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

  • Pediatr Neurol. 2017 Oct;75:66-72. doi: 10.1016/j.pediatrneurol.2017.06.014.
Kirk L Pappan  1 ,  Adam D Kennedy  1 ,  Pilar L Magoulas  2 ,  Neil A Hanchard  2 ,  Qin Sun  2 ,  Sarah H Elsea  3
Affiliations
  • 1. Metabolon, Inc., Morrisville, North Carolina.
  • 2. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
  • 3. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas. Electronic address: [email protected].
PMID: 28823629 DOI: 10.1016/j.pediatrneurol.2017.06.014
Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords
aromatic amino acid decarboxylase deficiency; biochemistry; diagnosis; dopamine; inborn error of metabolism; metabolomics; neurotransmitter; phenotype.
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