Most AADC deficiency patients fail to meet motor milestones: Analysis

A wide range of symptoms that affect several bodily systems are seen

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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About three-quarters of children and adults with aromatic l-amino acid decarboxylase (AADC) deficiency on standard care fail to meet any key motor milestones, according to a patient registry analysis.

People with the condition exhibited a wide range of symptoms that affected several bodily systems, the most common being developmental delays and movement disorders. The registry, called AADCAware, is sponsored by PTC Therapeutics, the developer of Upstaza (eladocagene exuparvovec), a gene therapy.

Upstaza became last year the first disease-modifying therapy approved for AADC deficiency patients, 18 months and older, in the European Union and the U.K. PTC plans to apply for approval in the U.S. in the coming months, according to an email correspondence with AADC News.

The registry findings were presented by PTC last month in the poster “Baseline clinical characteristics and disease burden of patients with aromatic ʟ-amino acid decarboxylase deficiency (AADCd) enrolled in the AADCAware registry,” (page 560) at the Society for the Study of Inborn Errors of Metabolism Annual Symposium 2023, in Jerusalem.

“The AADCAware registry will help to improve the understanding of the natural history of AADC deficiency progression without gene therapy treatment, its impact on patients, and diagnostic and management practices, as well as long-term safety and effectiveness of [Upstaza] gene therapy in patients with AADC deficiency,” the researchers wrote.

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The goal of AADCAware

AADC deficiency is very rare and there’s little information about its natural course, the factors that influence its prognosis, and the patterns of treatment responses.

PTC launched AADCAware to better understand the natural course of the disease (Part A) and to evaluate the long-term safety and effectiveness of Upstaza (Part B).

In the poster, scientists described the demographics and disease characteristics of the 45 AADC deficiency patients enrolled in Part A up to March 2023. This part of the registry intends to enroll 50 patients with a documented diagnosis who haven’t been treated with Upstaza and received only standard of care.

Participants will be monitored annually for a minimum of five years.

Enrolled patients had a median age of 3 at enrollment, ranging from 1-41 years. The onset of their symptoms came at a median age of 3 months, emerging in the first year of life for all the patients.

Most (71.1%) were still in the study in March. All but two of the 13 patients who left the registry did so to enroll in gene therapy clinical trials. Two died.

At enrollment, the most commonly reported symptoms associated with the central nervous system (brain and spinal cord) were developmental delay (88.9%), movement disorders (86.7%), muscle tone problems (84.4%), and behavioral issues (37.8%).

Most common symptoms associated with the autonomic nervous system, which regulates involuntary bodily functions, were upper respiratory tract issues (55.6%), excessive sweating (46.7%), gastrointestinal problems (42.2%), eye problems (33.3%), temperature instability (24.4%), and cardiovascular issues (13.3%)

“These results show that patients with AADC deficiency present with a wide spectrum of central nervous system and autonomic nervous system signs and symptoms,” the researchers wrote.

Of the 31 patients with available motor development data at enrollment, most (77.4%) hadn’t reached any key motor development milestones, including full head control, sitting unassisted, standing with support, and walking with support. Only six patients (19.4%) achieved all key developmental milestones and could walk with support at their enrollment.

The observed failure to meet important milestones indicates “a poor health-related quality of life and a substantial need for basic daily life support,” the researchers wrote.

The risk of misdiagnosing AADC deficiency

PTC also supported another study presented orally at the symposium, titled “An efficient workflow for diagnosis of AADC deficiency – A template for reducing health disparities in pediatric care.” (page 76)

Due to AADC deficiency’s rarity, doctors may not recognize its symptoms and misdiagnose it. The poor understanding of the impact of variations in the DDC gene — the cause of AADC deficiency — means other tests to look for disease-associated molecules in the spinal fluid are required for a diagnosis.These are invasive, however.

“Invasive testing is costly, burdensome, and limits access to diagnosis and care,” the researchers wrote in the abstract.

In the study, researchers in the U.S. reviewed data from 343 previously reported and new AADC deficiency cases from 1990 to 2023, including genetic data and analysis of metabolites in the blood and urine.

Reviewing it all together, the scientists determined that genetic testing alone may not be enough to identify cases of AADC deficiency, especially more mild ones.

They proposed a new, noninvasive diagnostic workflow that, in addition to genetic testing, involves looking for disease-associated metabolites in the bloodstream. This could help reach a diagnosis sooner.

“Diagnostic delays both amplify existing disparities and create new health and financial disparities in and across our communities,” the researchers wrote in the presentation. Combined metabolic and genetic analyses will “shorten the diagnostic journey, alleviate concerns for misdiagnosis, decrease health disparities, and broaden access to effective treatment,” they wrote.