Newborn Screening for Pompe in Italy Reports Successful Outcomes Over 7 Years, Large-scale Program Has Helped ID, Treat Babies

Newborn screening for Pompe disease is feasible at a large scale and can facilitate early treatment with better outcomes for babies with infantile-onset disease, according to a new study from Italy — the largest of its kind in Europe.

The study, “Newborn screening for Pompe disease in Italy: Long-term results and future challenges,” was published in the journal 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 laid out goals for its future.

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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 assessed for, among other factors, the activity of the GAA enzyme.

Pompe disease is caused by mutations in the gene coding for GAA.

Of all the screened newborns, 39 babies (0.019%) tested positive on the initial screen and were referred for confirmatory testing, including genetic analysis.

Three of these babies were ultimately 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 IOPD, while all three had elevated levels of muscle damage markers in lab tests.

The IOPD patients were started on enzyme replacement therapy (ERT), namely Lumizyme (alglucosidase alfa), between day 5 and day 19 of life. In two of these patients, heart function stabilized after a few months of ERT, and the babies showed age-typical motor development starting around the age of 1 year.

As of the study’s publication, these children were 3.5 and 1.5 years old. They’re both still on ERT without issue, and they “have age-appropriate motor development with no signs of cardiomyopathy [heart disease] and normal biochemical testing,” the researchers reported.

The third child’s course was more complicated due to the development of an immune response against the ERT.

After receiving supportive anti-inflammatory therapy, this child was switched to AT-GAA, an experimental treatment that was given under compassionate use. Since this switch, the child’s heart function has remained relatively stable, and although his motor function is delayed compared with what’s typical, he could walk by age 2.5 years.

Now age 3.5, this child is able to walk, eat, and breathe independently, although the researchers noted that he has delayed language development and shows difficulty with relationships.

Another eight babies were diagnosed with late-onset Pompe disease (LOPD) following confirmatory testing. None of these children showed signs of heart problems at birth, as is typical of 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 yet shown symptoms, and none have yet started on ERT.

The researchers noted that the guidelines address the management of confirmed IOPD and symptomatic LOPD cases.

However, “there is no consensus on the definition of ‘symptomatic’ LOPD,” they wrote.

“These guidelines should be revised based on new data available on LOPD cases identified through NBS programs,” the researchers wrote. They particularly stressed a 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 babies diagnosed via NBS were subsequently also diagnosed.

For example, two older siblings who had been born before the NBS program was launched were found to also have Pompe disease.

“Our study, the largest reported to date in Europe, demonstrates that [Pompe] NBS is feasible and readily extendable to the larger Italian newborn populations,” the scientists concluded.

The rest of the patients who were positive on the NBS were ultimately not diagnosed with Pompe disease after confirmatory testing. Four of these babies were found to be carriers of Pompe — meaning they won’t develop symptoms, but could pass 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 LOPD patients who may never develop symptoms, as issues that will need to be addressed going forward.

“The high pseudodeficiency frequency, ethical issues with early LOPD diagnosis, and difficulty predicting phenotypes based on biochemical parameters and genotypes, especially in LOPD, need further study,” the team concluded.

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