Metabolon, Inc., Morrisville, North Carolina.
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
Pediatr Neurol. 2017 Oct;75:66-72. doi: 10.1016/j.pediatrneurol.2017.06.014. Epub 2017 Jun 29.
Phenotyping technologies featured in the diagnosis of inborn errors of metabolism, such as organic acid, amino acid, and acylcarnitine analyses, recently have been supplemented by broad-scale untargeted metabolomic phenotyping. We investigated the analyte changes associated with aromatic amino acid decarboxylase (AADC) deficiency and dopamine medication treatment.
Using an untargeted metabolomics platform, we analyzed ethylenediaminetetraacetic acid plasma specimens, and biomarkers were identified by comparing the biochemical profile of individual patient samples to a pediatric-centric population cohort.
Elevated 3-methoxytyrosine (average z score 5.88) accompanied by significant decreases of dopamine 3-O-sulfate (-2.77), vanillylmandelate (-2.87), and 3-methoxytyramine sulfate (-1.44) were associated with AADC deficiency in three samples from two patients. In five non-AADC patients treated with carbidopa-levodopa, levels of 3-methoxytyrosine were elevated (7.65); however, the samples from non-AADC patients treated with DOPA-elevating drugs had normal or elevated levels of metabolites downstream of aromatic l-amino acid decarboxylase, including dopamine 3-O-sulfate (2.92), vanillylmandelate (0.33), and 3-methoxytyramine sulfate (5.07). In one example, a plasma metabolomic phenotype pointed to a probable AADC deficiency and prompted the evaluation of whole exome sequencing data, identifying homozygosity for a known pathogenic variant, whereas whole exome analysis in a second patient revealed compound heterozygosity for two variants of unknown significance.
These data demonstrate the power of combining broad-scale genotyping and phenotyping technologies to diagnose inherited neurometabolic disorders and suggest that metabolic phenotyping of plasma can be used to identify AADC deficiency and to distinguish it from non-AADC patients with elevated 3-methoxytyrosine caused by DOPA-raising medications.
在先天性代谢缺陷的诊断中应用表型技术，例如有机酸、氨基酸和酰基肉碱分析，最近已经被广泛的非靶向代谢组学表型分析所补充。我们研究了芳香族氨基酸脱羧酶（AADC）缺乏症和多巴胺药物治疗相关的分析物变化。
使用非靶向代谢组学平台，我们分析了乙二胺四乙酸血浆标本，通过将个体患者样本的生化特征与儿科为中心的人群队列进行比较，确定了生物标志物。
在两名患者的 3 个样本中，与 AADC 缺乏相关的是 3-甲氧基酪氨酸（平均 z 评分 5.88）升高，同时多巴胺 3-O-硫酸盐（-2.77）、香草扁桃酸（-2.87）和 3-甲氧基酪胺硫酸盐（-1.44）显著降低。在 5 名接受卡比多巴-左旋多巴治疗的非 AADC 患者中，3-甲氧基酪氨酸水平升高（7.65）；然而，接受芳香族 l-氨基酸脱羧酶升高药物治疗的非 AADC 患者的样本中，包括多巴胺 3-O-硫酸盐（2.92）、香草扁桃酸（0.33）和 3-甲氧基酪胺硫酸盐（5.07）在内的下游代谢物水平正常或升高。在一个例子中，血浆代谢组学表型指向可能的 AADC 缺乏症，并促使评估外显子组测序数据，发现已知致病性变异的纯合性，而在第二名患者的外显子组分析中，发现两种未知意义的变异的复合杂合性。
这些数据表明，结合广泛的基因分型和表型技术诊断遗传性神经代谢疾病的强大能力，并表明血浆代谢组学分析可用于识别 AADC 缺乏症，并将其与因升高多巴胺药物而导致 3-甲氧基酪氨酸升高的非 AADC 患者区分开来。
