Severe symptom burden found for AADC deficiency patients in Taiwan
But longer survival seen for children given Upstaza gene therapy
Most aromatic l-amino acid decarboxylase (AADC) deficiency patients treated at a center in Taiwan share a common mutation in the DDC gene and experience a severe symptom burden, a new study shows.
However, pediatric patients who received Upstaza (eladocagene exuparvovec) — a gene therapy for AADC deficiency now approved in Europe — in clinical trials survived significantly longer.
Also, the calculated frequency of the disease was lower than what would be expected according to newborn screening programs, suggesting that some patients in the Asian nation are going undiagnosed, according to researchers.
Altogether, the findings highlight “the importance of enhancing disease awareness and implementing newborn screening to improve diagnostic rates,” the scientists wrote.
The study, “Aromatic l-amino acid decarboxylase deficiency in Taiwan,” was published in JIMD Reports.
Medications don’t work for many with severe symptom burden
Most people with AADC deficiency have mutations in both copies of their DDC gene that cause the AADC enzyme — key for the production of certain brain signaling molecules — to be lacking or dysfunctional. As such, DDC mutations result in deficient levels of such signaling molecules, causing neurological symptoms evident early in life.
A particular DDC mutation called c.714+4A > T is prevalent in the Chinese population, including in Taiwan. It is associated with severe symptoms that may not be responsive to medications usually used to ease patients’ symptom burden.
Now, a team of researchers at the National Taiwan University Hospital (NTUH) investigated the frequency and burden of AADC deficiency in Taiwan by examining data from all patients seen at their hospital between January 2000 and March 2023.
The NTUH plays a significant role in the diagnosis and treatment of AADC deficiency in Taiwan — indeed, for all patients in the region. That’s in large part because clinical trials of Upstaza, the first disease-modifying therapy for AADC deficiency, were conducted there.
The gene therapy, developed by PTC Therapeutics, was approved last year for patients, 18 months and older, in the European Union and in the U.K. PTC also plans to seek regulatory approval in the U.S.
A newborn screening test for the disease also was developed and implemented at NTUH. Therefore, a majority of Taiwanese people with AADC deficiency, and some from neighboring countries, are seen there.
From 2000 to 2023, a total of 77 people with AADC deficiency visited NTUH — 41 female and 36 male patients.
“Among them, eight were international patients seeking a second opinion, and another two had one or both non-Chinese parents; all others were ethnically Chinese,” the team wrote.
The number of patients with AADC deficiency exceeded the 63 recorded cases in a national registry as of March 2023. That difference is likely because the registry “only included Taiwanese nationals and may have missed early cases,” the scientists wrote.
More than 90% of patients seen at NTUH had a severe symptom burden
Most patients — 72 of 77 or 93.5% — exhibited a severe symptom burden, while two had mild signs of the disease, and three were asymptomatic, meaning they did not show symptoms of the disorder.
Genetic sequencing data were available for 59 ethnically Chinese patients. The c.714+4A > T mutation accounted for 85% of all DDC mutations.
The three asymptomatic patients had the c.714+4A > T mutation in one copy of the gene, and another mutation in the other copy that was predicted to be have more mild consequences.
Of the 69 Taiwanese patients, 31 had received Upstaza in a clinical trial — 24 of whom were still alive. These individuals had a mean age of 10. The remaining seven had died at a mean age of 11.7.
Patients who have received gene therapy [Upstaza] survived longer than those who did not, regardless of whether they are alive, deceased, or have an unknown survival status.
Among the 38 patients who did not receive gene therapy, 18 were surviving at the time of the report — but with a much younger mean age of 4.9. The mean age at death or last visit of deceased patients was 3.9.
The survival status of remaining patients, including all international ones, was unknown.
“Patients who have received gene therapy [Upstaza] survived longer than those who did not, regardless of whether they are alive, deceased, or have an unknown survival status,” the team wrote.
Many surviving patients who remain untreated are awaiting gene therapy, which is not yet approved in Taiwan, according to the study’s authors.
“We hope gene therapy will be approved in Taiwan in the near future,” the team wrote, noting, however, that given the high cost of such therapies, “the burden of treating AADC deficiency in Taiwan is significant.”
Researchers say newborn screening missed up to 50% of cases in Taiwan
Based on data from these patients, the yearly incidence, or the number of new cases, of AADC deficiency in Taiwan from 1996 to 2022 ranged from 0.48 to 3.89 per 100,000 births. Surges in certain years could be mapped to the launch of gene therapy trials or newborn screening programs, according to the scientists.
Overall, the incidence of AADC deficiency cases from 1996-2022 was calculated at about 1.13 per 100,000 births. Considering only patients born after 2004, the incidence was about 1.5 per 100,000 births.
The scientists noted that these incidences were lower than the incidence of 3.12 cases per 100,000 births that they found in their previous pilot newborn screening study for AADC deficiency.
That indicates that “we likely missed 35%-50% of AADC deficiency cases in Taiwan,” the team wrote. The scientists don’t believe that most of the missing cases are simply patients that did not receive care at NTUH.
“There should be few diagnosed cases in Taiwan who were unaware of the gene therapy clinical trial or did not want to contact NTUH,” the team wrote, adding that “this implies that some patients may have never been diagnosed.”
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