Clinical Metabolomics to Segregate Aromatic Amino Acid Decarboxylase Deficiency From Drug-Induced Metabolite Elevations

Publication date: Available online 29 June 2017
Source:Pediatric Neurology
Author(s): Kirk L. Pappan, Adam D. Kennedy, Pilar Magoulas, Neil A. Hanchard, Qin Sun, Sarah H. Elsea
BackgroundPhenotyping 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. In this study, we investigate the analyte changes associated with aromatic amino acid decarboxylase (AADC) deficiency and dopamine medication treatment.MethodsUsing an untargeted metabolomics platform we analyzed EDTA plasma specimens and biomarkers were identified by comparing the biochemical profile of individual patient samples to a pediatric-centric population cohort.ResultsElevated 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 cases 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, while whole exome analysis in a second case revealed compound heterozygosity for two variants of unknown significance.ConclusionsThese 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 cases with elevated 3-methoxytyrosine caused by DOPA-raising medications.



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