[Natural history of spinal muscular atrophy type I]

Spinal muscular atrophy (SMA) is a group of genetically heterogeneous neuromuscular diseases characterized by the progressive loss of motor neurons in the anterior horns of the spinal cord. The prevalence of SMA is approximately 1 in 10.000 live births. The cause of SMA is a mutation in the SMN1 gene, which encodes a neuronal survival protein. The phenotype of the disease depends on the number of copies of the SMN2 gene, which encodes an unstable isoform of the same protein. Despite the emergence of new drugs that increase SMN protein levels, there remains a need to collect and systematize data on the natural history of the disease to evaluate the effectiveness of new therapeutic approaches. This review analyzed the results of 12 retrospective and prospective studies over the past 16 years, which examined the natural history of the disease in 646 children with SMA type I. The mean age of onset of symptoms was 2.1±0.7 months, with the first documented symptoms being muscle hypotonia, respiratory distress, and feeding difficulties. The mean age at death was 19.2±10.1 months, the median age at achievement of the composite endpoint (defined as death or the date of initiation of long-term respiratory support) was 7.7 months (95% CI 3.8; 13.9). For 310 children, the number of copies of the SMN2 gene was known, 81.5% of them had 2 copies, 3.7% had 1 copy, 14.5% had 3 copies, 0.3% had 4 copies. Age at death varied according to SMN2 gene copy number, children with three copies of the SMN2 gene lived on average significantly longer than children with two copies of SMN2 (22.7 months versus 6.6 months). Life expectancy was also positively influenced by the use of maintenance therapy, tracheostomy or gastrostomy.