Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, United States of America; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, United States of America.
Department of Pathology and Laboratory Medicine, Indiana University, Indianapolis, IN 46202, United States of America.
Mol Genet Metab. 2023 Nov;140(3):107680. doi: 10.1016/j.ymgme.2023.107680. Epub 2023 Aug 7.
The peroxisome is an essential eukaryotic organelle with diverse metabolic functions. Inherited peroxisomal disorders are associated with a wide spectrum of clinical outcomes and are broadly divided into two classes, those impacting peroxisome biogenesis (PBD) and those impacting specific peroxisomal factors. Prior studies have indicated a role for acylcarnitine testing in the diagnosis of some peroxisomal diseases through the detection of long chain dicarboxylic acylcarnitine abnormalities (C16-DC and C18-DC). However, there remains limited independent corroboration of these initial findings and acylcarnitine testing for peroxisomal diseases has not been widely adopted in clinical laboratories. To explore the utility of acylcarnitine testing in the diagnosis of peroxisomal disorders we applied a LC-MS/MS acylcarnitine method to study a heterogenous clinical sample set (n = 598) that included residual plasma specimens from nineteen patients with PBD caused by PEX1 or PEX6 deficiency, ranging in severity from lethal neonatal onset to mild late onset forms. Multiple dicarboxylic acylcarnitines were significantly elevated in PBD patients including medium to long chain (C8-DC to C18-DC) species as well as previously undescribed elevations of malonylcarnitine (C3-DC) and very long chain dicarboxylic acylcarnitines (C20-DC and C22-DC). The best performing plasma acylcarnitine biomarkers, C20-DC and C22-DC, were detected at elevated levels in 100% and 68% of PBD patients but were rarely elevated in patients that did not have a PBD. We extended our analysis to residual newborn screening blood spot cards and were able to detect dicarboxylic acylcarnitine abnormalities in a newborn with a PBD caused by PEX6 deficiency. Similar to prior studies, we failed to detect substantial dicarboxylic acylcarnitine abnormalities in blood spot cards from patients with x-linked adrenoleukodystrophy (x-ald) indicating that these biomarkers may have utility in quickly narrowing the differential diagnosis in patients with a positive newborn screen for x-ald. Overall, our study identifies widespread dicarboxylic acylcarnitine abnormalities in patients with PBD and highlights key acylcarnitine biomarkers for the detection of this class of inherited metabolic disease.
过氧化物酶体是一种具有多种代谢功能的必需真核细胞器。遗传性过氧化物酶体疾病与广泛的临床结果相关，大致分为两类，一类影响过氧化物酶体生物发生（PBD），另一类影响特定过氧化物酶体因子。先前的研究表明，酰基肉碱检测在通过检测长链二羧酸酰基肉碱异常（C16-DC 和 C18-DC）来诊断某些过氧化物酶体疾病方面具有一定作用。然而，这些初步发现的独立证实仍然有限，并且酰基肉碱检测并未在临床实验室中广泛采用。为了探讨酰基肉碱检测在过氧化物酶体疾病诊断中的应用价值，我们应用 LC-MS/MS 酰基肉碱方法对一组异质临床样本（n=598）进行了研究，其中包括 19 名 PEX1 或 PEX6 缺陷引起的 PBD 患者的残留血浆标本，严重程度从致死性新生儿发病到轻度晚发性发病不等。多种二羧酸酰基肉碱在 PBD 患者中显著升高，包括中链至长链（C8-DC 至 C18-DC）物种以及以前未描述的丙二酰肉碱（C3-DC）和非常长链二羧酸酰基肉碱（C20-DC 和 C22-DC）升高。在 100%和 68%的 PBD 患者中，最佳的血浆酰基肉碱生物标志物 C20-DC 和 C22-DC 检测到升高，但在没有 PBD 的患者中很少升高。我们将分析扩展到残留的新生儿筛查血斑卡，并能够在 PEX6 缺陷引起的 PBD 新生儿中检测到二羧酸酰基肉碱异常。与先前的研究类似，我们未能在 x-连锁肾上腺脑白质营养不良（x-ald）患者的血斑卡中检测到大量二羧酸酰基肉碱异常，这表明这些生物标志物可能有助于在 x-ald 新生儿筛查阳性患者中快速缩小鉴别诊断范围。总的来说，我们的研究在 PBD 患者中发现了广泛的二羧酸酰基肉碱异常，并突出了用于检测此类遗传性代谢疾病的关键酰基肉碱生物标志物。
