Japanese SMA Screening Program Could Help Speed Therapy

Still, investigators say there are gaps in spinal muscular atrophy (SMA) screening protocol that need to be filled.

New therapies have helped to improve outcomes for patients with spinal muscular atrophy (SMA), but those treatments are most effective when patients are receive their diagnosis and are treated early in the disease course.

In a new article in Molecular Genetics and Metabolism Reports, Japanese investigators described their experience with a new newborn screening program in that country and discussed ways to improve outcomes in SMA.

People with SMA have a mutation in the SMN1 gene that results in a deficiency of survival motor neuron proteins, which in turn causes progressive symmetrical limb and trunk paralysis, explained the authors. The disease is classified based on severity and age of onset. While patients with older-onset forms of the disease (types 3 and 4) can experience a normal life expectancy, those with type 1 typically get their diagnosis before 6 months of age; these patients are unable to sit upright, require a ventilator, and typically die before the age of 2.

With the arrival of new SMA therapies—including nusinersen (Spinraza), onasemnogene abeparvovec (Zolgensma), and risdiplam (Evrysdi)—has come a new urgency to identify people with SMA as soon as possible, since early treatment is most effective if it begins before symptoms arise, the authors wrote.

Many countries have started newborn screening programs to quickly identify infants with SMA. A real-time polymerase chain reaction (PCR) test has been developed that can detect the disease in most cases. Japan has joined that list of countries, with many regions setting up screening programs. The new study is based on the first year of the screening program in Kumamoto Prefecture, where the program launched in February 2021.

By January 2022, 13,587 newborns had been screened for SMA 4 to 6 days after birth as part of the program. One case of SMA was identified. The patient had no apparent abnormalities at birth and no family history of SMA. Yet, genetic evidence affirmed that he was likely to develop the disease, and so the infant was started on onasemnogene abeparvovec at age 42 days. Just before treatment, he had a score of 48 of 64 on the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND). By age 11 months, the child was able to stand by himself, had normal motor development, and had a CHOP-INTEND score of 60, the investigators said.

They noted that previous research suggests that the incidence of SMA in Japan is roughly 1 in 20,000 live births, but the experience in Kumamoto Prefecture suggests the actual incidence may be higher. Even with the new screening program, the investigators said it is unlikely that every infant with SMA will be identified. They said 96% of people with SMA have a homozygous deletion of SMN1 exon 7, but others have compound heterozygosity for SMN1 exon 7 deletion and other mutations that might not be identified by the PCR test.

“Therefore, it is important to understand that screening that targets SMN1 exon 7 is not likely to detect 5% of the patients with SMA,” they wrote.

The investigators also noted that although onasemnogene abeparvovec is the preferred SMA therapy because it acts fast and is cost-efficient, the therapy is only shipped from the United States and Europe and can take 10 to 14 days from its order date to be delivered. During that time, symptoms could begin to develop.

Nusinersen is more easily available in Japan, they said, and it can be administered ahead of onasemnogene abeparvovec, which may help ensure patients do not progress while waiting for the latter therapy.

Reference

Sawada T, Kido J, Sugawara K, et al. Newborn screening for spinal muscular atrophy in Japan: one year of experience. Mol Genet Metab. 2022;32:100908. doi:10.1016/j.ymgmr.2022.100908