四例戊二酸血症I型患儿临床资料分析与基因突变研究

Analysis of clinical features and GCDH gene mutations in four patients with glutaric academia type I

目的回顾分析4例戊二酸血症I型患儿临床资料特点，并探讨其基因突变类型。方法对戊二酸血症I型患儿进行头颅计算机断层扫描（computer tomography，CT）、磁共振成像（magnetic resonance imaging，MRI）影像学检查。应用串联质谱和气相色谱质谱分析患儿血氨基酸、肉碱和尿有机酸含量的改变。提取外周血基因组DNA，针对戊二酰辅酶A脱氢酶（glutaryl—CoA dehydrogenase，GCDH）基因设计特异性PCR引物，PCR扩增产物直接测序，确定GCDH基因突变类型。结果4例男性患儿表现为大头畸形，头围分别为50cm（14个月），47cm（9个月），46cm（5个月），51cm（14个月），均高于同龄儿的正常值。头颅影像学检查发现这4例患儿表现为大脑外侧裂及侧脑室扩大，额颞萎缩，蛛网膜下腔增宽，小脑蚓部异常等。4例患儿血戊二酰肉碱含量分别为：5．8μmol／L，7．5μmol／L，8．3μmol／L，7．9μmol／L（正常参考值为0～0．2μmol／L），同时发现尿中戊二酸含量大量增高。通过GCDH基因突变分析，证实4例患儿存在基因突变，其中C．146—149del4、IVS6-4一Ex7＋4de18、C．508A〉G（P．K170E）、c．797T〉C（P．M266T）和C．420del10为新发现的GCDH基因突变类型。结论戊二酸血症I型患儿以头围异常增大，神经系统损伤为主要临床表现，血串联质谱和尿气相色谱质谱分析对疾病的诊断起重要的提示作用，但确诊还需行基因突变分析。

Objective To review clinical features of four male patients with glutaric academia type I and screen glutaryl-CoA dehydrogenase （GCDH） gene mutations. Method The 4 patients underwent brain computer tomography （CT） and magnetic resonance imaging （MRI） analyses. Blood acylcarnitine and urine organic acid were analyzed with tandem mass spectrometry and gas chromatographic mass spectrometry. Genomic DNA was extracted from peripheral blood samples. The 11 exons and flanking sequences of GCDH gene were amplified with PCR and subjected to direct DNA sequencing. Result All patients have manifested macrocephaly, with head circumference measured 50 cm （14 months）, 47 cm （9 months）, 46 cm （5 months） and 51 cm （14 months）, respectively. Imaging analyses also revealed dilation of Sylvian fissure and lateral ventricles, frontotemporal atrophy, subarachnoid space enlargement and cerebellar vermis abnormalities . All patients had elevated glutarylcarnitine （5.8μmol/L, 7.5 μmol/L, 8.3 μmol/L and 7.9μmol/L, respectively） and high urinary excretion of glutaric acid. Seven mutations were identified among the patients, among which c. 146_149de14, IVS6-4_Ex7＋4del8, c. 508A〉G （p. K170E）, e. 797T〉C （p. M266T） and c. 420de110 were first discovered. Conclusion Maeroeephaly and neurological impairment are the most prominent features of glutaric academia type I . Blood tandem mass spectrometry and urine gas chromatographic mass spectrometry analysis can facilitate the diagnosis. The results can be confirmed by analysis of GCDH gene mutations.