A range of disease presentations, and of underlying genotypes, were observed in a study of aromatic l-amino acid decarboxylase (AADC) deficiency cases in mainland China. These findings broaden the known clinical signs associated with AADC deficiency, and they hint at connections between genotypes and disease course.
The study, “Aromatic L‐amino acid decarboxylase deficiency in 17 Mainland China patients: Clinical phenotype, molecular spectrum, and therapy overview,” was published in Molecular Genetics & Genomics Medicine.
Due to a founder effect, AADC deficiency is relatively more common in southeast Asia than elsewhere in the world (about half of known cases come from this region). However, until now there have been only three cases of AADC deficiency reported in mainland China.
In the new study, researchers detail the clinical presentation of those three cases, as well as 14 other cases that have never been reported before. These 14 cases ranged in age from one to five years at the time of publication. Initial AADC deficiency symptoms (e.g., poor head control) tended to emerge between the ages of two and five months.
All children in the group experienced symptoms typical of AADC deficiency, including developmental delay, oculogyric crisis (an abnormal upward movement of the eyes), and dystonia (involuntary muscle contractions). Most also exhibited an unconscious “tongue thrusting” behavior and had small hands and feet, both of which are common in AADC deficiency.
One of the children had significantly decreased bone density. This finding is noteworthy because altered bone density has not been reported previously in a person with AADC deficiency. The researchers speculated that the lack of certain neurotransmitters — specifically catecholamines — could hinder the proper growth of skeletal bone, though additional research will be needed to examine such a connection in detail.
Of the 12 children who underwent magnetic resonance imaging (MRI), seven had brain abnormalities, the most common being an unusually large amount of extracerebral space (the space between the brain and the skull). Whether MRI is a useful aid in diagnosing AADC deficiency is a matter of some debate, but this finding suggests it could be helpful, at least in some cases.
All of the children were given treatment, such as dopamine receptor agonists and/or monoamine oxidase inhibitors, but “the responses are not satisfactory particularly in patients having severe symptoms,” the researchers wrote, adding that even combination therapies were generally ineffective.
Two of the children did respond reasonably well to treatment. One was able to babble at about one-and-a-half years of age; the other could eat food using fingers at two years old. Researchers noted that both of these children had comparatively mild symptoms prior to treatment, suggesting that response to treatment “may depend, in large part, on the clinical phenotype.”
All of the children’s DDC genes were sequenced as part of confirming a diagnosis of AADC deficiency. Among the 17 children, 14 different mutations were identified, and computer modeling suggested all of these as likely pathogenic (disease-causing). Three of these mutations — dubbed c.565G>T (p.D189Y), c.170T>C (p.I57T), and c.1021+1G>A — have never been reported.
Using this information, as well as other previously published data, the researchers then looked for associations between individuals’ mutations and their clinical symptoms. Notably, they observed that certain mutations seemed to be associated with a more mild disease course. The researchers speculated this may be due to the particular effects of given mutations on the function of the AADC protein itself, but further research will be needed to know for sure.
“[O]ur research expands the clinical spectrum of AADCD and contributes to the knowledge of the genotype and phenotype correlation for the DDC gene,” the researchers concluded.