Unusually mild case of AADC deficiency reveals new mutation

Case report describes woman, 55, with 2 different DDC gene mutations

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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Genetic testing done for a 55-year-old woman diagnosed with an unusually mild case of AADC deficiency revealed a disease-causing gene mutation never before reported, according to researchers.

The newly identified mutation, while indeed found to be a cause of the patient’s genetic disease, still allowed for the relatively preserved function of the AADC protein. The researchers said in a case report that the increased protein function may be why the patient’s symptoms were mild.

Details were given in “An attenuated, adult case of AADC deficiency demonstrated by protein characterization,” which was published in the journal Molecular Genetics and Metabolism Reports. The work was funded in part by PTC Therapeutics, makers of the AADC deficiency gene therapy Upstaza (eladocagene exuparvovec).

The researchers said their approach in the woman’s case provided “the molecular basis for the mild presentation of the disease,” and added that “the experience … can also be useful for personalized therapeutic decisions in other mild AADC deficiency patients.”

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AADC deficiency patient likely had oculogyric crises as a child

AADC deficiency is caused by mutations in the DDC gene, which provides instructions for making the eponymous AADC enzyme. This enzyme is needed to make brain signaling molecules, or neurotransmitters, like dopamine and serotonin. Abnormally low levels of these neurotransmitters in AADC deficiency lead to disease symptoms.

Most people with AADC deficiency who do not receive treatment have very little ability to move or speak on their own. In marked contrast to the typical picture of severe disease, this patient had only some cognitive abnormalities and occasionally experienced moments of weakness in her legs. Overall, her cognitive issues were fairly mild, and she was able to walk and ascend stairs without too much difficulty.

The patient reported that her siblings also had experienced cognitive issues, and that, as a child, she had sometimes experienced episodes where her eyes would roll upward when she was tired. With the benefit of hindsight, the researchers suspect these childhood episodes may have been oculogyric crises, a characteristic symptom of AADC deficiency.

The woman sought medical attention in her mid-50s because she was experiencing mood swings, and the episodes of weakness in her legs had been getting worse, leading to sudden falls.

Analyses of the fluid around the patient’s brain indicated low levels of dopamine and serotonin, consistent with a diagnosis of AADC deficiency.

Tests of her blood showed AADC enzyme activity was about 28% of what’s considered normal — which is low enough to qualify for AADC deficiency, but only just, given that healthy AADC carriers typically have activity of 35% to 40%.

Every individual has two copies of the DDC gene, with one inherited from each biological parent. AADC deficiency only develops if both copies are mutated. Carriers, meanwhile, have one mutated copy and one healthy copy and, as such, don’t develop disease.

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High enzyme activity with these 2 mutations likely explains mild symptoms

Genetic testing of this patient showed one of her DDC genes carried a mutation dubbed p.Arg347Gln, which has previously been reported to cause AADC deficiency. Her other copy of the gene carried another mutation, p.Glu227Gln, which has never been reported before.

To better understand the molecular basis for this patient’s unusually mild symptoms, the researchers conducted a series of tests to characterize this combination of mutations. The AADC enzyme normally functions as a dimer — that is, two individual AADC enzymes join together to carry out the enzyme’s function.

The researchers found that when an AADC dimer contained two proteins both with the known disease-causing mutation p.Arg347Gln, the dimer had essentially no ability to function at all. By contrast, an AADC dimer with two enzymes carrying the novel p.Glu227Gln mutation had near-normal functionality. A dimer containing one enzyme with each mutation had about 75% of the activity of a normal AADC dimer.

Altogether these data suggest that these two mutations cause AADC deficiency that is characterized by comparatively high enzyme activity — likely explaining why this patient had such mild symptoms.

After the diagnosis of AADC deficiency was confirmed, the patient was started on treatment with vitamin B6 (pyridoxine). She reported more energy and less fatigue after starting the treatment.

“Interestingly, in the last few years, many previously undiagnosed or misdiagnosed patients have been identified as mild cases of AADC deficiency, expanding the phenotype [characteristics] of this neurotransmitter disease,” the researchers wrote.