Division of Medical Genetics/Pediatrics, University of Utah, Salt Lake City, UT, USA; Clinical Department of Pediatrics, University of Milan, San Paolo Hospital, Milan, Italy.
Division of Medical Genetics/Pediatrics, University of Utah, Salt Lake City, UT, USA; Clinical Department of Neuropsychiatry, University of Milan, San Paolo Hospital, Milan, Italy.
Mol Genet Metab. 2019 May;127(1):64-73. doi: 10.1016/j.ymgme.2019.04.001. Epub 2019 Apr 16.
Very-Long-Chain Acyl-CoA Dehydrogenase (VLCAD) deficiency is a disorder of fatty acid oxidation included in the recommended uniform newborn screening (NBS) panel in the USA. It can have variable clinical severity and there is limited information on the natural history of this condition, clinical presentation according to genotype and effectiveness of newborn screening.
Retrospective data (growth parameters, morbidity, biochemical and genetic testing results) were collected from patients with VLCAD deficiency, to evaluate biochemical and clinical outcomes. Descriptive statistics was used for qualitative variables, while linear regression analysis was used to correlate continuous variables.
VLCAD deficiency (screened by measuring elevated levels of C14:1-carnitine in blood spots) was more frequent in Utah than the national average (1:27,617 versus 1:63,481) in the first ten years of screening. Twenty-six patients had a confirmed diagnosis of VLCAD deficiency using DNA testing or functional studies. The c.848T>C (p.V283A) variant in the ACADVL gene was the most frequent in our population. Novel variants (c.623-21A>G (IVS7-21A>G); c.1052C>T (p.T351I); c.1183-7A>G (IVS11-7A>G); c.1281G>C (p.W427C); c.1923G>C (p.L641F); c.1924G>A (p.V642M)) were identified in this study, with their pathogenicity remaining unclear in most cases. C14:1-carnitine levels decreased with age and significantly correlated with CK levels as index of muscle involvement. There were no cases of HELLP syndrome nor liver disease during pregnancies in the mothers of VLCAD patients. None of our patients developed cardiac involvement after birth and all patients had normal growth parameters while on treatment. Clinical manifestations were related to concomitant infections and altered biochemical parameters.
VLCAD deficiency can be identified by neonatal screening. Most patients compliant with therapy normalized biochemical parameters and had no major clinical manifestations. Complications were completely prevented with a relatively low number of pre-emptive ER visits or hospital admissions. It remains unclear whether neonatal screening is now identifying less severely affected patient or if complications will arise as subjects become older. Observation beyond puberty is necessary to fully understand the impact of VLCAD deficiency on morbidity in patients with VLCAD deficiency.
极长链酰基辅酶 A 脱氢酶（VLCAD）缺乏症是脂肪酸氧化紊乱的一种，被纳入美国推荐的统一新生儿筛查（NBS）检测项目中。它的临床表现具有很大的变异性，且目前关于这种疾病的自然病史、基因型相关临床表现和新生儿筛查效果的信息有限。
通过收集 VLCAD 缺乏症患者的回顾性数据（生长参数、发病率、生化和基因检测结果），评估其生化和临床结局。采用描述性统计方法分析定性变量，采用线性回归分析相关连续变量。
VLCAD 缺乏症（通过检测血斑中 C14:1-肉碱水平升高来筛查）在犹他州比全美范围内更为常见（1:27617 比 1:63481），这一情况在前 10 年的筛查中尤为明显。26 名患者通过 DNA 检测或功能研究确诊为 VLCAD 缺乏症。在我们的研究人群中，ACADVL 基因中的 c.848T>C（p.V283A）变异最为常见。本研究还发现了一些新的变异（c.623-21A>G（IVS7-21A>G）；c.1052C>T（p.T351I）；c.1183-7A>G（IVS11-7A>G）；c.1281G>C（p.W427C）；c.1923G>C（p.L641F）；c.1924G>A（p.V642M）），但大多数情况下，其致病性仍不明确。C14:1-肉碱水平随年龄的增长而降低，且与 CK 水平显著相关，可作为肌肉受累的指标。VLCAD 患者的母亲在怀孕期间均未出现 HELLP 综合征或肝脏疾病。我们的患者在出生后均未出现心脏受累，且所有患者在接受治疗时的生长参数均正常。临床表现与伴随感染和生化参数改变相关。
VLCAD 缺乏症可通过新生儿筛查发现。大多数患者经治疗后生化参数可恢复正常，且无明显临床表现。通过预防性急诊就诊或住院治疗，可完全预防并发症。目前尚不清楚新生儿筛查是否能识别出病情较轻的患者，或者随着时间的推移，患者是否会出现并发症。需要对青春期后患者进行观察，以全面了解 VLCAD 缺乏症对患者发病率的影响。
