PDF(Pubmed)
Abstract：
Very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) is a rare autosomal recessive disorder of fatty acid metabolism with a variable presentation. The aim of this study was to describe five patients with VLCADD diagnosed through the pilot study and expanded newborn screening (NBS) program that started in 2018 in Slovenia. Four patients were diagnosed through the expanded NBS program with tandem mass spectrometry; one patient was previously diagnosed in a pilot study preceding the NBS implementation. Confirmatory testing consisted of acylcarnitines analysis in dried blood spots, organic acids profiling in urine, genetic analysis of ACADVL gene, and enzyme activity determination in lymphocytes or fibroblasts. Four newborns with specific elevation of acylcarnitines diagnostic for VLCADD and disease-specific acylcarnitines ratios (C14:1, C14, C14:2, C14:1/C2, C14:1/C16) were confirmed with genetic testing: all were compound heterozygotes, two of them had one previously unreported ACDVL gene variant each (NM_000018.3) c.1538C > G; (NP_000009) p.(Ala513Gly) and c.661A > G; p.(Ser221Gly), respectively. In addition, one patient diagnosed in the pilot study also had a specific elevation of acylcarnitines. Subsequent ACDVL genetic analysis confirmed compound heterozygosity. In agreement with the diagnosis, enzyme activity was reduced in five patients tested. In seven other newborns with positive screening results, only single allele variants were found in the ACDVL gene, so the diagnosis was not confirmed. Among these, two variants were novel, c.416T > C and c.1046C > A, respectively (p.Leu139Pro and p.Ala349Glu). In the first 2 years of the expanded NBS program in Slovenia altogether 30,000 newborns were screened. We diagnosed four cases of VLCADD. The estimated VLCADD incidence was 1:7,500 which was much higher than that of the medium-chain acyl-CoA dehydrogenase deficiency (MCADD) cases in the same period. Our study also provided one of the first descriptions of ACADVL variants in Central-Southeastern Europe and reported on 4 novel variants.
摘要：
极长链酰基辅酶A脱氢酶缺乏症（VLCADD）是一种罕见的常染色体隐性遗传疾病，具有可变的表现。这项研究的目的是描述通过试点研究和扩大的新生儿筛查（NBS）计划诊断的五名VLCADD患者，该计划于2018年在斯洛文尼亚开始。通过扩展的NBS程序和串联质谱法诊断了四名患者；在NBS实施之前，先前在一项初步研究中诊断了一名患者。验证性测试包括干血斑点中的酰基肉碱分析，尿液中的有机酸，ACADVL基因的遗传分析,和淋巴细胞或成纤维细胞中的酶活性测定。通过基因测试确认了四名诊断为VLCADD的酰基肉碱特异性升高和疾病特异性酰基肉碱比率（C14：1，C14，C14：2，C14：1/C2，C14：1/C16）的新生儿：均为复合杂合子，其中两个有一个以前未报道的ACDVL基因变体（NM_000018.3）c.1538C>G；（NP_000009）p。（Ala513Gly）和c.661A>G；p。（Ser221Gly），分别。此外,在初步研究中诊断出的一名患者的酰基肉碱也有特定的升高。随后的ACDVL遗传分析证实了复合杂合性。与诊断一致，5例患者的酶活性降低。在其他七个筛查结果为阳性的新生儿中，在ACDVL基因中只发现了单等位基因变异,所以诊断没有得到证实。其中,两个变体是新颖的，c.416T>C和c.1046C>A，分别（p。Leu139Pro和p.Ala349Glu)。在斯洛文尼亚扩大的NBS计划的头两年中，总共筛查了30,000名新生儿。我们诊断了4例VLCADD。估计的VLCADD发病率为1：7,500，远高于同期的中链酰基辅酶A脱氢酶缺乏症（MCADD）病例。我们的研究还提供了对中欧-东南欧ACADVL变体的最早描述之一，并报道了4种新变体。
