硫胺素焦磷酸激酶缺乏症一家系的临床特点及基因变异分析

Clinical characteristics and genetic analysis of a pedigree affected with thiamine pyrophosphokinase deficiency

目的探讨一个硫胺素焦磷酸激酶缺乏症(thiamine pyrophosphokinase deficiency,TPKD)家系的临床和基因变异特点。方法分析TPKD家系的临床表现、影像学特点,对家系成员行全外显子测序。结果先证者,女,2岁8个月出现发作性共济失调伴肌张力障碍,此后反复发作共济失调7~8次。11岁时因病情再次发作且逐渐加重就诊,入院后第4天死亡。MRI示脑实质弥漫对称性损害及脊髓病变。胞兄有类似症状,6岁时去世。父母系近亲婚配。基因测序显示先证者TPK1 c.161C>T纯合突变,关联疾病为TPKD;患儿父亲、母亲及姐姐均为c.161C>T杂合突变。结论对于婴幼儿期起病,呈发作性脑病、共济失调、肌张力障碍等表型的患儿,早期进行基因检测明确诊断,可以指导治疗及遗传咨询。

Objective To investigate the clinical characteristics and genetic variant in a pedigree affected with thiamine pyrophosphokinase deficiency(TPKD).Methods Clinical data of the pedigree were analyzed retrospectively and summarized from the perspectives of clinical manifestation,imaging,and genotype.Relevant literature was also reviewed.Results The proband,a female,has developed paroxysmal ataxia with dystonia at the age of 2-year-and-8-month.The ataxia has recurred for 7-8 times.The child had died at 11 years old due to recurrence and aggravation of the disease.MRI showed diffuse symmetrical lesions of brain parenchyma and spinal cord lesions.Her brother had similar symptoms and died at 6.The parents were consanguineous but healthy.Genetic testing revealed that the girl has carried homozygous c.161C>T variants of the TPK1 gene,suggesting the diagnosis of TPKD.So far 15 cases of TPKD have been reported,among which 9 were from consanguineous marriages.The disease usually occurs before 3-year-old,and most patients had featured paroxysmal encephalopathy and recurrent infections.Symmetrical celebral cortex,basal ganglia and cerebellum lesions were common.Missense mutations of the TPK1 gene were common.Vitamin B1 was effective in some cases.Conclusion For infants featuring encephalopathy,ataxia,dystonia and other phenotypes,early genetic testing should be recommended in order to provide guidance for treatment and genetic counseling.