PDF(Pubmed)
Abstract：
Propionic acidemia (PA) is an autosomal recessive condition (OMIM #606054), wherein pathogenic variants in PCCA and PCCB impair the activity of propionyl-CoA carboxylase. PA is associated with neurodevelopmental disorders, including intellectual disability (ID) and autism spectrum disorder (ASD); however, the correlates and mechanisms of these outcomes remain unknown. Using data from a subset of participants with PA enrolled in a dedicated natural history study (n = 33), we explored associations between neurodevelopmental phenotypes and laboratory parameters. Twenty (61%) participants received an ID diagnosis, and 12 of the 31 (39%) who were fully evaluated received the diagnosis of ASD. A diagnosis of ID, lower full-scale IQ (sample mean = 65 ± 26), and lower adaptive behavior composite scores (sample mean = 67 ± 23) were associated with several biomarkers. Higher concentrations of plasma propionylcarnitine, plasma total 2-methylcitrate, serum erythropoietin, and mitochondrial biomarkers plasma FGF21 and GDF15 were associated with a more severe ID profile. Reduced 1-13C-propionate oxidative capacity and decreased levels of plasma and urinary glutamine were also associated with a more severe ID profile. Only two parameters, increased serum erythropoietin and decreased plasma glutamine, were associated with ASD. Plasma glycine, one of the defining features of PA, was not meaningfully associated with either ID or ASD. Thus, while both ID and ASD were commonly observed in our PA cohort, only ID was robustly associated with metabolic parameters. Our results suggest that disease severity and associated mitochondrial dysfunction may play a role in CNS complications of PA and identify potential biomarkers and candidate surrogate endpoints.
摘要：
丙酸血症（PA）是一种常染色体隐性疾病（OMIM#606054），其中PCCA和PCCB中的致病性变体损害丙酰辅酶A羧化酶的活性。PA与神经发育障碍有关,包括智力障碍(ID)和自闭症谱系障碍(ASD)；然而，这些结局的相关性和机制尚不清楚.使用来自参与专门自然史研究的PA参与者子集的数据（n=33），我们探讨了神经发育表型与实验室参数之间的关联.20名（61%）参与者接受了身份诊断，31例接受全面评估的患者中有12例(39%)诊断为ASD.身份证的诊断，较低的全面智商(样本平均值=65±26)，较低的适应性行为综合评分(样本平均值=67±23)与几种生物标志物相关。血浆丙酰肉碱浓度较高,血浆总2-甲基柠檬酸盐，血清促红细胞生成素，和线粒体生物标志物血浆FGF21和GDF15与更严重的ID谱相关。1-13C-丙酸盐氧化能力的降低以及血浆和尿谷氨酰胺水平的降低也与更严重的ID谱有关。只有两个参数，血清促红细胞生成素增加，血浆谷氨酰胺减少，与ASD有关。血浆甘氨酸，PA的定义特征之一，与ID或ASD没有有意义的关联。因此，虽然在我们的PA队列中通常观察到ID和ASD，只有ID与代谢参数密切相关.我们的结果表明，疾病严重程度和相关的线粒体功能障碍可能在PA的CNS并发症中起作用，并确定潜在的生物标志物和候选替代终点。
