Study Addresses Dilemmas Regarding Newborn Screening and SMA Treatment

As newborn screening for spinal muscular atrophy (SMA) becomes more common, ethical dilemmas will arise about the best treatment strategy for individuals with four copies of the SMN2 gene, a new study contends.

The study, “Infants Diagnosed with Spinal Muscular Atrophy and 4 SMN2 Copies through Newborn Screening – Opportunity or Burden?” was published in the Journal of Neuromuscular Diseases.

SMA is caused by a lack of the protein survival motor neuron (SMN). This protein is encoded by two genes: SMN1 and SMN2. Mutations in SMN1 underly the development of SMA, as this gene produces most of the SMN protein; the SMN2 gene can make SMN protein, too, but less so (about 10–15%) and is a shorter version of the protein, so it typically cannot compensate for the lack of SMN1. Spinraza (nusinersen), an approved SMA treatment, works by increasing the ability of the SMN2 gene to make the SMN protein.

An individual can have varying numbers of copies of the SMN2 gene, and this greatly affects the course of the disease. (People with fewer copies generally have more severe disease.) In about 3–11% of patients with four SMN2 copies an intermediate SMA type 2 phenotype is observed.

“Most patients with 4 and more copies of SMN2 develop either type 2 or type 3 SMA,” the researchers wrote, adding that some of those patients will show no SMA symptoms despite having SMN1 mutations. “Most of these patients have 3–5 SMN2 copies and other known but separate SMA modifiers as well,” they explained.

Some individuals with four or more copies of SMN2 will develop SMA type 4. In those individuals, symptoms typically appear later in life (usually after age 35).

Nowadays, as SMA treatments have become available, accumulating data suggests that it is best to start treatment before symptoms develop. This has led to the implementation of newborn screening programs — the idea being that individuals can be identified shortly after birth, then treatment can be started soon after, maximizing effectiveness.

But this raises an ethical quandary in patients with four copies of the SMN2 gene: “The risk of potential irreversible loss of motor neurons has to be balanced against the costs and risks of a possibly unnecessary treatment,” the researchers wrote.

“There is an ongoing discussion about the management of children detected by NBS with 4 and more copies of SMN2 (…) [T]he American SMA NBS [newborn screening] Multidisciplinary Working Group recommended applying a strict follow-up strategy in these patients, well knowing that the overwhelming majority of patients with 4 and more SMN2 copies are expected to develop a loss of motoneurons which could be prevented by early treatment,” they added.

Researchers now discussed the limitations and medical and ethical issues associated with these recommended procedures, based on their experience with a newborn screening program in Germany, which screened 278,970 infants from January 2018 to November 2019. Of those, 38 lacked functional SMN1.

The number of SMN2 copies was identified in 37 individuals, and 15 of them (40%) had four copies of SMN2 (none had more than four). This relatively high frequency “emphasizes the necessity for a rational decision” in terms of treatment strategies, the researchers noted.

For those 15 families, it was suggested that regular follow-up, with routine examinations of nerve and muscle function, be implemented. The researchers detailed several cases that “highlight the specific challenges in this group.”

For example, one child started showing signs of muscle weakness at the age of eight months, which progressed until they were unable to bear any weight on their legs. The child was started on treatment with Spinraza, leading to improvements; the child was able to walk with assistance by the age of 17 months.

Another child had a family history of SMA (an aunt with SMA type 3). “Based on the knowledge about the impact of SMA in daily life, the family was not willing to accept solely a strict-follow up strategy,” the researchers wrote. As such, the child was started on Spinraza at 6 months of age, in the absence of symptoms.

In two other children, older siblings (who had not been screened as newborns) developed muscle weakness during follow-up and were found to have SMA. The siblings were started on treatment accordingly.

Other children either continued to receive receive regular follow-up, or their families elected not to participate.

Overall, the researchers concluded, “[T]here is still an ongoing discussion about the best strategy in SMA children with 4 copies of the SMN2 gene. (…) Up to now, a strict follow-up strategy still can be justified. Nevertheless, compliance problems, decisions based on personal experience of families and the fact that the prognosis of part of the children might be worsened by this strategy, will presumably modify this strategy in the future.”