Newborn screening for 3-OMD can lead to timely diagnosis, treatment

Early treatment may ease symptoms, result in better outcomes for patients

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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Measuring the levels of 3-O-methyldopa (3-OMD), a molecule that builds up in aromatic l-amino-acid decarboxylase (AADC) deficiency, can diagnose the disease in newborns, allowing it to be treated early in life, according to a German study.

The study, “Newborn screening for aromatic l-amino acid decarboxylase deficiency – Strategies, results, and implication for prevalence calculations,” were published in the journal Molecular Genetics and Metabolism.

AADC deficiency is caused by mutations in DDC, a gene that codes for an enzyme called AADC. This enzyme takes part in the process to produce neurotransmitters like dopamine and serotonin, two chemical messengers that relay signals between nerve cells and are critical for brain function.

Without enough of the AADC enzyme, nerve cells produce less dopamine and serotonin. As a result, children with AADC deficiency may take longer to hit developmental milestones and often have intellectual and motor challenges.

Newborn screening uses a few drops of blood taken from a newborn’s heel to look for rare but serious diseases that may not be apparent at birth. This allows steps to be taken toward timely treatment, which may give young patients the best chance of living healthier lives.

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Infant sleeping illustration.

Most experts support newborn DNA sequencing for AADC deficiency

Earlier research: 3-OMD is reliable marker for diagnosing AADC deficiency

While many experts are in favor of using genetic testing to screen for AADC deficiency in newborns, earlier work has shown 3-OMD is a reliable marker for diagnosing this very rare disease even before the first symptoms appear.

3-OMD is a metabolite that can accumulate in individuals with AADC deficiency, a result of impaired conversion of levodopa to dopamine. As a response to low dopamine levels, levodopa can be turned into 3-OMD through alternative pathways.

After a successful pilot study with a small number of newborns in Germany, researchers went on to test the effectiveness of measuring 3-OMD using a technique called tandem mass spectrometry (MS/MS) to identify newborns who may have AADC deficiency.

The study included 766,660 babies born in three centers in Heidelberg, Hanover, and Munich from January 2021 to June 2023. All got a heel prick on their second or third day of life to collect a few drops of blood on a special card that was sent off to a lab for testing.

Our study confirms the reliability of 3-OMD as a screening marker. The detection of one case with very mild symptoms highlights the importance of early diagnosis and the need for appropriate management of the disorder.

Thirteen newborns (about one in 59,000) tested positive for elevated 3-OMD and underwent genetic testing to check for the presence of disease-causing mutations in the DDC gene and confirm the diagnosis of AADC deficiency.

One baby boy, who had no family history of genetic diseases, was found to carry two mutations in the DDC gene. After diagnosis, he was started on daily vitamin B6 at 5-10 milligrams per kilogram of body weight. At 9 months of age, no symptoms had yet manifested. 

Another baby was highly suspected of having AADC deficiency but died of gastric perforation (a hole that forms through the stomach), brain bleeding, and sepsis (an extreme reaction to an infection) shortly after birth before genetic testing could be performed.

False positives, that is, results that indicated AADC deficiency may be present when it actually was not, occurred due to maternal use of levodopa, the mainstay treatment for Parkinson’s disease (two cases), and premature birth (two cases). In seven cases, the reason for false-positive results was unclear.

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Illustration of DNA strand.

AADC deficiency carriers found to be more than estimated in Sicily

Prevalence of AADC deficiency is one in every 766,660 newborns

The prevalence of AADC deficiency, or the number of babies born with the disease, was one in every 766,660. “The estimated birth prevalence supports earlier estimations and confirms [AADC deficiency] as a very rare disorder,” the researchers wrote.

“The exact worldwide incidence of AADC deficiency is not known,” Nenad Blau, PhD, from the University Children’s Hospital in Zurich, Switzerland, wrote in an editorial piece about the study. However, Blau noted one in 766,660 is “less common than initially expected.”

The study’s findings support newborn screening for 3-OMD in dried blood spots for the early detection of AADC deficiency. Timely treatment with vitamin B6, gene therapy, or other approved medications may ease symptoms and offer a chance for better outcomes.

“Our study confirms the reliability of 3-OMD as a screening marker,” the researchers concluded. “The detection of one case with very mild symptoms highlights the importance of early diagnosis and the need for appropriate management of the disorder.”