均有遗传学资料,均为错义突变/无义突变,高频变异为c.112T>C(p.C38R)。结论ARAN-NM是由HINT1基因变异引起的常染色体隐性遗传性罕见神经肌肉病,临床表现无民族差异,主要为肢体远端无力伴神经性肌强直,卡马西平可缓解部分症状,骨科矫形治疗可改善足部畸形和步态。

Objective To summarize the characteristics of autosomal recessive axonal neuropathy with neuromyotonia(ARAN-NM)caused by HINT1 gene mutation.Methods Retrospective case summary.Clinical data of 2 Tibetan siblings diagnosed with ARAN-NM in the Department of Pediatrics of Peking University First Hospital in August 2023 were retrospectively analyzed.A review of literature reporting relevant Chinese patients was conducted.Results The proband and her elder brother were aged 13 and 19,respectively.Both developed abnormal gait at the age of 11,followed by varus,claudication,and weak thumb strength.The proband also had neuromyotonia.Physical examinations showed that the proband and her elder brother had decreased muscle strength of the extremities,mainly in the thumbs and distal ends of lower limbs.The distal muscles of the proband′s lower extremities and the muscles of both hands of the proband′s elder brother were atrophied.Both feet showed talipes equinovarus in the proband and her elder brother.The proband′s electromyography(EMG)showed peripheral nerve injuries(motor and sensory axonal involvement,especially in distal ends)and myotonic potentials.The trio-whole exon sequencing detected homozygous pathogenic variation in HINT1 gene in both the proband and her elder brother,who were diagnosed as ARAN-NM based on c.169A>G(p.K57E).After the Carbamazepine treatment,the proband′s neuromyotonia,numbness and weakness were relieved.Both the proband and her elder brother underwent orthopaedic surgery and rehabilitation.Their foot deformities and gait were significantly improved.Two Chinese literatures(2 patients)and four English literatures(8 patients)were retrieved.Including the proband and her elder brother in this study,there were 12 ARAN-NM patients,10 of whom had clinical data.The ages of onset and diagnosis were 2-16(1 case unknown)and 13-33 years old,respectively.Myasthenia was present in 9 patients,especially in distal ends.Eight patients were complicated with neuromyotonia,nine patients with muscle atrophy,seven patients with foot deformity,and two patients with sensory disturbance.Creatine kinase(CK)was elevated in all 9 patients tested or CK.EMG showed neurogenic injuries in all patients and neuromyotonia discharge in six patients.Three patients were treated with Carbamazepine,and some symptoms were relieved.Missense/nonsense mutations were found in the 12 patients,and the high-frequency variation was c.112T>C(p.C38R).Conclusions ARAN-NM is a rare autosomal recessive neuromuscular disease caused by HINT1 gene mutation.There is no ethnic difference in clinical manifestations,mainly distal limb weakness with neuromyotonia.Carbamazepine can alleviate some symptoms,and orthopaedic surgery can improve foot deformity and gait.