两例晚发型戊二酸尿症Ⅱ型患者的临床及其ETFDH基因研究

Clinical features and ETFDH mutations of children with late-onset glutaric aciduria type Ⅱ: a report of two cases

目的报道2个ETFDH基因变异导致的晚发性戊二酸尿症Ⅱ型家系的临床及遗传学特点。方法利用靶向基因捕获二代测序的方法对疑似患者及其家庭成员进行基因测序分析,回顾性分析患者的临床特点并进行文献复习。结果两个家系的先证者分别于10岁和5岁6个月发病,均以肌无力、肌肉酸痛为表现。血清肌酸激酶及其同工酶、乳酸脱氢酶均明显升高。血串联质谱分析提示多种酰基肉碱升高;尿有机酸分析发现戊二酸升高。肌电图提示肌源性损害。基因检测发现患者1的ETFDH基因存在两个新突变:c.1331T>C(来自其母亲)和c.824C>T(来自其父亲),其弟弟为c.1331T>C突变携带者、表型正常。患者2的ETFDH基因检出一个新突变:c.177ins T,及一个已知突变:c.1474T>C,分别来自其父母,其家系检出多位携带者。两例先证者均确诊为戊二酸尿症Ⅱ型,予以高剂量维生素B2治疗,症状好转。结论对于肌无力、肌肉酸痛的患者应进行肌酶、血液酯酰肉碱、尿有机酸等检测,警惕戊二酸尿症Ⅱ型的可能,基因分析有助于确诊。

Objective To investigate the clinical and genetic features of two families with late-onset glutaric aciduria type Ⅱ caused by ETFDH mutations. Methods Target gene sequence capture and next generation sequencing were used for sequencing of suspected patients and their family members. The patients＇ clinical features were retrospectively analyzed and literature review was performed. Results The probands of the two families had a clinical onset at the ages of 10 years and 5.5 years respectively, with the clinical manifestations of muscle weakness and muscle pain. Laboratory examinations revealed significant increases in the serum levels of creatine kinase, creatine kinase-MB, and lactate dehydrogenase. Tandem mass spectrometry showed increases in various types of acylcarnitines. The analysis of urine organic acids showed an increase in glutaric acid. Electromyography showed myogenic damage in both patients. Gene detection showed two novel mutations in the ETFDH gene（c.1331T〉C from the mother and c.824CT from the father） in patient 1, and the patient＇s younger brother carried the c.1331T〉C mutation but had a normal phenotype. In patient 2, there was a novel mutation（c.177 ins T from the father） and a known mutation（c.1474T〉C from the mother） in the ETFDH gene. Several family members carried such mutations. Both patients were diagnosed with glutaric aciduria type Ⅱ. Their symptoms were improved after high-dose vitamin B2 treatment. Conclusions For patients with unexplained muscle weakness and pain, serum creatine kinase, acylcarnitines, and urinary organic acids should be measured, and the possibility of glutaric aciduria type Ⅱ should be considered. Genetic detection is helpful to make a confirmed diagnosis.