The study, “Neonatal screening for Pompe disease in Italy: long-term results and future challenges”, was published in the magazine Molecular Genetics and Metabolism Reports🇧🇷
Newborn screening or NBS involves testing babies shortly 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 the NBS in Italy
Over seven years, dried blood samples were collected from 206,741 newborns. Using a chemical analysis technique called tandem mass spectrometry, samples were evaluated for, among other factors, GAA enzyme activity.
Pompe disease is caused by mutations in the gene that encodes GAA.
Of all newborns screened, 39 babies (0.019%) tested positive at initial screening and were referred for confirmatory testing, including genetic analysis.
Three of these babies were diagnosed with infantile-onset Pompe disease (IOPD), with all three diagnoses confirmed within the first two weeks of life. Two newborns had a prenatal diagnosis of heart disease characteristic of IOP, while the three had elevated levels of markers of muscle damage in laboratory tests.
Patients with IDPI started enzyme replacement therapy (ERT), namely Lumizyme (alglucosidase alfa), between the 5th and 19th day of life. In two of these patients, cardiac function stabilized after a few months of ERT, and the infants showed age-typical motor development beginning around 1 year of age.
At the study publication, these children were 3.5 and 1.5 years old. Both are 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 evolution of the third child was more complicated due to the development of an immune response against ERT.
After receiving supportive anti-inflammatory therapy, this child was transferred to AT-GAA, an experimental treatment administered under compassionate use. Since this change, the child’s cardiac function has remained relatively stable, and although her motor function is lagging compared to normal, she can walk at 2.5 years of age.
Now 3.5 years old, this child is able to walk, eat and breathe independently, although researchers have noted that she has delayed language development and shows difficulty with relationships.
Another eight babies were diagnosed with late-onset Pompe disease (LOPD) after confirmatory testing. None of these children showed signs of heart problems at birth, as is typical with LOPD.
These eight children are being regularly evaluated for the development of Pompe symptoms. So far, with up to 5.5 years of follow-up, none of them have had symptoms and none have started ERT.
The researchers noted that the guidelines address the management of confirmed cases of symptomatic IOPD and LOPD.
However, “there is no consensus on the definition of ‘symptomatic’ LOPD,” they wrote.
“These guidelines should be revised based on new data available in cases of LOPD identified through NBS programs,” the researchers wrote. They particularly emphasized the need for better guidance on how to manage patients with LOPD who do not yet have symptoms.
In addition to these children, some family members of babies diagnosed with NBS were also later diagnosed.
For example, two older brothers who were born before the launch of the NBS program were also found to have Pompe disease.
“Our study, the largest reported so far in Europe, demonstrates that [Pompe] The NBS is feasible and readily extendable to the largest populations of Italian newborns,” the scientists concluded.
The rest of the patients who were NBS positive were not diagnosed with Pompe disease after the confirmatory test. Four of those babies were found to be Pompe carriers – meaning they won’t develop symptoms, but could pass on a disease-causing mutation to their children.
Others were found to have pseudodeficiency – a genetic variation known to cause a false positive on the screen – mutations not predicted to cause disease, or had 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 patients with LOPD who may never develop symptoms, as issues that will need to be addressed in the future.
“The high frequency of pseudodeficiency, ethical issues with early diagnosis of LOPD, and difficulty in predicting phenotypes based on biochemical parameters and genotypes, especially in LOPD, need further study,” concluded the team.