Crenshaw M M, D'Annibale O M, Schechter A, Sethuraman M, Porter C, Bonn G, Wright E, Wood T, Vockley J, Hall P L, Se McCandless
University of Colorado School of Medicine, Department of Pediatrics, Section of Genetics and Metabolism, 13123 E. 16th Ave. B065, Aurora, CO 80045, USA.
Biochemical Genetics Laboratory, Children's Hospital Colorado Anschutz Medical Campus, 13123 E. 16th Ave., Aurora, CO 80045, USA.
Mol Genet Metab. 2025 May;145(1):109104. doi: 10.1016/j.ymgme.2025.109104. Epub 2025 Apr 3.
Very long chain acyl-CoA dehydrogenase deficiency (VLCADD) is an autosomal recessive fatty acid β-oxidation disorder that has been identified by newborn screening (NBS) in most states since the early 2000s. Despite over 20 years of experience, there are aspects of VLCADD NBS that remain challenging. We conducted a retrospective chart review of abnormal NBS for VLCADD in Colorado between 2017 and 2023. We analyzed confirmatory plasma acylcarnitine profiles (P-ACP), genetic sequencing of ACADVL, Collaborative Laboratory Integrated Reports (CLIR) scores, patient enzyme analysis of VLCAD, and cell-based variant expression analysis. A real-world "Clinical Designation" was then compared to a variety of algorithms trialed on the data. Of the 67 infants with abnormal screens during this timeframe, 5 (7 %) had a Clinical Designation of affected, 4 (6 %) remained unclassified, and 58 (87 %) were discharged based on a designation of unaffected. A Kruskal-Wallis rank sum test showed the biomarker with the best discrimination between affected and unaffected individuals was C14:1/C12:1 [chi-squared 10.4 (p = 0.001)]. The highest performing algorithm was (Molecular testing + cell-based expression) + (P-ACP C14:1 OR P-ACP C14:1/C12:1). Excluding the missing data, this algorithm showed 96 % (46 of 48) agreement with the Clinical Designation. We conclude that there is not a single biomarker that can specifically discern affected from unaffected individuals who screen positive on NBS for VLCADD. Thus, we developed a standardized diagnostic approach to more accurately classify patients that starts with the molecular findings and requires at least one of the P-ACP C14:1 or P-ACP C14:1/C12:1 to agree with molecular findings. The algorithm needs to be trialed with a different data set, and will advance the conversation around maximizing benefits and minimizing harms for infants who screen positive for VLCADD.
极长链酰基辅酶A脱氢酶缺乏症（VLCADD）是一种常染色体隐性脂肪酸β氧化障碍疾病，自21世纪初以来，大多数州已通过新生儿筛查（NBS）识别出该疾病。尽管已有20多年的经验，但VLCADD的新生儿筛查仍存在一些具有挑战性的方面。我们对2017年至2023年科罗拉多州VLCADD的异常新生儿筛查进行了回顾性图表审查。我们分析了确证性血浆酰基肉碱谱（P-ACP）、ACADVL的基因测序、协作实验室综合报告（CLIR）评分、患者VLCAD酶分析以及基于细胞的变异表达分析。然后将实际的“临床诊断”与根据这些数据试用的各种算法进行比较。在此期间筛查异常的67名婴儿中，5名（7%）临床诊断为患病，4名（6%）仍未分类，58名（87%）基于未患病的诊断出院。Kruskal-Wallis秩和检验显示，在患病和未患病个体之间具有最佳区分度的生物标志物是C14:1/C12:1[卡方值10.4（p = 0.001）]。表现最佳的算法是（分子检测 + 基于细胞的表达）+（P-ACP C14:1或P-ACP C14:1/C12:1）。排除缺失数据后，该算法与临床诊断的一致性为96%（48例中的46例）。我们得出结论，没有单一的生物标志物能够特异性地区分在VLCADD新生儿筛查中呈阳性的患病和未患病个体。因此，我们开发了一种标准化的诊断方法，以更准确地对患者进行分类，该方法从分子检测结果开始，并且要求P-ACP C14:1或P-ACP C14:1/C12:1中的至少一项与分子检测结果一致。该算法需要在不同的数据集上进行试验，这将推动围绕使VLCADD筛查呈阳性的婴儿受益最大化和危害最小化的讨论。
