Department of Pediatric Endocrinology and Genetic Metabolism and Shanghai Institute for Pediatric Research, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200092, China.
World J Pediatr. 2014 May;10(2):119-25. doi: 10.1007/s12519-014-0480-2. Epub 2014 May 7.
Very long chain acyl-CoA dehydrogenase deficiency (VLCADD) is an inherited metabolic disease caused by deleterious mutations in the ACADVL gene that encodes very long chain acyl-CoA dehydrogenase (VLCAD), and which can present as cardiomyopathy in neonates, as hypoketotic hypoglycemia in infancy, and as myopathy in late-onset patients. Although many ACADVL mutations have been described, no prevalent mutations in the ACADVL gene have been associated with VLCADD. Herein, we report the clinical course of the disease and explore the genetic mutation spectrum in seven Chinese patients with VLCADD.
Seven Chinese patients, from newborn to 17 years old, were included in this study. Tandem mass spectrometry was performed to screen for VLCAD deficiency. All exons and flanking introns of the ACADVL gene were analyzed using polymerase chain reaction and direct sequencing. Online analysis tools were used to predict the impact of novel mutations.
All cases had elevated serum levels of tetradecanoylcarnitine (C14:1) which is the characteristic biomarker for VLCADD. The phenotype of VLCADD is heterogeneous. Two patients were hospitalized for hypoactivity and hypoglycemia shortly after birth. Three patients showed hepatomegaly and hypoglycemia in infancy. The other two adolescent patients showed initial manifestations of exercise intolerance or rhabdomyolysis. Three of the patients died at the age of 6-8 months. Eleven different mutations in the ACADVL gene in the 7 patients were identified, including seven reported mutations (p.S22X, p.W427X, p.A213T, p.G222R, p.R450H, c.296-297delCA, c.1605+1G>T) and four novel mutations (p.S72F, p.Q100X, p.M437T, p.D466Y). The p.R450H and p.D466Y (14.28%, 2/14 alleles) mutations were identified in two alleles respectively.
The clinical manifestations were heterog-eneous and ACADVL gene mutations were heterozygous in the seven VLCADD Chinese patients. R450H may be a relatively common mutation in Asian populations. The genotype and phenotype had a certain correlation in our patients.
极长链酰基辅酶 A 脱氢酶缺乏症（VLCADD）是一种遗传性代谢疾病，由编码极长链酰基辅酶 A 脱氢酶（VLCAD）的 ACADVL 基因的有害突变引起，可在新生儿中表现为心肌病，在婴儿期表现为低酮性低血糖症，在晚发性患者中表现为肌病。尽管已经描述了许多 ACADVL 突变，但在 ACADVL 基因中没有与 VLCADD 相关的常见突变。在此，我们报告了 7 例中国 VLCADD 患者的疾病临床过程，并探讨了基因突变谱。
本研究纳入了 7 例从新生儿到 17 岁的中国患者。采用串联质谱法筛查 VLCAD 缺乏症。使用聚合酶链反应和直接测序分析 ACADVL 基因的所有外显子和侧翼内含子。使用在线分析工具预测新突变的影响。
所有病例的血清十四烷酰肉碱（C14:1）水平均升高，这是 VLCADD 的特征性生物标志物。VLCADD 的表型具有异质性。2 例患儿出生后不久因活动减少和低血糖住院。3 例患儿在婴儿期表现为肝肿大和低血糖。另外 2 例青少年患者最初表现为运动不耐受或横纹肌溶解。3 例患者在 6-8 个月时死亡。在 7 例患者的 ACADVL 基因中发现了 11 种不同的突变，包括 7 种已报道的突变（p.S22X、p.W427X、p.A213T、p.G222R、p.R450H、c.296-297delCA、c.1605+1G>T）和 4 种新突变（p.S72F、p.Q100X、p.M437T、p.D466Y）。p.R450H 和 p.D466Y（14.28%，2/14 等位基因）突变分别存在于 2 个等位基因中。
7 例中国 VLCADD 患者的临床表现存在异质性，ACADVL 基因突变呈杂合性。R450H 可能是亚洲人群中较为常见的突变。本研究患者的基因型和表型具有一定相关性。
