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. Epub 2017 Jun 29.


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.

Publication types

  • Case Reports

MeSH terms

  • Amino Acid Metabolism, Inborn Errors / blood*
  • Amino Acid Metabolism, Inborn Errors / metabolism
  • Aromatic-L-Amino-Acid Decarboxylases / blood
  • Aromatic-L-Amino-Acid Decarboxylases / deficiency*
  • Aromatic-L-Amino-Acid Decarboxylases / metabolism
  • Aromatic-L-Amino-Acid Decarboxylases / therapeutic use
  • Carbidopa / therapeutic use*
  • Child
  • Child, Preschool
  • Cohort Studies
  • Dopamine / analogs & derivatives
  • Dopamine / blood
  • Dopamine Agonists / therapeutic use*
  • Drug Combinations
  • Edetic Acid / blood
  • Female
  • Humans
  • Infant
  • Levodopa / therapeutic use*
  • Male
  • Metabolic Networks and Pathways
  • Metabolomics / methods*
  • Vanilmandelic Acid / blood


  • Dopamine Agonists
  • Drug Combinations
  • carbidopa, levodopa drug combination
  • dopamine 4-O-sulfate
  • Levodopa
  • Vanilmandelic Acid
  • Edetic Acid
  • Aromatic-L-Amino-Acid Decarboxylases
  • 3-methoxytyramine
  • Carbidopa
  • Dopamine

Supplementary concepts

  • Aromatic amino acid decarboxylase deficiency