Study Examines Newborn Screening for Lysosomal Storage Diseases in Taiwan

A multiplex test using a drop of dried blood can be used to screen newborns for eight different lysosomal storage diseases, including Sanfilippo syndrome, a new study shows.

The study, “Newborn screening for Morquio disease and other lysosomal storage diseases: results from the 8-plex assay for 70,000 newborns,” was published in the Orphanet Journal of Rare Diseases.

Lysosomal storage diseases are characterized by impairments in lysosomal enzymes. These can be thought of as cells’ recycling machinery; they are used to break down certain types of molecules so the parts can be re-purposed. The lack of these enzymes in lysosomal storage diseases leads to the abnormal buildup of substrates (the molecules that usually get broken down), which can be toxic to body tissues.

For some lysosomal storage diseases, such as Pompe disease, there are available enzyme replacement therapies (ERTs), which, as their name suggests, involve replacing the impaired lysosomal enzyme by external administration. Similar approaches are being investigated for Sanfilippo syndrome, with one such ERT, called BMN 250 (NAGLU-IGF2), currently being tested in a Phase 1/2 clinical trial (NCT02754076).

This approach can be beneficial, but often, damage done to systems like the skeleton and nervous system is irreversible, remaining even after ERT. As such, it is widely believed that starting such treatments at the earliest possible time will lead to maximal clinical benefit.

This necessitates newborn screening, so that lysosomal storage diseases can be detected early — often before the onset of symptoms — and prompt treatment can begin.

The Newborn Screening Center at the National Taiwan University Hospital (NTUH) performs newborn screening for about a third of the children born in Taiwan — as estimated 70,000 newborns per year. The first lysosomal storage disease screen implemented was for Pompe disease in 2005.

Then, a four-plex assay, which simultaneously tested for Pompe disease, Gaucher disease, Fabry disease, and Mucopolysaccharidosis (MPS) type I, was implemented in 2015. This was expanded to an eight-plex assay, which tested for four additional mucolipidoses, in 2018. Among the added conditions were MPS type 3 (Sanfilippo syndrome) and MPS type 4a (Morquio syndrome).

This test is done using a drop of dried blood, which can be collected easily from newborns via a heel prick. Conceptually, it works by measuring the ability of enzymes in the blood to break down various substrates; if one of the substrates isn’t broken down as much as normal, it is indicative of an enzymatic deficiency.

The new study reports data for 73,743 newborns who were screened with this test at NTUH from March 2018 to April 2019. Overall, 99.3% of these had normal enzyme activity, in keeping with the relative rarity of lysosomal storage diseases.

For newborns who did have low enzyme levels on initial screen, generally, second samples were requested to confirm the result. For newborns found to have a treatable lysosomal storage disease, such as Pompe or Gaucher disease, ERT was initiated early in life.

In total, 23 newborns were determined to have lysosomal storage disease, an overall incidence of one in 3,206 newborns. Of these, there were three instances of Sanfilippo syndrome (one in 24,581 newborns).

After the initial screening, there were 70 newborns with low enzyme activity associated with Morquio syndrome. A secondary assay revealed 12 still presented low enzyme activity and subsequent clinical examination revealed six of these to have Morquio syndrome — a frequency of one in 12,291. This is a higher rate than previous estimates.

Researchers believe that newborn screening using dry blood spots is feasible to measure the relevant enzymatic activity for all eight lysosomal storage diseases tested.

However, they caution that there is the need for “careful patient follow-up in cases detected by newborn screening, where later-onset symptoms are predicted, and the full understanding of pseudodeficiencies is still needed. Thus, the long-term follow-up of these infants will be essential to understand the phenotypes detected by newborn screening fully.”