Nerve function tests may help track response to SMA treatment in babies
Testing could assess disease in presymptomic infants diagnosed via screening
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- Nerve function tests can track disease activity and treatment response in presymptomatic infants diagnosed with SMA via newborn screening.
- Such testing revealed differing disease severity among infants based on underlying genetics when standard motor exams could not.
- Following treatments such as Zolgensma, both nerve function and motor scores generally showed meaningful improvements.
In infants diagnosed via newborn screening with spinal muscular atrophy (SMA), measures of nerve function may be a useful way to quickly evaluate disease activity and track how these young patients respond to SMA treatments.
That’s according to a new U.S. study, which found that results of tests of nerve activity vary based on underlying genetics — even when measures of motor function are indistinguishable.
When using nerve function tests, “serial … measurements demonstrated significant longitudinal changes following treatment, … supporting the potential value of electrophysiological monitoring in the era of [new] disease-modifying therapies,” the researchers wrote.
The scientists say their work shows that the results of such tests can provide “markers of [disease] severity in presymptomatic newborns with SMA.” Newborn screening, the team noted, can diagnose infants with the genetic disease before the first symptoms manifest, allowing for earlier treatment.
The study, “Compound muscle action potential amplitudes in newborn screen positive spinal muscular atrophy,” was published in the journal Clinical Neurophysiology.
SMA is a genetic disorder chiefly caused by mutations in the SMN1 gene, which provides instructions to make the protein SMN. People with SMA don’t produce enough SMN, which results in the death of motor neurons, the nerve cells that control movement.
A second gene called SMN2 also provides instructions to make this protein, but due to a quirk of the genetic sequence, much less SMN is produced from this gene. Still, SMN2 can act as a partial backup when SMN1 is faulty. As such, people with SMA who have extra copies of the SMN2 gene typically have less severe disease.
More babies now diagnosed earlier due to newborn screening
Newborn screening involves testing all babies for SMA and other medical conditions soon after birth. Such testing can allow children with SMA to be diagnosed and start treatment before they begin developing symptoms. This type of screening is now standard in all 50 U.S. states and many other parts of the world.
Still, the researchers noted that signs of SMA “during the presymptomatic phase [remain] difficult to quantify, underscoring the need for objective, noninvasive, feasible, reproducible, and sensitive biomarkers capable of detecting early disease progression.”
In this study, six scientists from four U.S. states examined whether motor function tests could identify such markers. The team analyzed compound muscle action potential (CMAP) measurements in 21 babies diagnosed with SMA via newborn screening in the state of Georgia. CMAP basically is a measure of electrical activity where a motor neuron signals a muscle cell to move.
Among the infants, 11 had two copies of the SMN2 gene, and 10 had three copies of this backup gene. After being diagnosed, all of these babies underwent CMAP tests in the hand and lower leg. Each was also assessed with a standardized measure of motor function called the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders, or CHOP-INTEND.
At the initial assessment, CHOP-INTEND scores were comparable among the children regardless of whether they had two or three copies of the SMN2 gene, the results showed.
CMAP measurements, however, indicated significantly worse nerve function in babies with two copies of the backup gene compared with those with a third copy.
“Our study demonstrated statistically significant lower CMAP amplitudes in presymptomatic infants with two SMN2 copies versus those with three SMN2 copies identified through the State sponsored SMA newborn screening program,” the researchers wrote.
According to the team, “these findings are clinically relevant because baseline [initial] neurological examinations and CHOP-INTEND scores were unable to distinguish between the two versus three SMN2 copies number patients.”
Additionally, the scientists noted that CMAP results “were often available before confirmatory genetic testing results, providing additional objective information during the initial clinical evaluation of newborn screen-positive SMA infants.” These findings suggest that nerve function tests can help complement the genetic testing used to confirm the diagnosis after a positive newborn screen.
Nerve function tests show gradual changes over time
After their diagnosis, all of the children in this study were given the gene therapy Zolgensma (onasemnogene abeparvovec-xioi), which delivers a working copy of SMN1 to the body’s cells. It is one of a number of disease-modifying treatments approved for SMA in the last decade. Among these babies, Zolgensma was sometimes given in combination with other SMA treatments.
Following treatment, both CMAP and CHOP-INTEND scores generally improved. However, the researchers noted that while CMAP values tended to show gradual changes over time, most patients hit the maximum score on CHOP-INTEND, making it impossible to track further changes using this measure of motor function.
A total of 15 infants (88%) achieved developmental milestones expected for their age at the time of their first follow-up visit, and were able to sit independently by about age 6.5 months. By an average age of 1.5 years, 11 (65%) were able to stand and walk without assistance. All toddlers with two SMN2 copies had delayed motor milestones, the data showed.
“The observed relationships between CMAP amplitudes, SMN2 copy number, and motor functions support a potential role for CMAP measurements as an [add-on] tool in disease assessment,” the researchers wrote, adding that “this may be particularly valuable in infants identified through newborn screening, in whom overt clinical manifestations are frequently absent and functional assessments may offer limited discrimination.”
Overall, according to the team, “these findings suggest that [measures of nerve electrical activity] provide additional information regarding motor neuron involvement and disease severity in presymptomatic infants identified through newborn screening.” As such, nerve function tests may help assess disease activity and monitor treatment response, the researchers noted.
Still, “future prospective studies incorporating larger cohorts, standardized assessment protocols … and longer follow-up periods are needed to validate these observations,” the team concluded.
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