Girl with seizures found to have mild AADC deficiency: Report

Diagnosis made 'by chance' after genetic testing for childhood epilepsy

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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Researchers say childhood epilepsy and mild attention deficits were effectively “hiding” a case of mild aromatic l-amino acid decarboxylase (AADC) deficiency in a teenage girl, according to a new case report.

“In this study, we describe a 13-year-old girl with late-onset, mild, and atypical AADC deficiency diagnosed ‘by chance’ with a next-generation sequencing (NGS) multigene panel,” the researchers wrote.

The girl had experienced seizures from age 10, and was given a neuropsychological examination that “highlighted a mild impairment in executive functions, affecting attention span and visual-spatial abilities,” the team wrote. Further assessments after that diagnosis revealed two variants underlying AADC deficiency.

This relatively mild case, with late-onset symptoms and a combination of a known and a newly identified disease-causing mutation, highlights how variable AADC deficiency can be, the researchers noted.

The study, “Case report: Childhood epilepsy and borderline intellectual functioning hiding an AADC deficiency disorder associated with compound heterozygous DDC gene pathogenic variants,” was published in Frontiers in Neurology.

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AADC deficiency is caused by mutations in both copies of the DDC gene, which provides instructions for making the AADC enzyme. This enzyme is needed to make certain neurotransmitters, or signaling molecules that nerve cells use to communicate with each other and the rest of the body.

In this rare disease, a dysfunctional or nearly absent AADC enzyme results in abnormally low levels of neurotransmitters, ultimately giving rise to disease symptoms that usually manifest in the first year of life.

These can include developmental delay, movement disorders, seizures, and autonomic dysfunction. The autonomic nervous system regulates the body’s involuntary functions, such as the heartbeat, body temperature, and blood pressure.

In this report, scientists in Italy described the case of a girl who was found to have late-onset, mild, and atypical AADC deficiency based on a genetic testing panel that actually included the DDC gene.

The girl, whose father had childhood seizures, started to experience seizures when she was age 10. She was started on daily treatment with the anti-seizure medication levetiracetam (sold as Keppra and other brand names), and for the next two years she was seizure-free.

But when levetiracetam was gradually stopped, seizures returned, and she restarted treatment.

On additional examination, the physicians noted she had smaller than expected hands and feet, mildly drooping eyelids, mild slowness of movement, and was clumsy in certain motor tasks.

A neuropsychiatric evaluation revealed she was somewhat below average in some cognitive function measures, particularly those related to attention span and the ability to process visual information. Otherwise she didn’t have any obvious neurological issues, and imaging of her brain was normal.

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

Girl found to have 2 DDC gene mutations – 1 known plus 1 new

Clinicians were uncertain on the cause of the girl’s seizures, but they suspected she probably had some form of genetic epilepsy. So, they conducted genetic tests based on a commercial gene panel covering 886 genes associated with seizure-related conditions.

To their surprise, the test revealed two DDC mutations, one in each gene copy, strongly suggesting AADC deficiency as the cause of her symptoms. One mutation, called Arg347Gln, was already known to cause the disease, resulting in the production of a nearly non-working AADC enzyme.

The other mutation, called Leu391Pro, had not been previously reported, but leads to a change in a single amino acid, protein’s building blocks, in a particular position of the resulting protein.

Computer-based analyses indicated that Leu391Pro results in the production of an AADC enzyme that likely works less than normal, but still retains some ability to produce neurotransmitters.

Taking the findings collectively, the girl was diagnosed with AADC deficiency. Her condition was notably milder than what is typical in AADC deficiency, which the researchers hypothesized may be because the newly identified mutation didn’t fully remove AADC enzyme function.

Thus, the combination of a severe and a mild genetic mutation in this case led to a clinical profile “with mild and late-onset symptoms, of which seizures were the clinical sign, leading to medical attention,” the researchers wrote.

[This case] highlights how [variable] this condition is, thus underlying the probability that it might still be underdiagnosed.

After the diagnosis, clinical re-evaluation revealed other AADC deficiency symptoms that had previously been overlooked. For instance, the girl showed several signs of autonomic dysfunction, such as frequent nasal congestion, excessive sweating, and fainting in hot days or when very stressed.

The girl was maintained on the anti-seizure therapy levetiracetam and started to receive vitamin B6 supplements, a standard AADC deficiency treatment — which the researchers report has stopped her occasional fainting. After six months of treatment, there also were signs of cognitive improvements.

“In conclusion, the present case enlarges the [clinical] spectrum of AADC deficiency, encompassing less-disabling conditions, such as borderline cognitive functioning, drug-responsive epilepsy, and prevalent autonomic dysfunction,” the researchers wrote.

The case also “highlights how [variable] this condition is, thus underlying the probability that it might still be underdiagnosed,” the team added.