8例戊二酸血症1型患儿临床表型及GCDH基因突变分析

Clinical phenotype and GCDH gene mutation in 8 children with glutaric aciduria type 1

目的探讨戊二酸血症1型(glutaric aciduria type 1, GA1)患儿临床特点及基因突变类型。方法 8例GA1患儿,采用串联质谱和气相色谱-质谱联用技术检测患儿血清氨基酸、酰基肉碱和尿有机酸水平,行头颅MRI检查,采用医学全外显子测序技术检测遗传病基因,并采用Sanger测序法对8例患儿及其父母的GCDH基因变异进行验证。结果 8例GA1患儿经新生儿筛查发现4例,因运动发育落后经遗传代谢病检测确诊4例;主要临床表现为四肢肌张力高或降低2例,癫痫3例,运动发育落后4例,黄疸2例,睾丸鞘膜积液2例。8例患儿血戊二酰肉碱、戊二酰肉碱/辛酰肉碱水平均升高,尿戊二酸水平升高6例。脑MRI检查4例显示双侧额颞部蛛网膜下腔增宽,双侧基底节区域对称性长T2信号;3例有额颞部蛛网膜下腔增宽、基底节区域异常信号;1例无明显改变。8例患儿GCDH基因检测结果均为复合杂合突变。结论 GA1患儿有多发神经损伤,对MRI表现为额颞部蛛网膜下腔增宽、基底节区域异常信号的患儿和尿戊二酸浓度正常的可疑GA1患儿,应及时进行实验室检查和基因突变分析;GCDH基因为GA1的致病基因。

Objective To investigate the clinical characteristics and gene mutation types of 8 children with glutaric aciduria type 1(GA1). Methods In 8 children with GA1, tandem mass spectrometry and gas chromatography-mass spectrometry were used to detect the levels of serum amino acids, acylcarnitines and urine organic acids.In parallel, head MRI examination and medical all-exome sequencing technology were used for detecting genetic diseases.Sanger sequencing method was used to verify the GCDH gene mutations of 8 children and their parents. Results In 8 children with GA1, 4 were found by newborn screening, and 4 were diagnosed by genetic and metabolic diseases screening due to delayed motor development.The main clinical demonstrations included hypertonia or hypomyotonia in 2 children, epilepsy in 3, jaundice in 2, and hydrocele in 2.The levels of blood glutaryl carnitine and glutaryl carnitine/octanoyl carnitine increased in all patients, and urine glutaric acid increased in 6.Brain MRI examination showed that the subarachnoid space in the frontotemporal region was widened on both sides, and the basal ganglia area had symmetrical long T_(2) signals in 4 children;3 children had widening of the subarachnoid space in the frontotemporal region and abnormal signals in the basal ganglia area;1 child had no significant change.The GCDH gene results were compound heterozygous mutations in all children. Conclusions Children with GA1 have multiple nerve injuries.For suspected GA1 children with MRI manifestations of frontotemporal subarachnoid space widening, abnormal signals in the basal ganglia, and normal urinary glutaric acid concentration, the laboratory examination and gene mutation analysis should be done in time.GCDH is the pathogenicity gene of GA1.