Study uncovers genetic mutations linked to milder AADC deficiency
More mild cases being recognized, warrant attention: Researchers
Researchers have uncovered the effects of gene mutations that are associated with mild or moderate forms of aromatic L-amino acid decarboxylase (AADC) deficiency.
In general, DDC gene mutations linked to milder cases were associated with greater residual activity of the AADC enzyme than in severe cases.
Because most known cases of AADC deficiency are severe, less had been known about the genetic mutations linked to milder forms of the condition. However, with better awareness and screening strategies, more mild cases are being recognized and warrant attention, researchers note.
“This cluster of mild/moderate patients needs consideration for a more appropriate and aimed therapeutic approach,” they wrote.
Their study, “Mild/moderate phenotypes in AADC deficiency: Focus on the aromatic amino acid decarboxylase protein,” was published in the Journal of Inherited Metabolic Disease. It was funded in part by a grant from PTC Therapeutics, which markets the AADC deficiency gene therapy Upstaza (eladocagene exuparvovec).
AADC deficiency is caused by mutations in both copies of the DDC gene that’s responsible for producing AADC, an enzyme critical for the production of a number of important brain signaling chemicals called neurotransmitters.
Lack of AADC enzyme leads to severe neurological symptoms
In many cases, a lack of AADC gives rise to severe neurological symptoms that emerge early in life, including a failure to achieve motor milestones such as sitting unassisted or head control.
However, some cases of a more mild or moderate disease have also been described. These patients, for example, may be able to walk on their own but have milder motor or cognitive issues.
Before 2019, about 21 patients had been diagnosed with mild or moderate AADC deficiency, according to the researchers, but that number has about doubled in the years since. They believe this is likely due to better disease awareness, advances in genetic testing, and newborn screening programs that allow milder cases to be accurately diagnosed.
The degree of disease severity is likely in part related to the specific DDC mutation a person has. Different types of mutations will have varying effects on gene activity and subsequent production of the AADC enzyme.
In the study, the researchers reviewed the genetic mutations associated with mild or moderate cases of the disease.
This cluster of mild/moderate patients needs consideration for a more appropriate and aimed therapeutic approach.
They noted this more mild disease is most often associated with a compound heterozygous genetic makeup, in about 70% of cases. This means that a person has two different DDC mutations, one on each copy of the gene inherited from either parent. The opposite would be a homozygous mutation, where the same mutation is found on both copies of the gene.
Known homozygous disease-causing mutations associated with around 21% of severe cases in certain Asian populations were not found in these mildly affected patients.
Often, scientists use the characteristics of a gene mutation to predict what effect it will have on the protein produced, in this case the AADC enzyme. Only mutations expected to actually affect protein production or function are predicted to cause disease.
In general, the researchers found that prediction models based on how the mutation would affect AADC structure were not useful for distinguishing mild/moderate from more severe disease presentations.
They did find, however, that DDC mutations associated with mild/moderate disease corresponded to parts of the gene encoding different protein regions than have been previously observed with severe mutations.
Specifically, these mild mutations corresponded to protein regions where alterations wouldn’t be expected to dramatically affect AADC enzyme function.
Researchers identify threshold of residual AADC activity for mild disease
Notably, the researchers identified a threshold of residual AADC activity that’s necessary for the disease to be mild. Any activity level below that would correspond to more severe disease.
In people with homozygous mutations, this threshold is around 8% of residual enzyme activity. In compound heterozygotes, it’s around 15%.
The researchers noted healthy people who carry one mutated copy of DDC are often found to have AADC enzyme activity at about 35%-40% of normal. It is not clear yet exactly what range of AADC activity would distinguish these people from those with mild or moderate AADC deficiency.
Overall, the researchers believe the findings support continued efforts for neonatal screening and early disease identification, as prompt treatment, even of mild cases, “has a deep impact, especially at an early age.”
In Europe, Upstaza is approved for AADC deficiency in patients 1.5 years and older, and is mainly used in those with severe disease.
The scientists believe “decisions regarding gene therapy treatment should also be considered for mild patients who could benefit from a remarkable life improvement.”
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