Vanessa Pataia, Author at AADC News

Although an ultra-rare condition, aromatic L-amino acid decarboxylase (AADC) deficiency appears to be more common among people being tested for neurological problems of unknown origin than thought, with an estimate of about 1 in every 900 at-risk patients, a study reports. Its researchers also suggest that people meeting a single diagnostic criterion should be considered as having this disease, rather than what guidelines now recommend: at least two of three established criteria. The study, “Prevalence of Aromatic l-Amino Acid Decarboxylase Deficiency in At-Risk Populations,” was published in the journal Pediatric Neurology. AADC deficiency is caused by mutations in the DDC gene, which provides instructions to make the AADC enzyme. It generally strikes very young children, but "diagnosis typically occurs years later, indicating the difficulty in recognizing this condition," the study noted. The disease is confirmed in about 120 people worldwide. But due to a founder effect (the limited gene pool of an isolated region), AADC deficiency is relatively more common in southeast Asian countries, such as Taiwan, where it is estimated to affect 1 in every 32,000 people screened for the condition. However, not much is known about the disorder's prevalence elsewhere, which led researchers at the Medical Neurogenetics Laboratories, in the U.S., to test how common it was in people considered at-risk for the condition based on neurological deficits of unknown cause. These people were tested from 2008 to 2016 to identify the root cause of their problems. While this diagnostic lab is headquartered in Atlanta, it receives samples worldwide, meaning these findings are not exclusive to patients in the U.S. The study's analysis included nearly 20,000 samples submitted for any of three tests used to diagnose AADC deficiency: an analysis of neurotransmitter metabolites in the cerebrospinal fluid (CSF, the fluid surrounding the brain and spinal cord), a test that measures the activity of the AADC enzyme in the blood, and a genetic analysis that examines the DDC gene for mutations. Current guidelines recommend at least two test results indicating AADC deficiency to confirm a diagnosis, but in cases where results were available for only one test, researchers considered that one positive result was enough to diagnose the condition. Among the 19,577 samples examined for metabolite levels in the CSF, 22 tested positive for AADC deficiency, including 16 that were confirmed with assessment of enzymatic activity, and nine confirmed with genetic analysis. Three positive cases had data for metabolite levels only. An additional nine cases of AADC deficiency were identified from 81 requests for measures of AADC activity in blood samples. None of these cases tested positive in the CSF analysis, and only five were confirmed by genetic analysis. The remaining four had no genetic sequencing data. Finally, five new cases were identified among 59 requests for genetic analysis of the DDC gene. These cases had no available data for the two other tests. Combining results from these analyses, researchers found a total of 36 new cases of AADC deficiency among 19,684 unique samples, translating to about 1 in every 900 at-risk patients having the condition. "If only the cases that conformed to the consensus guidelines for a diagnosis of AADC deficiency were included in our analyses ... the total number of identified cases would be 24 and the estimated prevalence would be approximately 0.122%, or roughly 1:800," the researchers said, adding that these rates are comparable to those obtained with a single test. “In our experience, any one of these three diagnostic criteria is sufficient for a diagnosis of AADC deficiency without any accompanying analyses,” the researchers wrote. Overall, DNA sequencing results linked the condition to 26 different variants of the DDC gene, including the founder mutation seen in southeast Asia. Seven new variants were described in this study, all of which came back as likely pathogenic after a computer model evaluation that took into account the neurotransmitter metabolite and AADC enzyme activity tests. These results emphasize “the importance of functional studies when investigating pathogenicity of variant changes in this gene,” the researchers concluded.

Vanessa Pataia, —

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