Department of Clinical Chemistry, Laboratory Genetic Metabolic Diseases, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Department of Paediatric Gastroenterology and Metabolic Diseases, Wilhelmina Children's Hospital, UMC Utrecht, Utrecht, the Netherlands.
Genet Med. 2015 Dec;17(12):989-94. doi: 10.1038/gim.2015.22. Epub 2015 Apr 2.
Very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency (VLCADD) is an inherited disorder of mitochondrial long-chain fatty acid β-oxidation (LC-FAO) and is included in many newborn screening (NBS) programs worldwide. Patients may present with hypoketotic hypoglycemia, cardiomyopathy, and/or myopathy, but clinical severity varies widely and the clinical outcome is unpredictable. We investigated predictive markers that may determine clinical severity.
We developed a clinical severity score (CSS), which was determined for 13 Dutch patients with VLCADD, all of whom were diagnosed before the introduction of VLCADD in NBS to prevent bias from early diagnosis. In cultured skin fibroblasts from these patients, we measured LC-FAO flux (the rate of oleate oxidation), VLCAD activity, and acylcarnitine profiles following palmitate loading.
The strongest correlation (r = 0.93; P < 0.0001) was observed between LC-FAO flux and the CSS. VLCAD activity measurement and the C14/C16-to-acylcarnitine ratio correlated much less. A median LC-FAO flux of 6% of control values (range 5.6-6.8%) was associated with cardiomyopathy (P < 0.01), and 32.4% (range 5.6-50.5%) was associated with myopathy (P < 0.05).
Our results demonstrate a very strong correlation between LC-FAO flux in fibroblasts and the clinical severity of VLCADD. LC-FAO flux measurements may thus predict whether patients are likely to develop symptoms.
极长链酰基辅酶 A 脱氢酶（VLCAD）缺乏症（VLCADD）是一种遗传性的线粒体长链脂肪酸β氧化（LC-FAO）障碍，已被纳入全球许多新生儿筛查（NBS）项目中。患者可能表现为低酮性低血糖、心肌病和/或肌病，但临床严重程度差异很大，临床结局不可预测。我们研究了可能决定临床严重程度的预测标志物。
我们制定了一种临床严重程度评分（CSS），用于评估 13 名荷兰 VLCADD 患者，这些患者均在 NBS 中引入 VLCADD 以预防早期诊断带来的偏倚之前确诊。我们在这些患者的培养皮肤成纤维细胞中，测量了经棕榈酸负载后 LC-FAO 通量（油酸氧化率）、VLCAD 活性和酰基肉碱谱。
LC-FAO 通量与 CSS 之间存在最强的相关性（r = 0.93；P < 0.0001）。VLCAD 活性测定和 C14/C16-酰基肉碱比值的相关性要低得多。LC-FAO 通量中位数为对照值的 6%（范围为 5.6%-6.8%）与心肌病相关（P < 0.01），32.4%（范围为 5.6%-50.5%）与肌病相关（P < 0.05）。
我们的结果表明，成纤维细胞中 LC-FAO 通量与 VLCADD 的临床严重程度之间存在很强的相关性。因此，LC-FAO 通量测量可能可以预测患者是否可能出现症状。
