Spinal Muscular Atrophy Added to Recommended Uniform Screening Panel

According to Secretary Azar’s summary in his July 2 letter of acceptance, the evidence review suggested that “early screening and treatment can lead to decreased mortality for individuals with SMA and improved motor milestones.”

“SMA can be detected through newborn screening, and treatment is now available that can not only reduce the risk of death, but decrease the development of neurologic impairment,” he said in an interview. “As with adding any condition to newborn screening, public health laboratories will need to develop strategies to incorporate the screening test. The current FDA-approved treatment, nusinersen, is delivered by lumbar puncture into the spinal fluid. In addition, there are exciting advances in gene therapy leading to new treatment approaches.”

Symptom Onset Distinguishes the Types of SMA

Approximately 95% of SMA cases result from the deletion of exon 7 from both alleles of SMN1. Other, rarer cases are caused by mutations in different genes. Without the SMN protein produced by SMN1, a person gradually loses muscle function.

A similar gene, SMN2, also can produce the SMN protein, but in much lower amounts—typically less than 10% of what a person needs. People can, however, have multiple copies of SMN2, which can produce slightly more SMN protein and slow the disease process.

The five types of SMA are determined according to symptom onset, which directly correlates with disorder severity and prognosis. Approximately 54% of SMA cases are Type I, in which progressive weakness occurs over the first six months of life and results in early death. Only 18% of children with Type I live past age 4, and 68% die by age 2. Type 0 is rarer, but more severe, usually causing fetal loss or early infant death.

Type II represents 18% of SMA cases and causes progressive weakness by age 15 months. Most people with Type II survive to their 30s but later experience respiratory failure and rarely reach their 40s. Individuals with Types III and IV typically have a normal lifespan and only begin to see progressive muscle weakness after age 1 or in adulthood.

Dr. Kemper’s group focused on the three types diagnosed in infancy: Types I, II, and III. “It will be critical to make sure that infants diagnosed with SMA through newborn screening receive follow-up shortly afterward to determine whether they would benefit from nusinersen,” said Dr. Kemper. “More information is needed about the long-term outcomes of those infants who begin treatment following newborn screening, so we not only know about outcomes in later childhood and adolescence, but treatment approaches can be further refined and personalized.”

Long-Term Data on Nusinersen Are Lacking

Nusinersen alters the splicing of precursor messenger RNA in SMN2 so that the mRNA strands are longer, which increases the amount of SMN protein produced. Concerns about the medication, however, have included its cost—$750,000 in the first year and $375,000 every following year for life—and potential adverse events from repeated administration. Nusinersen is injected into the spinal canal four times in the first year and once annually thereafter, and the painful injections require patient immobilization. Potential adverse events include thrombocytopenia and nephrotoxicity, along with potential complications from repeated lumbar punctures over time.²

Other concerns about the drug include its limited evidence base, lack of long-term data, associated costs with administration (eg, travel costs), the potential for patients taking nusinersen to be excluded from future clinical trials on other treatments, and ensuring parents have enough information on the drug’s limitations and potential risks to provide adequate informed consent.²