脑脊髓病样表现的生物素酶缺乏症1例报告并文献复习

Biotinase deficiency manifested as encephalomyelopathy: a case report and literature review

目的探讨脑脊髓病样表现的生物素酶(BTD)缺乏症的诊断和治疗。方法回顾分析1例BTD缺乏症患儿的临床资料,并分析相关文献。结果患儿,男,6岁,入院前3个月进行性双下肢痉挛性瘫痪;既往在3岁感冒后出现类似情况;平时手易脱皮,有口角炎。外院检查示视听诱发电位异常。入院后查脑脊液正常,头颅磁共振成像(MRI)示双侧枕叶、基底节区多发点片状稍长T1长T2异常信号;入院后出现延髓麻痹表现,给予气管插管呼吸机辅助通气。尿气相色谱-质谱(GC/MS)分析,尿乳酸、3-羟基异戊酸、3-甲基巴豆酰甘氨酸、甲基枸橼酸及3-羟基丙酸排泄量增高;血串联质谱技术(MS/MS)分析,丙酰基肉碱、3-羟基异戊酰肉碱(C5-OH)浓度明显升高;血BTD活性明显降低0.076 pmol/(min·mm^3),确诊为BTD缺乏症。给予生物素40 mg/d口服,3天后撤机成功,2周后可行走,皮疹消退;3周后复查头颅MRI示原病灶消失,脊髓MRI未见异常。PCR直接测序法检测BTD基因,发现患儿第2号外显子上T172T/C杂合突变和第4号外显子上T1413C纯合突变,家系验证及数据库查询证实后者为致病性突变。出院后继续给予生物素口服20 mg/d,随访2年无异常。结论 BTD缺乏症表现复杂多样,尿GC/MS及血MS/MS分析可协助诊断,BTD活性测定及BTD基因检测可进一步确诊此病,及时给予生物素治疗疗效显著。

Objective To explore the diagnosis and treatment of biotinase deficiency （BTD） manifested as encephalomyelopathy. Methods The clinical data of one child with BTD were retrospectively analyzed. The pertinent literatures were reviewed. Results A six-year-old male child suffered from progressive spastic paralysis of lower limbs for 3 months before admission. A similar symptoms occurred after a cold in 3-year-old. It was easy to peel skin on her hands and she had angular stomatitis. Audio visual evoked potential was detected to be abnormal in other hospital. After hospitalizion, the cerebrospinal fluid examination was normal, and MRI showed long T1 long T2 signals bilateral occipital lobe and basal ganglia region. Because the child represented medulla palsy, and so the tracheal intubation ventilator was administrated to assist ventilation. Urine gas chromatography/mass spectrometry （GC/MS） analysis showed increases of lactic acid, 3-hydroxy acid, 3-tiglyl glycine, methylcitric acid, and ethylene lactic acid. Serum MS/MS analysis showed that the concentrations of propionyl carnitine and 3-hydroxyisovaleryl camitine were increase obviously. The serum biotinase level was significantly decrease to 0.076 pmol/（min,mm^3）. The diagnosis of BTD was confirmed. After supplementation biotin, 40 mg/d, the ventilator was successfully weaned on the third day, the child walked again after 2 weeks, and the rash was vanished. After 3 weeks, the head MRI showed disappearance of the original lesion, and there was no abnormal in spinal cord. The BTD gene detected by PCR direct sequencing showed a heterozygosis mutation of T172T/C in the second exon and a homozygous mutation of T1413C in the fourth exon, which was confirmed as a pathogenic mutation by pedigree verification and database query. After discharge, the oral administration of biotin 20 mg/d continued, and no abnormality was found in 2 years of follow-up. Conclusions The manifestations of BTD are complex and diverse. The analysis of urine GC/MS and serum MS/MS can assist the diagnosis. The determination of biotinase activity and gene detection of BTD can further confirm the diagnosis. Timely biotin supplementation has significant treatment efficacy.