A small study aimed to increase the likelihood of detecting minor neurological symptoms of spinal muscular atrophy via a combination of tests specifically suited to newborns.
As the spinal muscular atrophy (SMA) treatment landscape has changed in recent years, diagnosing infants and initiating disease-modifying treatments as early as possible has become imperative. Neonatal screening has potential to identify more infants with SMA who do not have obvious signs of the condition, and a recent study published in the European Journal of Pediatrics combined 2 assessments to improve the likelihood of spotting early indicators of SMA in newborns.
SMA is a hereditary, autosomal neurodegenerative disease caused by mutations of the survival motor neuron 1 (SMN1) gene that inhibit sufficient SMN protein expression. While patients with SMA have at least 1 copy of the SMN2 gene, SMN2 does not produce enough fully functional SMN protein to offset SMN1 mutation.
Insufficient SMN protein production leads to muscle weakness and atrophy, limited mobility, respiratory problems, and other clinical symptoms depending on the severity of a patient’s case. It is a rare condition, and patients with SMA are stratified by symptom severity and time of onset. Infants typically show symptoms of the most severe neonatal form, type 1 SMA (SMA1), by 6 months of age.
With 3 FDA approvals for SMA therapies in recent years — nusinersen in 2016, onasemnogeneabeparvovec-xioi in 2019, and risdiplam in 2020 — it has become increasingly important to identify and treat patients as early as possible.
“Recent studies have clearly demonstrated that the use of these new therapeutic options in infants before the onset of symptoms leads to a dramatic reduction of the onset and severity of clinical signs with a magnitude of improvement much larger than that observed in patients who had already developed symptoms at the time of treatment,” study authors wrote.
But the tools currently used to diagnose SMA1, mainly the Hammersmith Infant Neurological Examination (HINE) or the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND), are only validated in older infants and could miss minor neurological signs in newborns. Evidence from current screening programs suggests that some infants are paucisymptomatic, showing only minor signs that quick or suboptimal neonatal checks may not identify.
Therefore, the current study used the Hammersmith Neonatal Neurological Examination (HNNE) and a module specifically designed for floppy infants to determine whether early neurological signs can be caught via more comprehensive neonatal screening.
A total of 17 patients were identified, all of whom were part of a pilot study of neonatal SMA screening in Italy. Each patient underwent an exam consisting of the HNNE and the module for floppy infants, which entailed sections on neurological characteristics, physical examination, and additional information such as antenatal history. Diagnoses were confirmed via blood testing to confirm SMN1 deletion and the number of SMN2 copies each patient had.
Of the 17 patients identified, 9 had normal results on both examination scales and were therefore considered asymptomatic at the time of examination, 3 had mild signs of neurological dysfunction and were considered paucisymptomatic, and 5 showed more obvious characteristics of SMA.
“Our results also confirmed that, even in the absence of obvious clinical signs, a number of infants classically defined as presymptomatic, may have isolated minimal signs, such as hypotonia, tongue fasciculations, and weak/absent reflexes,” the authors wrote.
SMN2 copy number was associated with neurological signs of SMA in this cohort. The only infant with type 0 SMA (antenatal onset with severe symptoms at birth) had 1 SMA copy, whereas infants with 3 or more SMN2 copies mostly showed normal results with both the HNNA and floppy infant module. However, patients with 2 copies of SMN2 had variable clinical signs of SMA, which is in line with previous studies.
Although the cohort was relatively small, the results suggest that a combination of the HNNE and floppy infant module increases the likelihood of identifying early neonatal signs of SMA. The hope is that using these tools could also help determine subtle or obvious early neurological symptoms that might be predictive of therapeutic outcomes.
Pane M, Donati MA, Cutrona C, et al. Neurological assessment of newborns with spinal muscular atrophy identified through neonatal screening.Published online May 6, 2022. Eur J Pediatr. doi:10.1007/s00431-022-04470-3