Objective: To investigate the clinical and genetic features of a Chinese child with hyperekplexia and review the related literature. Method: The clinical and genetic data of one patient with hyperekplexia, who had visited the department of Pediatrics, Peking University First Hospital in July 2012, were analyzed. "Hyperekplexia" "startle disease" "GLRB" were used as key words to search at CNKI, Wanfang and PubMed from the database from creation to August 2016. Result: The one-year-old female patient showed exaggerated startle reflexes and generalized stiffness in response to external sudden, unexpected stimuli at 2 hours after birth, which existed every day. Her younger twin sister died of severe apnea due to a continuous generalized stiffness at the age of 7 months. Physical examination exhibited the positive nose-tapping reflex. There were no obvious abnormalities in laboratory tests, electroencephalogram (EEG) and neuroimaging tests. The patient was revealed to have compound heterozygous mutations in GLRB gene, c. 298-1G>A (or IVS4-1G>A) inherited from the father and c. 347T>C (p. L116P) inherited from the mother. The mutation L116P in GLRB gene was not reported before. During the follow-up until 5 years old, the girl's symptoms of startle reflexes and generalized stiffness were controlled with clonazepam treatment. Her mental development was normal, but she walked very carefully as wide-based gait to avoid of external sudden stimuli. Literature retrieval obtained 8 reports (all in English) with 39 GLRB-related cases. Combined analysis of the data of the 39 foreign cases and our case showed that the onset age of all 40 cases was in neonatal or in utero, and all presented exaggerated startle reflexes and generalized stiffness in response to external stimuli. Other symptoms included neonatal apneas (83%, 20/24), falls (56%, 15/27) and squint (42%, 10/24) etc. EEG (13/13) and brain imaging (90%, 28/31) were normal, or unrelated/nonspecific to hyperekplexia. In the total 17 mutations of GLRB gene found in 28 cases, the most frequent mutations were GLRB gene M177R (9 cases) and IVS5+ 5G>A (5 cases). Most cases (82%, 32/39) had received the treatment of clonazepam. The symptoms of hyperekplexia all could be improved in different degree after treatment, and 84% (32/38) of the cases were completely controlled or only existed exaggerated startle reflexes. The psychomotor development could be normal (13 cases) or retarded (25 cases). Conclusion: The patient presented typical clinical manifestations of hyperekplexia and had a good response to clonazepam. The patient carried GLRB gene mutations found by genetic analysis, and was finally diagnosed with hyperekplexia. The younger twin sister died due to lack of timely diagnosis and treatment, suggesting the significance of early detection and proper treatment for this disease.
目的： 总结1例过度惊吓反应症患儿的临床及遗传学特点，并进行文献复习。 方法： 对2012年7月就诊于北京大学第一医院儿科的1例过度惊吓反应症患儿的临床诊疗随访过程及基因检测结果进行总结。并以"过度惊吓反应症" "hyperekplexia" "startle disease" "GLRB"为检索词查询CNKI、万方及PubMed数据库(建库起至2016年8月)，对国内外GLRB基因突变病例进行总结分析。 结果： 患儿 女，1岁。出生后2 h在突然的外界刺激后出现过度惊跳及全身僵硬表现，并每天持续存在。患儿双胞胎妹妹于生后2 h也出现类似症状，7月龄时因一次持续全身僵硬导致窒息死亡。患儿体格检查示点鼻反射阳性。实验室检查、脑电图及神经影像学检查均无明显异常。基因突变分析揭示GLRB基因复合杂合突变，第4内含子c. 298－1G>A(IVS4－1G>A)杂合剪切位点突变和第5外显子c. 347T>C(p. L116P)杂合错义突变，该错义突变为国际上未报道的新突变。其父携带GLRB基因IVS4－1G>A突变，其母携带GLRB基因L116P突变。末次随访年龄为5岁，一直口服氯硝西泮，未再出现明显惊跳及全身僵硬症状，智力发育基本正常，但性情胆小，走路时呈宽基底步态。文献检索共搜集到8篇(均为英文文献)报道39例GLRB基因突变确诊病例，加上本例资料共40例进行合并分析。所有病例均为新生儿期或宫内起病，均可由外界刺激诱发过度的惊吓反应及全身僵硬症状；其次可出现窒息(83%，20/24)，摔倒(56%，15/27)，斜视(42%，10/24)等表现。脑电图(13例检测者全部)及头颅影像学(90%，28/31)正常或存在与本病不相关或非特异性异常。28例共报道GLRB基因17种突变位点，其中GLRB基因M177R(9例)及IVS5＋5G>A(5例)较常见。多数病例(82%，32/39)接受氯硝西泮治疗。经治疗后所有症状均有不同程度的减轻，84%(32/38)症状完全消失或仅存在过度的惊吓反应。38例患儿中，智力、运动发育正常13例、落后25例。 结论： 本例患儿具有过度惊吓反应症的典型临床表现和对氯硝西泮有效的治疗反应，基因突变分析发现GLRB基因突变最终确诊本病。患儿双胞胎妹妹因未能得到及时诊治而死亡，提示早期诊断以及恰当治疗对本病的重要性。.
Keywords: Gene, GLRB; Mutation; Startle reaction.