Urine Test May Help Diagnose AADC Deficiency, Study Says

Steve Bryson, PhD avatar

by Steve Bryson, PhD |

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AADC protein structure

A simple urine test using widely available methods may help diagnose people with aromatic L-amino acid decarboxylase (AADC) deficiency, a study reports. 

The study, “Semi-quantitative detection of a vanillactic acid/vanillylmandelic acid ratio in urine is a reliable diagnostic marker for aromatic L-amino acid decarboxylase deficiency,” was published in the journal Molecular Genetics and Metabolism

AADC deficiency is a genetic condition caused by mutations in the DDC gene, which carries the instructions for the enzyme AADC. The condition results in low levels of signaling molecules in the brain called neurotransmitters

Current diagnostic tests for AADC deficiency include measuring the levels of AADC enzyme activity in the blood and the levels of neurotransmitters in the cerebrospinal fluid found in the brain and spinal cord. 

Genetic screening for mutations in the DDC gene is conducted to support a diagnosis. Typically, two test results are necessary to confirm the condition.

In a 2010 report, elevated levels of a neurotransmitter breakdown product called vanillactic acid (VLA) was found in urine samples of AADC deficient patients and may represent an additional diagnostic tool. 

However, the “change is often subtle and a normal VLA concentration does not exclude AADC deficiency,” the researchers wrote. 

In the study, investigators at the University Children’s Hospital Heidelberg, in Germany, wondered if the ratio of VLA and another breakdown product found in urine called vanillylmandelic acid (VMA) could be a novel diagnostic marker for AADC deficiency.

The team collected urine samples from 10,095 people without AADC deficiency, ranging in age from infancy to 85 years, as well as from 14 patients with confirmed AADC deficiency between the ages of nearly 5 months to 23 years. 

Urine samples were analyzed to measure the levels of VLA and VMA using standard methods to assess metabolites. They were reported against a standard measure of creatinine — a waste product found in urine made by muscles as part of everyday activity. Results for VLA and VMA were given in millimole per mole (mmol/mol) of creatinine.

The analysis found a mean concentration of VLA in non-AADC samples of 0.3 mmol/mol creatinine, whereas the mean level in patients was higher at 10.77 mmol/mol creatinine. The concentration of VMA in non-AADC urine samples was 5.59 mmol/mol creatinine, while the level in patients was found to be 0.45 mmol/mol creatinine. 

The researchers found that VLA levels were negatively correlated with age, where older patients had lower levels. VMA levels were overall stable at different ages.

The average ratio of VLA to VMA in control samples was found to be 0.07. In contrast, the average ratio calculated from measurements from nine AADC deficient patients was 23.16, “corresponding to a [approximately] 350-fold increase,” the researchers wrote.

Further analysis based on multiple measurements found that while VMA concentrations remained stable over time, VLA levels decreased. In non-AADC deficient subjects, the average VLA/VMA ratio appears to be age-dependent as well.

“VLA concentration has a particular impact on the overall decreasing VLA/VMA ratio over time,” the researchers suggested.

Based on the findings, the team proposed VLA/VMA ratio cut-off values for three age groups: a VLA/VMA ratio of 8 for infants up to 1 year old, 6 for those between 1 and 10 years of age, and 0.8 for individuals older than 10.

To investigate the stability of the method, variability was assessed by measuring the same sample 10 times during one day as well as measuring one sample on 10 consecutive days collected from one patient with borderline VLA and VMA levels but with a VLA/VMA ratio above the cut-off value.

The average VLA/VMA ratio measured 10 times during one day (intra-day variability) was 1.29, with values between 1.19 and 1.4, whereas the average VLA/VMA ratio measured on consecutive days (inter-day variability) was 0.78, with values between 0.7 and 0.84. These results showed the measurements were stable.

“A low intra- and inter-day variability … is in accordance with previous reports on the reliability of organic acid analysis in urine,” the researchers wrote.

“Thus, the VLA/VMA ratio in urine has an additional diagnostic value for the identification of AADC deficient patients across different age groups,” they concluded.

“This information should be incorporated into a new version of the AADC deficiency guideline, in order to incorporate the VLA/VMA ratio into the diagnostic evaluation of urinary organic acid analysis helping pediatricians around the world to be better equipped for the diagnosis and ultimately therapy of patients with AADC deficiency.”