生物素酶缺乏症的临床分析与基因诊断1例及文献复习  

Clinical analysis and genetic diagnosis of biotinidase deficiency:a case report and literatures review

作　　者：马秀伟 朱丽娜 杨尧 封志纯 

机构地区：[1]陆军总医院附属八一儿童医院神经发育科,北京100700

出　　处：《发育医学电子杂志》2016年第4期229-234,共6页Journal of Developmental Medicine (Electronic Version)

基　　金：中国博士后科学基金(20100471758)

摘　　要：目的探讨生物素酶缺乏症的临床特征、诊断与治疗方法。方法患儿男,2个月,于2016年4月因"间断抽搐1个月"收入陆军总医院附属八一儿童医院。通过血串联质谱分析、尿有机酸分析、生物素酶活性检测、全外显子芯片捕获及高通量测序等技术进行诊断,总结分析其临床表现和诊治过程。结果视频脑电图显示多灶性放电,片断样高峰失律。口服丙戊酸钠后症状加重,托吡酯效果不佳。血串联质谱分析示游离肉碱、丙酰肉碱、羟基异戊酰肉碱浓度升高。尿有机酸分析示3羟基异戊酸排泄量显著增高,并伴有3羟基丙酸、甲基枸橼酸、焦谷氨酸的增高。生物素酶活性分析示0.076 pmol?(分钟·3 mm)。全外显子测序显示BTD基因外显子区域c.637delC缺失突变,c.491dupG插入突变,导致氨基酸改变p.H213fs移码突变,p.R164fs移码突变,为复合杂合突变,父母验证结果显示此双杂合突变分别来自于父母。口服生物素10 mg?d和左卡尼汀10 ml?d,患儿抽搐控制。出院后家长自行停用抗癫痫药物。4个月龄时复诊,无抽搐,视频脑电图正常,Gesell发育评估显示发育商85分。结论婴儿期发病的难治性癫痫并伴有发育迟缓时需注意生物素酶缺乏症的可能,生物素治疗疗效显著,生物素酶活性测定及基因突变检测可协助确诊。Objective To investigate the clinical features, diagnosis and treatment of biotinidase deficiency. Methods The two-month-old male patient was hospitalized in Bayi Children＇s Hospital affiliated to PLA Army General Hospital in April 2016 because of frequent convulsion for one month. Blood tandem mass spectrometry, urinary organic acid analysis, blood biotinidase activity assay and exome sequencing were performed to confirm the diagnosis. His clinical manifestations, diagnosis and treating process were analyzed. Results Video electroencephalogram （VEEG） showed multiple local discharges and fragmental hypsarrhythmia. The symptom aggravated after administration of sodium valproated. There was no effect to topiramate therapy. Blood tandem mass spectrometry demonstrated that levels of CO, C3 and C5-OH were elevated. Urine organic acid analysis showed that the level of 3 hydroxy isovaleric acid was elevated, with elevated 3 hydroxy acrylic acid, Me-citrate, and Pyroglutamic aid. Biotinidase activity assay on dried blood spot was 0.076 pmol/（min.3 mm）. Exome sequencing revealed that there were c.637delC deletion mutation and c.491dupG insertion mutationin in the exon regions of BTD gene, leading to p.H213fs and p.R164fs amino acid changes. The compound heterozygous mutations were from his parents respectively throughfamily validation. Biotin （10 mg/d） supplementation and 1-carnitine （10 ml/d） led to a dramatic effect of the epilepsy. His parents stopped the antiepileptic drugs after discharge. The patient had no convulsion and VEEG was normal at 4-month-old return visit. Gesell test showed that his development quotient was 85. Conclusions Biotinidase deficiency should be considered in infancy with intractable epilepsy and developmental delay. Biotin administration can greatly improve the clinical symptoms. Biotinidase activity assay and gene mutation analysis may be helpful for the definite diagnosis.

关 键 词：生物素酶缺乏 生物素 癫痫 基因诊断 

分 类 号：R742.1[医药卫生—神经病学与精神病学]