New DDC Mutation Identified in Emirati Boy With AADC Deficiency

Boy's oculogyric crises were mistaken for seizures, leading to initial misdiagnosis

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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A new mutation in the DDC gene was identified as the cause of aromatic L-amino acid decarboxylase (AADC) deficiency in a baby boy in the United Arab Emirates (UAE), scientists report.

This marks the first documented case of AADC deficiency in the UAE and one of the few reported in the Middle Eastern region, the researchers noted.

Before the correct diagnosis, the boy’s oculogyric crises — a common symptom of AADC deficiency characterized by the fixed upward gaze of the eyes — were mistaken for seizures and he was initiated on anti-seizure therapy.

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“Improvements to the accurate and timely diagnosis of AADC deficiency around the world, including in the Middle East, are crucial to ensure patients achieve early access to multidisciplinary management teams and potentially life-changing treatments,” the researchers wrote.

The patient was found to have a disease-causing mutation in the DDC gene that has not been described previously.

The study, “Case report: First case report of an Emirati child with a novel gene variant causing aromatic L-amino acid decarboxylase deficiency,” was published in Frontiers in Pediatrics.

AADC deficiency is a rare disease characterized by low muscle tone, developmental delay, involuntary muscle contractions, oculogyric crises, excessive sweating, and drooping eyelids. Patients may also experience other symptoms, including sleeping difficulties and behavior problems, such as irritability and excessive crying.

During an episode of oculogyric crisis, which can last for hours with the progression of the disease, a patient’s gaze is involuntarily fixed upward. These crises are usually accompanied by protruding tongue, restricted neck movement, and lip-smacking — closely resembling what happens in epileptic seizures.

As such, oculogyric crises can be mistaken for seizures in these patients, leading to delayed diagnosis and disease-specific treatment.

AADC deficiency is caused by reduced activity of AADC, an enzyme involved in the production of brain chemical messengers, due to mutations in both copies of the DDC gene.

In the report, researchers in the UAE, along with colleagues in the U.K., described the case of an Emiri baby boy with AADC deficiency caused by a previously unknown DDC mutation.

The boy was the third child born to consanguineous (biologically related) parents, both of whom were in good health. The couple’s first two children died in early childhood due to a suspected neurodegenerative disease that was never diagnosed and for which no genetic tests were performed.

After an uneventful pregnancy, the couple’s third child was delivered via emergency Cesarean section due to concerns about a slow fetal heart rate, but once he was delivered, he appeared healthy, and no further intervention was performed.

Symptoms begin to show at 3 months

At age 3 months, the boy began to exhibit episodes of sudden body stiffening and upward-facing gaze, which occurred nearly every day and could last up to eight hours. Clinical tests done at a local hospital, including brain imaging and lab tests of liver function, all came back normal.

These episodes of oculogyric crisis were mistaken for epileptic seizures, and the patient was started on anti-seizure medication. However, he experienced another prolonged episode of body stiffening at 5 months of age that prompted hospitalization and further treatment with other anti-seizure medication.

Despite these treatments, the oculogyric crises continued to occur, lasting for up to four hours at a time.

The boy also started to exhibit unusual periods of unsettledness and limb twisting and stiffening, and unexplained bouts of excessive crying and insomnia. He showed excessive sweatiness, drooling, and nasal congestion, and experienced frequent respiratory infections.

Physical examination showed that the boy was very small for his age, and had low muscle tone and subtle physical abnormalities, such as an unusually small jaw, overhanging upper lip, and an undescended testicle.

Also, “developmental assessment revealed global developmental delay,” the team wrote.

“Given the severe symptoms and signs, the negative investigations from brain imaging and [brain activity] studies, the consanguinity of the parents, and the positive family history of early death in other siblings, a genetic cause was suspected,” the researchers added.

Genetic test reveals new mutation in DDC gene

Comprehensive genetic testing, conducted at around 5 months of age, revealed a new mutation (c.1144G>T) in both copies of the DDC gene — one inherited from each of his parents. Genetic testing of the parents confirmed they carried one mutated copy of the gene and one healthy copy.

The mutation was located on a region affected by other known disease-causing mutations and resulted in a change in one of the amino acids of the AADC protein. (Amino acids are the building blocks of proteins.)

While no further functional tests were conducted, the data, along with the boy’s symptoms, strongly suggested that the newly identified mutation caused a change in the AADC enzyme that affected its function.

Analyses of the fluid surrounding the boy’s brain and spinal cord (cerebrospinal fluid, or CSF) showed an altered profile of brain chemical messengers consistent with AADC deficiency.

“Based on the genetic results, the CSF … analysis and the clinical manifestations, a diagnosis of AADC deficiency was confirmed at 9 months of age,” the researchers wrote.

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Following the genetic results at around 6 months of age, the patient stopped receiving anti-seizure medications and started treatment for AADC deficiency according to standard guidelines. This included vitamin B6 and other supplements, as well as therapies designed to normalize brain chemical messengers.

Subsequently, the frequency of oculogyric crises decreased from nearly daily to every week or two. The boy’s sleep also improved, and his limb twisting diminished.

The boy is being cared for by a multidisciplinary care team, with monitoring every few months at a specialist center. At 5 years old, he could not sit or reach out, and was unable to express himself through language, though he could understand a few words and smile in response to someone smiling at him.

“This is the first detailed case report of AADC deficiency in the UAE and is amongst very few case reports in the Middle Eastern region,” the researchers wrote.

However, “the number of cases is expected to rise given the increasing availability of … genetic tests,” they added.

The team also noted that diagnosis of this condition will become increasingly important as new therapies become available.