Report Describes Sisters With Very Mild AADC Deficiency

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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Two sisters with unusually mild cases of aromatic L-amino acid decarboxylase (AADC) deficiency were described in a recent report.

“Our patients may show the most attenuated [mild] type of AADC deficiency. This indicates the importance of ruling out the possibility of AADC deficiency in patients who present with similar features,” the researchers wrote, noting that identifying atypical cases of the disease will be especially important as new therapies are developed.

The report, “Novel variants in aromatic L-amino acid decarboxylase deficiency: Case report of sisters with mild phenotype,” was published in Brain and Development.

AADC deficiency is caused by mutations in the DDC gene, which provides instructions for making the AADC protein. This protein is needed to make dopamine and serotonin, which are important neurotransmitters — signaling molecules that help brain cells “talk” to each other to coordinate everything from movement to cognition.

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Only about 120 cases of AADC deficiency have been reported. Usually, the disease manifests with severe developmental delay, as well as motor and cognitive problems. Untreated, most patients are completely bedridden and are never able to speak.

Here, scientists in Japan present the cases of two sisters with AADC deficiency manifesting with comparatively mild symptoms.

The older sister experienced some marked developmental delay; she first rolled over at age 9 months, and started walking unsupported just before she turned 2. (For context, most babies start rolling over around 4 months, and start walking around at 1 year).

An examination when she was 7 years old revealed some abnormal facial structure features, such as abnormally spaced eyes and an unusually small lower jaw. She also had generally low muscle tone, experienced chronic fatigue that tended to get worse later in the day, and had recurrent oculogyric crises — when gaze is involuntarily fixed upward due to spasms in the eye muscles.

“Although her gait was unsteady, she was able to perform daily activities by herself and enjoy soccer games with healthy friends outside,” the researchers wrote.

Additionally, while her speech tended to be slow and sound slurred, an assessment done when she was 10 showed “she was able to verbalize her thoughts in three-word-phrases freely and write Chinese and Japanese characters.”

The girl’s younger sister has experienced generally similar symptoms. She didn’t start walking without support until age 30 months, had some of the same facial abnormalities, and an assessment done when she was 4 years  showed “mild developmental delay,” the researchers reported.

Both of the girls underwent genetic testing, which revealed mutations in both of their copies of the DDC gene — one inherited from each parent. Additional testing confirmed the sisters’ mother carried one mutation, and their father carried the other.

The researchers conducted analyses to predict how the particular mutations identified are likely to affect the AADC protein. Notably, results revealed that the changes to the protein caused by these mutations are outside of the catalytic site, which is the part of the protein mainly responsible for making dopamine and serotonin.

The scientists speculated that because the catalytic site is relatively unchanged it might mean these mutations don’t have as detrimental an effect on the AADC protein as other disease-causing mutations. That may account for why these patients more milder symptoms than typical AADC deficiency patients.

Both girls have been started on treatment with selegiline, a medication that works by blocking the activity of proteins that normally degrade dopamine and serotonin. After a year on this treatment, “gait unsteadiness tended to reduce, [but] the medication was not effective for the oculogyric crisis,” the researchers reported.