Results of the first year of newborn screening for X-linked adrenoleukodystrophy (X-ALD) in Minnesota showed that the birth prevalence of the disease is five times greater than previously anticipated, and confirms the benefits of adding X-ALD to the routine newborn screening program.
The X-ALD newborn screening program not only identified the disease in 14 infants at a very early stage before symptoms onset, but also enabled doctors to detect the disease in 41 family members of these children, who remained undiagnosed until then.
The study “A report on state‐wide implementation of newborn screening for X‐linked Adrenoleukodystrophy” was published in the American Journal of Medical Genetics.
X-ALD is a rare disorder affecting mostly males, with an overall estimated incidence in the U.S. of about one in 17,000 births, and one in 21,000 males.
The disease is caused by mutations in the ABCD1 gene, which result in excess accumulation of very long-chain fatty acids (VLCFAs), especially in the brain and adrenal glands. That leads to progressive damage to the brain and/or the hormone-producing adrenal glands.
Most males with X‐ALD develop primary adrenal insufficiency (a condition in which the adrenal glands do not produce adequate amounts of steroid hormones), and about 35% develop childhood cerebral ALD (CALD). That condition is marked by progressive loss of intellectual capacities, as well as vision, hearing, and motor deterioration.
Men who do not develop childhood disease will, in most cases, develop adrenomyeloneuropathy (AMN) later in life, characterized by difficulty walking, a progressive weakness and stiffness in the legs, and a loss in the ability to coordinate muscle movements.
ALD is asymptomatic at birth, and it is not possible to predict whether a child will develop the more severe form of the disease, CALD, or AMN during adulthood.
As such, newborn screening is crucial to identify children carrying a genetic predisposition for ALD, and those who should undergo regular exams for neurological signs.
In the U.S., New York became the first state to include X-ALD in its routine newborn screening program in 2013.
In the study, researchers analyzed the results from the first year of universal newborn screening for X-ALD in Minnesota, the fourth state to enact such screening in 2017.
A newborn screening test for ALD includes a first test to check if the infant has high levels of VLCFA, using a blood sample taken from the newborn’s heel. A genetic test is then used to confirm the presence of mutations in the ABCD1 gene, and achieve a final diagnosis.
Data showed that among 67,836 infants screened, 14 infants (nine males, five females) were positive for the disease based on VLCFA levels.
In 12 of these infants, initial genetic testing confirmed the presence of X-ALD in three newborns. In five others, likely disease-causing ABCD1 mutations were identified, while four infants carried variants of uncertain significance. In those latter infants, and two others who did not undergo genetic testing, family history helped reach a final diagnosis of X-ALD.
As a result, all 14 infants who tested positive in the initial screening were confirmed to have the disease.
This corresponds to a birth prevalence of X-ALD of one in 4,845 in the overall population, and one in 3,878 males — more than five times higher than reported previously.
After analyzing the family history of each infant, 17 male and 24 female relatives also were diagnosed with X‐ALD. These family members presented clinical manifestations, including two males and seven females who reported mild neuropathy symptoms, and a young boy who had CALD and adrenal insufficiency.
Researchers noted fewer cases of CALD and adrenal insufficiency than expected in male family members (5.9% of males for both), compared to prior observations.
“Together, these findings suggest that the spectrum of X‐ALD may be broader than previously described, and that milder cases may previously have been underrepresented,” researchers wrote, adding that “X-ALD was much more common than anticipated.”
According to the team, other issues that the universal newborn screening program identified were the high frequency of ABCD1 variants of uncertain significance, and the inability to predict disease severity.
“Overall, adding X‐ALD to Minnesota’s newborn screening program proved immediately beneficial. Not only were a high number of probands [cases] detected and placed on a monitoring protocol, but a number of affected family members were also subsequently detected, including one young male with early, clinically‐silent cerebral disease, and adrenal insufficiency” researchers wrote.
“With the higher anticipated birth prevalence and subsequent detection and diagnosis of numerous family members, thoughtful planning and coordination by specialists will be imperative for successful implementation of population‐based screening for X‐ALD,” they concluded.
