Delayed AADC deficiency diagnosis costly for 3 children in Saudi Arabia

Symptoms evident soon after birth not recognized for months or years

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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A diagnosis of AADC deficiency is often delayed, leading to poor clinical outcomes, as reported for three children in Saudi Arabia, one of whom carried a previously unidentified disease-causing DDC gene mutation.

“There is an urgent need to raise awareness and improve diagnostic testing for rare diseases such as AADC deficiency in the [Kingdom of Saudi Arabia]  in order to improve outcomes, particularly as innovative disease-targeting therapies become available,” the scientists wrote.

The report, “Case report: Aromatic L-amino acid decarboxylase deficiency in three patient cases from the Kingdom of Saudi Arabia,” was published in Frontiers in Pediatrics.

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AADC deficiency not diagnosed in one girl until age 18

AADC deficiency is caused by mutations in the DDC gene, which provides instructions to produce an enzyme called aromatic L-amino acid decarboxylase, or AADC. The enzyme is needed to make dopamine and serotonin, two major neurotransmitters, or chemical messengers involved in nerve cell communication.

Disease-causing DDC mutations result in too little enzyme being available or an enzyme that doesn’t work as it should. This leads to a range of symptoms, from low muscle tone (hypotonia) and movement problems to developmental delay, seizures, and oculogyric crises — characterized by the fixed upward gaze of the eyes.

Patients may also have problems with their autonomic nervous system, which controls functions such as heart rate, blood pressure, sweating, and digestion.

The disease begins to manifest early in life, and first symptoms can appear at birth or within a few months of life. Correctly diagnosing AADC deficiency is important because early treatment can lead to better outcomes.

“A timely diagnosis is critical to prevent secondary complications, promote development, and optimize outcomes from future innovative treatment options, such as gene therapy,” the researchers wrote.

AADC deficiency only develops if a child inherits two mutated copies of the DDC gene, one from each parent. Carriers of one mutated copy usually don’t show any symptoms, but can pass the disease-causing mutation to their children.

Scientists at King Faisal Specialist Hospital and Research Center, in Riyadh, reported the cases of three children with AADC deficiency caused by a mutation in both copies of the DDC gene. In one child, the mutation had not been reported previously.

The first case was a girl born to first-degree cousins. Two of her siblings had movement problems; one had died and the other was diagnosed with AADC deficiency after the girl’s diagnosis. One other sibling died in the womb.

The girl showed hypotonia at birth, and at 6 months old she began to experience seizures along with oculogyric crises that lasted for a few minutes and occurred up to three times each week.

Her other symptoms included global developmental delay, abnormal movements, and excessive sweating. She was given supportive treatment and anti-seizure medications.

At age 9 months, the girl was referred to the hospital for further brain activity, genetic, and molecular tests, which showed a neurotransmitter profile in the cerebrospinal fluid (CSF) consistent with AADC deficiency.

Genetic test results didn’t come back until she was 18 months old. They revealed a previously unknown DDC mutation, called c.245G>A. Despite treatment, her symptoms remained largely unchanged and she died at a local hospital when she was 3 years old. An exact cause was not given.

The other two children, a girl and a boy, also were born to related parents, and both had siblings or cousins with symptoms suggesting AADC deficiency. Some were later confirmed to have the disease.

The girl was initially diagnosed with a developmental delay and seizures, despite showing disease symptoms of such as poor head control, global developmental delay, and excessive sweating. She was first treated at the Riyadh hospital when she was 15 years old.

Her AADC deficiency diagnosis was confirmed through genetic testing at age 18, with a known disease-causing mutation (c.206C>T) in both DDC gene copies.

At last follow-up, she was 21 years old. Treatment, started at age 12 and adjusted after her diagnosis, resulted in a “slight reduction in the frequency and severity of seizures,” the researchers wrote, but “these changes were temporary,” with no long-term improvement evident, the scientists wrote.

First symptoms of AADC deficiency appeared in the boy at age 6 weeks, including hypotonia, oculogyric crises, global developmental delay, and seizures. He was referred to the Riyadh hospital at 3 months old and genetic testing, requested four months later, was outsourced to the U.S.

Results, received about nine months later, showed a previously reported disease-causing mutation (c.175G>A) in both DDC copies. He also showed an AADC deficiency-characteristic CSF neurotransmitter profile, further confirming the diagnosis.

Treatment helped to lower his seizure frequency, and at last follow-up, he was 5 years old.

Delays partly due to slow referral to specialty center, outsourced testing

While all three children manifested the disease from birth, their diagnoses were delayed “for several reasons, including delayed referral to a specialist center and considerable delays in receiving results from outsourced genetic tests,” the researchers wrote.

“Delays were further exacerbated by the requirement to outsource CSF analysis,” they added.

While a multidisciplinary group of specialists worked together to manage the cases, all three children lacked prompt treatment.

“The findings from this small case series corroborate previous case reports indicating that globally, patients with AADC deficiency frequently have a delayed diagnosis and that long-term clinical outcomes are generally poor,” the scientists wrote.

“In Middle Eastern countries, increased disease awareness among primary and pediatric physicians, reduced time to obtain genetic and biochemical diagnostic test results, and an increase in the number of local specialists will be required to improve outcomes for patients with AADC deficiency,” they added.

The children’s families also were “offered genetic counseling in accordance with the guidelines,” the scientists wrote, adding that such counseling “is crucial for immediate family,” since “if both parents are carriers for the gene variant, there is a 1 in 4 risk of disease recurrence.”