The emerging spectrum of neurodevelopmental comorbidities in early-onset Spinal Muscular Atrophy

Spinal muscular atrophy (SMA) type 1, or early-onset SMA, is the most common and severe form of SMA 5q, an autosomal recessive neuromuscular disorder caused by bi-allelic deletions or pathogenic variants in the SMN1 gene. The resulting deficiency of the survival motor neuron (SMN) protein leads to degeneration of motor neurons in brainstem and spinal cord [1]. The median age of death is ∼12 months and most children do not survive into the second year of life if not on supportive care. In the last few years, three approved SMN-enhancing medications have dramatically improved the natural history of the disease, with most treated SMA 1 babies now surviving longer and a proportion achieving unprecedented motor milestones like sitting, standing, and walking with support [2]. However, much less is known about the neurodevelopment of these treated children. Recent reports on small cohorts of treated SMA 1 children, like that from Tosi et al. [3], have shown that most patients who underwent formal testing scored below average on cognitive and communication scales [3,4], although this was in some cases imputed to low gross motor function scores. While the observation of cognitive and communication defects contrasts with previous assumptions that SMA is a pure motor neuronopathy, this is in line with what many clinicians are observing now that most of these children are on treatment and therefore survive longer and can be followed in their overall development.