Newborn screening for Pompe disease is feasible on a large scale and may facilitate early treatment with better outcomes for children with childhood-onset disease, according to a new Italian study, the largest of its kind in Europe.
I study, “Newborn screening for Pompe disease in Italy: long-term results and future challenges”, was published in the magazine Relationships of molecular genetics and metabolism.
Newborn screening or NBS involves testing babies soon after birth for genetic disorders such as Pompe disease.
In Italy, a newborn screening program for Pompe and related disorders was established in 2015. In this study, researchers shared their experiences during the program and set goals for its future.
Evaluating NBS in Italy
Over the course of seven years, dried blood spot samples were collected from 206,741 newborns. Using a chemical analysis technique called tandem mass spectrometry, the samples were evaluated for GAA enzyme activity, among other factors.
Pompe disease is caused by mutations in the gene that codes for GAA.
Of all newborns screened, 39 infants (0.019%) tested positive at initial screening and underwent confirmatory testing, including genetic analysis.
Three of these infants were eventually diagnosed with infantile-onset Pompe disease (IOPD), with all three diagnoses confirmed within the first two weeks of life. Two infants had a prenatal diagnosis of heart disease characteristic of IOPD, while all three had elevated levels of muscle damage markers in laboratory tests.
Patients with IOPD started enzyme replacement therapy (ERT), namely Lumizyme (alglucosidase alfa), between day 5 and day 19 of life. In two of these patients, cardiac function stabilized after a few months of ERT, and the children showed age-typical motor development starting from approximately 1 year of age.
At the time of publication of the study, these children were 3.5 and 1.5 years old. They are both still on ERT with no problems and “have age-appropriate motor development with no signs of cardiomyopathy [heart disease] and normal biochemical tests,” the researchers reported.
The third child’s course was more complicated due to the development of an immune response against ERT.
After receiving supportive anti-inflammatory therapy, this child was switched to AT-GAA, an investigational treatment that was given for compassionate use. After this switch, the child’s heart function remained relatively stable, and although his motor function is delayed from typical, he could be walking by age 2.5 years.
Now, at age 3.5, this child is able to walk, eat and breathe on his own, though researchers have noted that he has delayed language development and exhibits difficulties with relationships.
Eight other children were diagnosed with late-onset Pompe disease (LOPD) following confirmatory testing. None of these babies showed signs of heart problems at birth, as is typical of LOPD.
These eight children are routinely evaluated for the development of Pompe symptoms. So far, with up to 5.5 years of follow-up, none of them have yet shown symptoms and none have started ERT yet.
The researchers noted that the guidelines address the management of confirmed cases of IOPD and symptomatic LOPD.
However, “there is no consensus on the definition of ‘symptomatic’ LOPD,” they wrote.
“These guidelines should be revised based on newly available data on LOPD cases identified through NBS programs,” the researchers wrote. They particularly stressed the need for better guidance on how to manage LOPD patients who are not yet showing symptoms.
In addition to these children, some family members of children diagnosed via NBS were also subsequently diagnosed.
For example, two older brothers born before the launch of the NBS program also had Pompe disease.
“Our study, the largest so far reported in Europe, demonstrates this [Pompe] NBS is feasible and easily extendable to the largest Italian newborn populations,” concluded the scientists.
The rest of the NBS-positive patients were ultimately not diagnosed with Pompe disease after confirmatory testing. Four of these children were found to be Pompe carriers, which means they will not develop symptoms, but could pass a disease-causing mutation to their children.
Others have been found to have pseudodeficiency — a genetic variation known to cause a false positive on screen — mutations not predicted to cause disease or mutations whose clinical relevance is uncertain.
The researchers highlighted the relatively high number of false positive rates, as well as the lack of guidance for LOPD patients who may never develop symptoms, as issues that will need to be addressed in the future.
“The high frequency of pseudodeficiency, the ethical issues with early diagnosis of LOPD, and the difficulty of predicting phenotypes based on biochemical parameters and genotypes, especially in LOPD, warrant further study,” the team concluded.