Dopamine-related Metabolites Could Help Diagnose AADC Deficiency Non-invasively, Study Says

Alejandra Viviescas, PhD avatar

by Alejandra Viviescas, PhD |

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AADC deficiency and gene therapy

A technique that measures the levels of different metabolites — the products of cellular metabolism — of dopamine could serve as a non-invasive method to diagnose AADC deficiency, a study says.

The study, “Clinical Metabolomics to Segregate Aromatic Amino Acid Decarboxylase Deficiency From Drug-Induced Metabolite Elevations,” was published in Pediatric Neurology.

Aromatic l-amino acid decarboxylase (AADC) deficiency is a rare genetic disorder caused by mutations in the DDC gene, which holds the instructions to produce the AADC enzyme.

The AADC enzyme is responsible for transforming the amino acids tyrosine and tryptophan into neurotransmitters (molecules that mediate the communication between neurons) such as dopamine and serotonin. Neurotransmitters are subsequently reduced in these patients and cause different motor and cognitive symptoms.

Diagnosing AADC deficiency is difficult because most symptoms are shared with other conditions. Currently, diagnosis methods include measuring the levels of AADC enzyme, determining all the neurotransmitters that are present in the cerebrospinal fluid (liquid surrounding the brain and spinal cord), and examining the sequence of the DDC gene to detect mutations. But these methods are either expensive, invasive, or take a long time.

A molecule called 3-methoxytyrosine is involved in the production of dopamine and accumulates in AADC deficiency patients, serving as an indicator of the condition. Measuring 3-methoxytyrosine levels in the blood can be a non-invasive and inexpensive way to diagnose the disease.

However, the use of dopamine medications also increases 3-methoxytyrosine, which reduces the capacity of diagnosis using this molecule alone.

To solve this problem, researchers at the Baylor College of Medicine, Houston, Texas, used a method called non-targeted metabolomic profiling to measure all the metabolites of dopamine present in the blood. They wished to possibly identify a specific combination that separates AADC deficiency from other factors leading to increased 3-methoxytyrosine.

Researchers evaluated two AADC deficiency patients. The first one started showing symptoms of delayed development, low muscle tone, and seizures when he was 11 months old.

After being diagnosed with AADC deficiency, he was lost to follow-up for approximately two years. At four years old, he had severe motor impairment.

The second patient was a girl of Taiwanese descent of a non-consanguineous (unrelated) marriage. Shortly after birth, her parents noticed she had difficulties breathing and feeding. At six months, she also showed delayed motor development and low muscle tone.

An MRI showed impaired brain development and reduced amounts of myelin, which is a mixture of proteins and lipids that cover the neurons and is essential for their survival. Further analysis confirmed the AADC deficiency diagnosis.

The investigators measured the metabolites of the two patients and compared their results to those of five subjects without AADC deficiency who were taking dopamine medications. All the individuals showed increased levels of 3-methoxytyrosine.

However, AADC deficiency patients had lower levels of three other metabolites — dopamine 3-O-sulfate, vanillylmandelate, and 3-methoxytyramine sulfate — while subjects taking dopamine medications had normal or elevated levels of these compounds.

“The results presented here suggest that identification by [global profiling] can be strengthened by dopamine pathway-level analysis considering [dopamine metabolites]. Differential changes of these metabolites segregated AADC-deficient patients from non-AADC-deficient patients treated with drugs to raise brain levels of dopamine and catecholamines,” researchers noted.

This method of diagnosis can analyze different molecules and distinguish different conditions using a single test instead of differently specialized examinations.

“[The method] can differentiate signatures of disease from those signatures of treatment associated with the same biochemical pathway. Early detection of disease can result in expedited treatment, and biochemical phenotyping can then track effects of treatment,” the researchers concluded.