共患戊二酸血症Ⅰ型的单卵双胞胎临床表型与基因突变分析

Clinical investigation of monozygotic twins with glutaric acidemia type Ⅰ and gene mutation analysis

目的 回顾分析1例戊二酸血症Ⅰ型家系临床资料特点,并探讨其戊二酰辅酶A脱氢酶（GCDH）基因突变类型.方法 收集家系中发病患儿临床资料,包括体格检查,头颅CT、MRI,尿液有机酸分析,血液肉碱串联质谱分析结果.抽取先证者及其家系成员（2代共5人）外周血,提取基因组DNA.PCR扩增GCDH基因11个外显子及其侧翼区序列,扩增产物纯化后直接测序.结果 先证者头围正常,无外貌畸形,格拉斯哥指数（GCS）评分15分;四肢活动正常,肌力Ⅴ级,肌张力正常,巴氏征未引出,布氏征、克氏征阴性.CT示双侧额颞部硬膜下间隙增宽,轻度脑积水,右侧额顶部弧形等密度影.MRI示双侧额、颞叶体积缩小、脑沟脑裂增宽,外侧裂明显增宽,颞极前蛛网膜下腔增宽,双侧苍白球、额叶中央白质区可见对称性稍长T1稍长T2信号影,弥散加权成像呈高信号,双侧大脑半球脑白质偏少,右侧颞顶部硬膜下见等T1稍长T2信号影,液体衰减反转恢复呈高信号.遗传代谢病尿液筛查发现尿中戊二酸大量增高;血液氨基酸和肉碱串联质谱分析结果中戊二酰肉碱为0.34 μmol/L（正常参考值为0～0.20μmol/L）.GCDH基因测序分析证实先证者为c.1205G＞A和IVS10-2A＞C的复合杂合突变.戊二酸血症Ⅰ型家系分析发现先证者单卵双生的胞妹也为戊二酸血症Ⅰ型患儿,其基因型与先证者完全一致,临床症状表现和疾病严重程度相近.结论 具有相同遗传背景的戊二酸血症Ⅰ型患儿,其临床表型与临床症状的严重程度相近.IVS10-2A＞C是GCDH基因的突变类型中最常见的致病突变.

Objective To review the clinical features of a Chinese family with glutaric acidemia type Ⅰ and analyze the glutaryl-CoA dehydrogenase（GCDH） gene mutation.Methods The patient＇s clinical data were collected from glutaric acidemia type Ⅰ family,including data of brain computer tomography （CT）,magnetic resonance imaging （MRI） examination,urine organic acid and blood carnitine tandem mass analysis.The family members＇ genomic DNA was extracted from peripheral blood leukocytes.The 11 exons and their flanking sequences of GCDH gene were amplified with PCR and subjected to direct DNA sequencing.Results The proband＇s head circumference and visible exterior were normal.The Glasgow Coma Scale（GCS） score of the patient was 15.The four limbs activities and muscular tension were normal.The muscle strength was grade Ⅴ.The Babinski sign,Brinell syndrome and Klinefelter syndrome were negative.CT findings revealed widened bilateral frontotemporal subdural interval,mild hydrocephalus,equidensite arc shadow at the right frontal parietal.MRI findings demonstrated bilateral frontotemporal atrophy,broadened cerebral sulci,fissures,sylvian fissure and subarachnoid space in the front temporal lobe.The T1,T2 and diffusion weighted image showed abnormal signals in the bilateral globus pallidus and the central white matter of the frontal lobe.The density of cerebral hemisphere white matte was attenuated.In the temporal parietal subdural,equal T1,moderate T2 and high intensity fluid-attenuated inversion recovery signals were detected.The inherited metabolic diseases screening showed high urinary glutaric acid excretion.The blood glutarylcarnitine was 0.34 μmol/L （0-0.20 μmol/L as normal reference） which was detected by tandem mass spectrometry.GCDH gene sequencing analysis confirmed that the proband was compound heterozygous mutations with c.1205G 〉 A and IVS10-2A 〉 C.The pedigree analysis revealed that the proband＇s monozygotic twin little sister was also an glutaric acidemia type Ⅰ patient.The genotype of the little sister was completely consistent with proband.The clinical symptoms and disease severity were similar between the monozygotic twins.Conclusions The monozygotic twins who shared the same mutation and genetic background can have similar phenotypes and clinical symptoms.IVS10-2A 〉 C is the prevalent GCHD gene mutation type in Chinese glutaric acidemia type Ⅰ patients.