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

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.

• Authors: Kirk L Pappan, Adam D Kennedy, Pilar L Magoulas, Neil A Hanchard, Qin Sun, Sarah H Elsea
• Journal: Pediatric neurology (Pediatr Neurol) Vol. 75 Pg. 66-72 (Oct 2017) ISSN: 1873-5150 [Electronic] United States
• PMID: 28823629 (Publication Type: Case Reports, Journal Article)
• Copyright: Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• 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

Topics

• Amino Acid Metabolism, Inborn Errors (blood, metabolism)
• Aromatic-L-Amino-Acid Decarboxylases (blood, deficiency, metabolism, therapeutic use)
• Carbidopa (therapeutic use)
• Child
• Child, Preschool
• Cohort Studies
• Dopamine (analogs & derivatives, 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)