The frequency with which spinal muscular atrophy (SMA) is found in newborns may be lower than previously thought, according to one-year data from an SMA screening program in the state of New York.
Based on expected disease frequency, the program anticipated that 20 to 38 of the more than 225,000 newborns screened would have tested positive for the neuromuscular disease, but only eight babies were identified as having SMA.
Results from other state screening programs underway will help to better assess SMA’s actual frequency in the U.S., the researchers said.
The study, “Implementation of population-based newborn screening reveals low incidence of spinal muscular atrophy,” was published in the journal Nature: Genetics in Medicine.
Spinal muscular atrophy is the most common genetic cause of death in infants and children, with an estimated frequency of between 1 in every 6,000 and 1 in every 11,000 births.
In most cases (95%–98% of all incidences), it is caused by the complete loss of exon 7 in the SMN1 gene, which affects the production of SMN, a protein essential for muscle health. Exons are the sections of a gene that contain instructions for protein production.
The existence of a second SMN gene, called SMN2, partly compensates for the loss of SMN1-produced SMN. Typically, the more SMN2 gene copies a person has, the less severe the disease.
SMA is inherited in an autosomal recessive manner, meaning a child must acquire two mutated copies of the SMN1 gene — one from the father and one from the mother — to develop the disease. People with only one defective SMN1 copy will not have this disease but will be carriers, meaning they can pass the mutation to their children.
Given the approval of a first SMA treatment — Spinraza, by Biogen — in late 2016, the findings of a pilot SMA newborn screening study in New York state, and the importance of early detection and treatment in preventing lifelong disability, SMA was added to the U.S. Recommended Uniform Screening Panel (RUSP) for newborns in 2018.
As of March, 19 states were screening all newborns for SMA, and others either had legislation pending or were running pilot screening programs. To date, none of these states have reported on SMA frequency based on their screening programs.
Newborns are screened for SMA via a genetic test that checks for the absence of exon 7 in both SMN1 copies. In some states, such as New York, the program also includes assessing SMN2 copy number in infants screening positive for SMA.
Researchers looked at data from Oct. 1, 2018, through Sept. 30, 2019 — the first full year of the New York state’s SMA newborn screening program.
Of the 225,093 infants screened, eight carried exon 7 deletions in both copies of SMN1. Three of these babies had two copies of SMN2 (likely to develop SMA type 1, a severe form), three had three copies (likely to develop type 2 or 3 disease), and two had at least four copies (likely to develop SMA type 3 or 4).
All infants were asymptomatic at diagnosis, and seven were treated with Zolgensma (by AveXis, a subsidiary of Novartis) — an SMA gene therapy approved in May 2019 — including two babies (with two and three SMN2 copies) initially treated with Spinraza.
All continued to show no symptoms of the disease at a last follow-up (ranging from two to 12 months). One infant with at least four SMN2 copies was not treated, and “is being carefully monitored long-term for signs predictive of disease onset,” the researchers wrote.
None of the parents had reported knowing of a family history of SMA.
The team noted that, based on current SMA incidence estimates, 20 to 38 newborns were expected to screen positive for SMA among newborns in New York, a number far above the eight positive infants found.
The New York program had an SMA frequency of 1 in 28,137 births (range of 1 in every 14,259 to 55,525 births), which was between 2.6 and 4.7 times lower than expected (1 in 6,000 to 11,000 births).
Including data collected through the end of February — 15 positive cases among some 314,000 newborns screened — the resulting frequency was still low, about 1 in 21,000 births, the team noted.
This low SMA frequency, it added, cannot be solely attributed to the 2%–5% of SMA patients missed by newborn screening, due to other SMA-causing mutations than exon 7 deletion.
Instead, this discrepancy is likely due to imprecise or biased estimates (most are based on small European populations that may not be representative of the U.S. population), as well as better “informed reproductive decisions” such as “increased awareness, access to and uptake of carrier screening, genetic counseling, cascade testing, prenatal diagnosis, and advanced reproductive technologies,” the researchers wrote.
Longer-term data from this and other screening programs “will shed light on the true incidence” of SMA in the U.S., they added.
They also recommended strongly that screening programs continue, and expand across states.
“SMA newborn screening ensures equity in diagnosis of a common genetic condition in infants, such that affected children of families who cannot or choose not to undergo carrier screening … are universally afforded the same benefit of new, life-saving treatments that are most effective when identified prior to symptom onset,” the researchers wrote.
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