母源性3-甲基巴豆酰辅酶A羧化酶缺乏症临床及基因突变分析

Clinical and mutational features of maternal 3-methylcrotonyl-coenzyme deficiency

目的报告5例母源性3-甲基巴豆酰辅酶A羧化酶缺乏症（maternal 3-methylcrotonyl—eoenzyme A earboxylase deficiency，MCCD），通过基因突变分析证实其临床诊断。方法将串联质谱新生儿筛查发现3一羟基异戊酰肉碱（C5-OH）增高的5例新生儿及其母亲纳入研究。用尿气相色谱质谱分析进行MCCDI艋床诊断；基因突变检测及功能分析明确诊断。结果（1）发现5例无症状母亲血C5-OH浓度明显增高，尿3-羟基异戊酸、3-甲基巴豆酰甘氨酸增高，诊断为良性MCCD。其新生儿血C5-OH浓度增高，3例随访后浓度逐步下降或达正常。（2）发现4种MCCC1基因新变异：e．insl680A（25％）、c．203C〉T（P．A68V）、C．572T〉C（P．L191P）、C．639＋5G〉T和2种MCCC2基因突变e．1406G〉T（P．R469L，新变异）及e．592C〉T（P．Q198X）。新变异可能影响蛋白结构和功能。结论对筛查血C5一OH增高的新生儿母亲应常规检测以诊断母源性MCCD。MCCCl基因突变多见。

Objective To report on 5 patients with maternal 3-methylcrotonyl-coenzyme A earhoxylase deficiency （MCCD） and to confirm the clinical diagnosis through mutation analysis. Methods Five neonates with higher blood 3-hydroxy-isovalerylcarnitine （C5-OH） concentration detected upon newborn screening with tandem mass spectrometry and their mothers were recruited. Urinary organic acids were analyzed with gas chromatography mass spectrometry. Gene mutation and protein [unction analysis were performed by PCR-direct sequencing and PolyPhen-2 software. Results Higher blood C5 OH concentrations （5. 11 21.77μmol/L） and abnormal 3-hydroxy isovalerate and 3-methylerotonyl-glycine in urine were detected in the five asymptomatic mothers, who were diagnosed as benign MCCD. Higher C5- OH concentration was also detected in their neonates by tandem mass spectrometry, which had gradually decreased to normal levels in three neonates. Four new variations, i. e. , c. ins1680A（25%）, c. 203C〉T（p. A68V）, c. 572T〉C（p. 1.191P） and c. 639＋5G〉T were detected in the MCCC1 gene, in addition with 2 mutations Ec. 1406G〉T（p. R469L,novel variation） and c. 592C〉T（p. Q198X）]. The novel variations were predicted to have affected protein structure and function. Conclusion For neonates with higher C5-OH concentration detected upon neonatal screening, their mothers should he also tested to rule out MCCD. Mutations in MCCCl gene are quite common.