Rapid Screening of Newborns for AADC Deficiency Possible, Study Says

Diagnosing aromatic L-amino acid decarboxylase (AADC) deficiency in newborns is “feasible” using dried blood spots and readily available equipment, allowing for earlier and more effective treatment, researchers report.

The study detailing this method, “Detection of 3-o-methyldopa in dried blood spots for neonatal diagnosis of aromatic l-amino-acid decarboxylase deficiency: the North-eastern Italian experience,” was published in the journal Molecular Genetics and Metabolism.

AADC symptoms typically appear within the first months after birth, leading to developmental delays and movement disorders. Available treatment options available work best the sooner they are given, making early diagnosis of AADC deficiency critical.

An investigative gene therapy by PTC Therapeutics, called PTC-AADC, that is now under review for approval in Europe, also shows best results when given at younger ages, “emphasizing the role of newborn screening (NBS) in early identification,” the study noted.

Because biomarkers for AADC deficiency are elevated in the cerebrospinal fluid of AADC patients, current tests for the disorder typically involve a spinal tap to collect that fluid. The disease can then be confirmed through genetic tests for mutations in the DDC gene or an analysis of AADC enzyme activity in plasma.

But several recent studies showed that one of these biomarkers, called 3-O-methyldopa (3-OMD), could be easily detected in dried blood samples collected from newborn infants. In their current study, a team of European scientists reported developing a fast and accurate test for 3-OMD using chemicals already found in newborn screening kits.

One of these chemicals, an amino acid called tyrosine, is structurally similar to 3-OMD, allowing scientists to detect it using some of the same lab tools used to detect tyrosine. The researchers reported that they could accurately measure the 3-OMD in a dried blood spot sample, with negligible variation between experiments.

They tested their method in an NBS program throughout northeastern Italy. The level of 3-OMD in newborns’ blood samples generally declined with age. On average, infants 2 to 3 days old had 1.50 umol/L of 3-OMD, those between 7 days and 1 year old had 1.19 umol/L of 3-OMD, and babies older than age 1 had 0.65 umol/L of 3-OMD.

By comparison, 3-OMD levels in a 25-year-old previously diagnosed with AADC deficiency were 10.51 umol/L.

In April 2020, the test was incorporated into an expanded NBS program in northeastern Italy, to gather more data and further refine the technique. At the time this report was written, 21,867 newborns had been screened using the test; none were diagnosed with AADC deficiency.

One newborn triggered a false positive test result on account of a high 3-OMD concentration due to the mother receiving L-dopa therapy. L-dopa accumulates inside the cells of those with AADC deficiency, where it is converted to 3-OMD.

“Adding the 3-OMD biomarker to NBS programs will allow estimation of AADC deficiency incidence in various populations to inform healthcare resource decisions,” the researchers wrote.

“Although our study is limited, introduction of our method in expanded neonatal screening is feasible and could facilitate deployment of screening, allowing for early diagnosis that is important for effective treatment,” they concluded.