Epilepsy gene panel ‘instrumental’ in child’s AADC deficiency diagnosis

Researchers credited inclusion of DDC gene in the screening

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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The case of a girl with unexplained seizures in whom an epilepsy gene panel screening was the key toward a correct diagnosis of aromatic L-amino acid decarboxylase (AADC) deficiency was described in a report.

“This case report shows that AADC deficiency can be the underlying diagnosis in patients with suspected epilepsy,” the researchers wrote, adding it also highlights the importance of testing for potential AADC deficiency in people with unexplained seizures.

The case study, “Diagnosis of Aromatic L-Amino Acid Decarboxylase (AADC) Deficiency via Epilepsy Gene Panel Screening in a Patient with Atypical Presentation,” was published in Child Neurology Open.

AADC deficiency is caused by reduced activity of the AADC enzyme due to mutations in both copies of the DDC gene. This deficiency impairs the production of certain brain signaling molecules essential for many aspects of brain activity. It leads to a range of symptoms, from low muscle tone (hypotonia) and movement problems to developmental delay, sleep problems, and oculogyric crises.

An oculogyric crisis, which can last for hours with advanced disease, features the fixed upward gaze of the eyes. This and other features of it mimic many observed aspects of epileptic seizures, which may also occur with AADC deficiency.

Because AADC deficiency is so rare and disease symptoms can vary from person to person, diagnosing the condition is often a challenge.

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Gene screening leads to AADC deficiency diagnosis

Researchers at the University of Alabama, Birmingham, described the case of a 4-year-old African American girl with AADC deficiency whose diagnosis was achieved mainly through an epilepsy gene panel screening.

When she was nearly 2, the girl went to their clinic with poor head control, hypotonia, developmental delay, and difficulty swallowing, and was referred to a child neurologist.

She was lost to follow-up but returned to the clinic a year later due to periods of prolonged staring and brief episodes of fixed upward gaze — raising concerns about possible seizures.

She continued to show developmental delay in motor milestones and also in language — she could say words, but was unable to speak in full sentences. She also showed uncoordinated movement while walking.

Analyses of the electrical activity in her brain confirmed she was having seizures, leading to a diagnosis of unprovoked epilepsy, meaning seizures in the absence of specific triggers.

The diagnosis made the girl eligible for a no-cost genetic testing program for children with epilepsy that looks for mutations in more than 150 genes associated with seizures. One of the genes included on the panel was DDC.

Results revealed two distinct mutations in each of the two copies of the DDC gene, one from each of the girl’s parents.

One mutation, c.272C>T, is classified as likely disease-causative. The other, c.116G>C, was previously suggested to have a negative effect in AADC enzyme production, but is listed as of “unknown significance.”

Deficient AADC enzyme activity in the blood and higher than normal levels of 3-O-methyldopa, a molecule that accumulates in the blood of AADC deficiency patients, was also shown.

The girl was diagnosed with AADC deficiency at age 4, based on the results.

She was started on standard treatment, including vitamin B6 and pramipexole, a dopamine receptor agonist, and monoamine oxidase inhibitors.

The girl is being followed for treatment effectiveness every four to six months. The family’s distance from the specialty center and financial constraints have affected their ability to attend appointments, however.

The researchers noted that the “the initial epilepsy diagnosis was instrumental in achieving the correct diagnosis of AADC deficiency because of the inclusion of DDC in the epilepsy gene panel.” The finding “supports future inclusion of DDC in other gene panels and access to genetic testing for children with epilepsy,” they wrote wrote, noting that making such testing more widely available could help facilitate faster diagnoses for this rare genetic disorder.