GLRB基因变异所致新生儿过度惊吓反应症的临床及分子遗传学分析并文献复习

Clinical and genetic analysis of neonatal hyperekplexia caused by GLRB mutations and its literature review

摘要:

目的：对成都市妇女儿童中心医院1例新生儿过度惊吓反应症的临床及遗传学特点进行分析报道，并进行文献复习，探讨该病新生儿期的早期诊断及治疗方案。方法：对2019年9月在成都市妇女儿童中心医院新生儿重症监护病房（neonatal intensive care unit，NICU）就诊的过度惊吓反应症患儿的临床诊疗过程及基因检测结果进行分析总结。并以“新生儿过度惊吓反应症”“neonatal hyperekplexia”“newborn”“startle disease”为检索词查询万方、PubMed数据库（建库起至2019年9月），对国内外早期诊断病例（2个月以内，基因检测阳性）进行总结分析。结果：本例及文献检索共纳入19例进行合并分析。所有患儿均在新生儿期起病，对不可预知的刺激发生过度惊吓反应，57.8%的患儿发生需要复苏的强直窒息发作。全部病例叩鼻试验阳性，脑电图和头颅影像学无特异性异常。氯硝西泮对此病有较好疗效。维杰瓦诺策略（Vigerano manoenvre）可缓解急性发作。本例患儿全外显子组基因测序检测到符合临床提示的基因变异。基因突变GLRB c.844_846delGTT p.（Val282del）源于父亲；GLRB c.527G>A p.（Argl76Lys）源于母亲。纳入病例中的73.6%为GLRA1变异，15.8%为SLC6A5变异，10.5%为GLRB变异。结论：本例患儿具有过度惊吓反应症的典型临床表现，通过基因突变分析发现了与此病相关的GLRB变异。该病可以治疗但容易误诊，常在新生儿期发生危及生命的全身僵硬及窒息发作，提示早期诊断非常重要。叩鼻试验阳性可作为诊断的特征性线索。因涉及多个基因，可采用全外显子二代基因测序。氯硝西泮对此病有较好疗效，具体用药剂量及时间尚需进一步临床研究。

Abstract:

Objective：To report the clinical and genetic features of a newborn with hyperekplexia，to review the related literature and to investigate the early diagnosis and treatment of neonatal hyperekplexia. Methods：The clinical and genetic data of a newborn diag－nosed with hyperekplexia，who was admitted to our NICU in September，2019，was analyzed. In addition，key words including “Neonatal hyperekplexia”，“newborn” and “startle disease” were searched in Wan Fang and PubMed database（from establishment to September，2019），and cases with early diagnosis at home and abroad（within 2 months）were summarized and analyzed by positive gene test. Results：A total of 19 cases（one case in our hospital and 18 cases from reports） were analyzed. Onset of all patients was in the neonatal period，and patients had excessive startle response to unpredictable stimulation，among which 57.8% patients（including one patient in our hospital） had tonic-apneic spells requiring resuscitation. All cases were positive in nose-tapping test，and there was no specific abnormality in EEG and cephalography. Clonazepam has a good effect on this disease. Vigerano manoenvre was able to alle－viate the acute attack. In our report，gene variation detected by all exon gene sequencing was consistent with clinical condition. The gene mutation GLRB c.844_846delGTT p.（Val282del） originated from father and GLRB c.527G>A p.（Argl76Lys） from mother. A total of 73.6% included patients were GLRA1 mutations，15.8% SLC6A5 mutations and 10.5% GLRB mutations. Conclusion：Patient in this study has the typical clinical manifestation of hyperek－plexia and gene mutation analysis demonstrates that it is corre－lated with GLRB mutation. The disease can be treated but usu－ally be misdiagnosed，often occurs life-threatening systemic stiffness and apnoea attack in the neonatal period，suggesting the importance of early diagnosis. The positive result of nose-tapping test can be used as the characteristic clue of diagnosis. Because multiple genes are involved，the whole exon second generation gene can be sequenced. Clonazepam has a good effect on this disease，but the accurate dosage and time need further clinical study.