Alcaide Patricia, Ferrer-López Isaac, Gutierrez Leticia, Leal Fatima, Martín-Hernández Elena, Quijada-Fraile Pilar, Bellusci Marcello, Moráis Ana, Pedrón-Giner Consuelo, Rausell Dolores, Correcher Patricia, Unceta María, Stanescu Sinziana, Ugarte Magdalena, Ruiz-Sala Pedro, Pérez Belén
Centro de Diagnóstico de Enfermedades Moleculares (CEDEM), Universidad Autónoma Madrid, CIBERER, IDIPAZ, 28049 Madrid, Spain.
Centro de Referencia Nacional (CSUR) y Europeo (MetabERN) para Enfermedades Metabólicas, Hospital Universitario 12 de Octubre, 28041 Madrid, Spain.
J Clin Med. 2022 May 23;11(10):2933. doi: 10.3390/jcm11102933.
The determination of acylcarnitines (AC) in dried blood spots (DBS) by tandem mass spectrometry in newborn screening (NBS) programs has enabled medium-chain acyl-coA dehydrogenase deficiency (MCADD) to be identified in presymptomatic newborns. Nevertheless, different confirmatory tests must be performed to confirm the diagnosis. In this work, we have collected and analyzed the NBS results and confirmatory test results (plasma AC, molecular findings, and lymphocyte MCAD activity) of forty individuals, correlating them with clinical outcomes and treatment, with the aim of obtaining useful diagnostic information that could be applied in the follow-up of the patients. Our results led us to classify patients into two groups. The first group (14 cases) had high increased octanoylcarnitine (C8) levels, biallelic pathogenic variants, and severe impaired enzyme activity (<10% of the intra-assay control (IAC)); all of these cases received nutritional therapy and required carnitine supplementation during follow-up, representing the most severe form of the disease. The second group (16 patients) was a heterogeneous group presenting moderate increases in C8, biallelic likely pathogenic/pathogenic variants, and intermediate activity (<41% IAC). All of them are currently asymptomatic and could be considered as having a milder form of the disease. Finally, eight cases presented a normal−mild increase in plasma C8, with only one pathogenic variant detected, and high−intermediate residual activity (15−100%). Based on our results, we confirm that combined evaluation of acylcarnitine profiles, genetic findings, and residual enzyme activities proves useful in predicting the risk of future metabolic decompensation, in making decisions regarding future treatment or follow-up, and also in confirming the clinical effects of unknown clinical variants.
在新生儿筛查（NBS）项目中，通过串联质谱法测定干血斑（DBS）中的酰基肉碱（AC），使得在无症状新生儿中能够识别出中链酰基辅酶A脱氢酶缺乏症（MCADD）。然而，必须进行不同的确诊试验来确认诊断。在这项工作中，我们收集并分析了40名个体的NBS结果和确诊试验结果（血浆AC、分子检测结果和淋巴细胞MCAD活性），并将它们与临床结果和治疗情况相关联，目的是获得可应用于患者随访的有用诊断信息。我们的结果使我们将患者分为两组。第一组（14例）辛酰肉碱（C8）水平大幅升高，存在双等位基因致病性变异，酶活性严重受损（<分析内对照（IAC）的10%）；所有这些病例均接受了营养治疗，且在随访期间需要补充肉碱，代表了该疾病最严重的形式。第二组（16例患者）是一个异质性组，C8有中度升高，存在双等位基因可能致病性/致病性变异，酶活性中等（<IAC的41%）。他们目前均无症状，可被视为患有该疾病较轻的形式。最后，8例患者血浆C8呈正常 - 轻度升高，仅检测到一个致病性变异，残余活性高 - 中等（15 - 100%）。基于我们的结果，我们证实，对酰基肉碱谱、基因检测结果和残余酶活性进行综合评估，对于预测未来代谢失代偿的风险、做出关于未来治疗或随访的决策以及确认未知临床变异的临床影响均被证明是有用的。
