The work suggests that this method could be successfully implemented in other states and countries to provide highly specific and sensitive detection of X-ALD in newborns.
The study, “Evaluation of X-Linked Adrenoleukodystrophy Newborn Screening in North Carolina,” was published in the journal JAMA Network Open.
X-ALD is a rare disorder caused by mutations in the ABCD1 gene located on the X chromosome, one of the two sex chromosomes that play a part in determining gender. These mutations result in the toxic build-up of very-long-chain fatty acids (VLCFAs) and related molecules, called C26:0-lysophosphatidylcholine (LPC) and C24:0-LPC. This accumulation occurs in several tissues and organs, but mainly affects the brain and the adrenal glands (small hormone-producing glands located above the kidneys).
Since men have only one X chromosome, those who inherit a mutated ABCD1 gene will develop the disease, while in women — who have two X chromosomes — a healthy ABCD1 gene copy partly compensates for a mutated one. Women with a mutated copy of the ABCD1 gene are called X-ALD carriers, and usually develop none of the symptoms or milder symptoms of the disease, with age as a major risk factor.
X-ALD is asymptomatic at birth, and it is not possible to predict which of the three types of X-ALD — childhood cerebral adrenoleukodystrophy, adrenomyeloneuropathy, and Addison’s disease — the child will develop.
Thus, newborn screening is crucial to identify children carrying a genetic predisposition for X-ALD — who should undergo regular exams for neurological signs — and ALD carriers.
In the U.S., X-ALD is part of the Recommended Uniform Screening Panel, meaning that it is included in the list of genetic disorders to be screened in newborns.
Newborn screening for X-ALD is usually a three-part process, including two tests to check, and then confirm, the presence of high levels of C26:0-LPC in dried blood spots from newborns. A genetic test is then used to confirm the presence of mutations in the ABCD1 gene for a final diagnosis.
In the study, researchers in North Carolina developed a potential new method of X-ALD newborn screening that relies on a single test to detect the presence of high levels of VLCFAs. It is based on a powerful method, called high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS), which separates all the molecules in a sample and detects their levels with a high degree of specificity and sensitivity.
This new approach analyzes the levels not only of C26:0-LPC, but also of C24:0-LPC in dried blood spots, increasing its diagnostic power.
The researchers tested this method in a newborn screening pilot study that included 52,301 dried blood spot samples from newborns in North Carolina. Confirmatory tests assessing VLCFA levels and the presence of ABCD1 mutations were conducted in newborns testing positive for high levels of C26:0-LPC and C24:0-LPC.
Results showed that the new screening method detected high levels of C26:0-LPC and C24:0-LPC in 12 newborns. Confirmatory testing identified a genetic disorder in eight of them: three boys had X-ALD, three girls were X-ALD carriers, one girl had a peroxisome biogenesis disorder, and another girl had Aicardi-Goutières syndrome.
Boys with X-ALD showed high levels of both C26:0-LPC and C24:0-LPC, suggesting that assessing the levels of C24:0-LPC in addition to C26:0-LPC is a valuable strategy to identify newborns with X-ALD or other VLCFA-related disorders. The researchers emphasized, however, that C24:0-LPC should not be considered the primary marker in X-ALD newborn screening.
The other four newborns with a positive test (among the 12 identified) included three girls who were considered unaffected (classified as having false-positive results), and one boy with indeterminate results on confirmatory testing.
“The positive predictive value for X-ALD or other genetic disorders for the [single]-tier assay was 67%, with a false-positive rate of 0.0057%,” the researchers wrote.
These results revealed an estimated X-ALD frequency of one in 8,717 births in North Carolina, which was slightly higher than that observed by the New York NBS program and lower than that reported by the Minnesota NBS program.
Overall, the team said that the data supports the successful implementation of this simpler, faster method based on dried blood spots to screen newborns for X-ALD in a public health program, with minimal risk to the population.
“The findings will support other state laboratories planning to implement newborn screening for X-ALD and related disorders,” the researchers wrote.
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