Analyzing Patients’ Urine for Organic Acids May Speed Diagnosis

Analyzing levels of certain organic acids in the urine can be a useful first step in diagnosing aromatic L-amino acid decarboxylase (AADC) deficiency, a new report highlights.

Using urine analyses for detecting the neurometabolic disorder would be less invasive than current tests, which require a spinal tap, the researchers noted.

The report, “Urine organic acid as the first clue towards aromatic L-amino acid decarboxylase (AADC) deficiency in a high prevalence area,” was published in Clinica Chimica Acta.

Because biomarkers for AADC deficiency are elevated in the cerebrospinal fluid or CSF — the fluid around the brain and spinal cord — of people with AADC, current tests for the disorder typically involve a lumbar puncture, known as a spinal tap, to collect that fluid. The disease can then be confirmed through genetic tests for mutations in the DDC gene or through an analysis of AADC enzyme activity in plasma.

However, “diagnosis of AADC deficiency is difficult as evidenced by months, or even years, of delay between symptom onset and age of diagnosis,” the researchers wrote.

Now, scientists in Hong Kong have demonstrated the efficacy of urine analysis, with a focus on some organic acids — specifically, neurotransmitter metabolites — to diagnose suspected AADC deficiency. Such measurements could be a new first diagnosis step.

“This could potentially eliminate the risk from invasive CSF analysis and may also shorten the time-to-diagnosis,” the researchers wrote.

In “the latest and largest case series of AADC deficiency in Hong Kong,” the team described the cases of eight children with the disorder who were diagnosed at their center between 2008 and 2019. The age at symptom onset ranged from 2–8 months, with the children’s age at diagnosis ranging 3 months to 15 years.

All of the patients had characteristic symptoms of AADC deficiency, such as abnormal muscle contractions known as dystonia, and oculogyric crises, which are a type of eye disorder in which the eyes move to a fixed position.

Usually in an oculogyric crisis, the eyes look directly up, but the researchers noted that this was not the case for all of the patients in this group. Some looked down during crises and others looked to one side, sometimes with strabismus — when the eyes don’t look in the same direction. The team stressed the need for clinicians to be mindful, when examining patients, of the different ways in which oculogyric crises can present.

The eight children all underwent a battery of assessments leading up to their diagnosis. A noteworthy finding from these analyses is that all eight patients had elevated levels of an organic acid called vanillactic acid (VLA). Six of the eight patients also had unusually high levels of another acid, called N-acetylvanilalanine.

In half of the patients, the abnormal levels of these organic acids in the urine “provided the first clue to the diagnosis of AADC deficiency,” the team wrote.

Of note, both of these acids are involved in some of the same biological pathways as the AADC enzyme that is functionally lacking in AADC deficiency. Prior research also has suggested abnormal levels of these acids may occur in patients with the disorder.

As such, the team suggested that testing for VLA and N-acetylvanilalanine in urine should be done as a first step when people present with symptoms indicative of AADC deficiency. Individuals with high levels can then be referred for subsequent genetic testing to confirm a diagnosis.

A particular advantage is that testing urine is less invasive than other tests, such as analyzing cerebrospinal fluid, the researchers noted.