Propionic acidemia (PA) is caused by inherited deficiency of mitochondrial propionyl-CoA carboxylase (PCC) and results in significant neurodevelopmental and cardiac morbidity. However, relationships among therapeutic intervention, biochemical markers, and disease progression are poorly understood. Sixteen individuals homozygous for PCCB c.1606A > G (p.Asn536Asp) variant PA participated in a two-week suspension of therapy. Standard metabolic markers (plasma amino acids, blood spot methylcitrate, plasma/urine acylcarnitines, urine organic acids) were obtained before and after stopping treatment. These same markers were obtained in sixteen unaffected siblings. Echocardiography and electrocardiography were obtained from all subjects. We characterized the baseline biochemical phenotype of untreated PCCB c.1606A > G homozygotes and impact of treatment on PCC deficiency biomarkers.

Therapeutic regimens varied widely. Suspension of therapy did not significantly alter branched chain amino acid levels, their alpha-ketoacid derivatives, or urine ketones. Carnitine supplementation significantly increased urine propionylcarnitine and its ratio to total carnitine. Methylcitrate blood spot and urine levels did not correlate with other biochemical measures or cardiac outcomes. Treatment of PCCB c.1606A > G homozygotes with protein restriction, prescription formula, and/or various dietary supplements has a limited effect on core biomarkers of PCC deficiency. These patients require further longitudinal study with standardized approaches to better understand the relationship between biomarkers and disease burden.

丙酸血症（PA）是由线粒体丙酰辅酶A羧化酶（PCC）的遗传缺陷引起的，并导致明显的神经发育和心脏疾病。然而，人们对治疗干预，生化标记和疾病进展之间的关系了解甚少。16名PCCB c.1606A> G（p.Asn536Asp）变体PA纯合的个体参加了为期两周的治疗暂停。在停止治疗之前和之后，获得了标准的代谢标记物（血浆氨基酸，血斑甲基柠檬酸，血浆/尿液酰基肉碱，尿液有机酸）。这些相同的标记是在16个未受影响的兄弟姐妹中获得的。从所有受试者获得超声心动图和心电图。我们表征了未经治疗的基线生化表型PCCB c.1606A> G纯合子以及治疗对PCC缺乏生物标志物的影响。

治疗方案差异很大。停止治疗不会明显改变支链氨基酸水平，其α-酮酸衍生物或尿酮。补充肉碱可显着增加尿液中的丙酰肉碱及其与总肉碱的比率。柠檬酸甲酯的血斑和尿液水平与其他生化指标或心脏预后无关。用蛋白质限制剂，处方配方和/或各种饮食补充剂治疗PCCB c.1606A> G纯合子，对PCC缺乏症的核心生物标志物的作用有限。这些患者需要采用标准化方法进行进一步的纵向研究，以更好地了解生物标志物与疾病负担之间的关系。