极长链酰基辅酶A脱氢酶缺乏症11例的临床和ACADVL基因突变谱分析

Clinical features and ACADVL gene mutation spectrum analysis of 11 Chinese patients with very long chain acyl-CoA dehydrogenase deficiency

目的 探讨极长链酰基辅酶A脱氢酶缺乏症（VLCADD）的临床表现,实验室检查特点以及基因型与表型的相关性.方法 对2006年9月至2014年5月在上海新华医院儿科就诊的11例极长链酰基辅酶A脱氢酶缺乏症的临床表现、实验室检查、基因型、诊治和预后等进行分析.11例患儿中男9例、女2例,就诊年龄2d～17岁,诊断主要依靠血串联质谱和基因分析结合临床及其他检查.结果 11例均有血十四烯酰基肉碱（C14∶1）特异性升高.6例为新生儿早发型,3例为婴儿型,2例为成人迟发型.其中4例新生儿早发型和2例婴儿型在生后2～8个月死亡,目前存活的2例新生儿早发型患儿均通过新生儿疾病筛查得以早期诊断和治疗.11例中共检出17种ACADVL基因突变,检出率95.45％（21/22）,包括11种已知突变（p.S22X,p.G43D,p.A213T,p.C215R,p.G222R,p.W427X,p.R450H,p.R456H,p.R511Q,c.296-297delCA,c.1605＋ 1G＞T）和6种新突变（p.S72F,p.Q100X,p.M437T,p.D466Y,c.1315delG insAC,IVS7 ＋4 A＞G）.p.R450H检出率最高,占总突变的13.63％ （3/22）,其次为S22X和D466Y突变,各占9.09％（2/22）.结论 11例VLCADD患儿的ACADVL基因突变谱具有高度异质性,新生儿型和婴儿型较成人迟发型患者死亡率高,提示基因型和表型间存在一定相关性.早期的诊断和治疗对患者的预后有重要意义.

Objective To investigate the clinical and laboratory features of very long chain acylCoA dehydrogenase deficiency （VLCADD） and the correlations between its genotype and phenotype.Method Eleven patients diagnosed as VLCADD of Shanghai Jiaotong University School of Medicine seen from September 2006 to May 2014 were included.There were 9 boys and 2 girls,whose age was 2 d-17 years.Analysis was performed on clinical features,routine laboratory examination,and tandem mass spectrometry （MS-MS）,gas chromatography mass spectrometry （GC-MS） and genetic analysis were conducted.Result All cases had elevated levels of blood tetradecanoylcarnitine （C14∶1） recognized as the characteristic biomarker for VLCADD.The eleven patients were classified into three groups：six cases in neonatal onset group,three in infancy onset group form patients and two in late onset group.Neonatal onset patients were characterized by hypoactivity,hypoglycemia shortly after birth.Infancy onset patients presented hepatomegaly and hypoglycemia in infancy.The two adolescent patients showed initial manifestations of exercise intolerance or rhabdomyolysis.Six of the eleven patients died at the age of 2-8 months,including four neonatal onset and two infant onset patients,with one or two null mutations.The other two neonatal onset patients were diagnosed since early birth through neonatal screening and their clinical manifestation are almost normal after treatments.Among 11 patients,seventeen different mutations in the ACADVL gene were identified,with a total mutation detection rate of 95.45% （21/22 alleles）,including eleven reported mutations （p.S22X,p.G43D,p.R511Q,p.W427X,p.A213T,p.C215R,p.G222R,p.R450H,p.R456H,c.296-297delCA,c.1605 ＋ 1G 〉 T） and six novel mutations （p.S72F,p.Q100X,p.M437T,p.D466Y,c.1315delG insAC,IVS7 ＋ 4 A 〉 G）.The p.R450H was the most frequent mutation identified in three alleles （13.63%,3/22 alleles）,followed by p.S22X and p.D466Y mutations which were detected in two alleles （9.09%,2/22 alleles）.Conclusion The ACADVL gene mutations were heterozygous in our patients.The mortality of neonatal onset form and infant onset form is much higher than the late onset form patients,suggesting a certain correlation between the genotype and phenotype was found.The earlier diagnosis and treatment of VLCADD are of vital importance for the improvement of the prognosis of the patients.