Spinal Muscular Atrophy: The Past, Present, and Future of Diagnosis and Treatment

Abstract

Spinal muscular atrophy (SMA) is a lower motor neuron disease with autosomal recessive inheritance. The first cases of SMA were reported by Werdnig in 1891. Although the phenotypic variation of SMA led to controversy regarding the clinical entity of the disease, the genetic homogeneity of SMA was proved in 1990. Five years later, in 1995, the gene responsible for SMA, SMN1, was identified. Genetic testing of SMN1 has enabled precise epidemiological studies, revealing that SMA occurs in 1 of 10,000 to 20,000 live births and that more than 95% of affected patients are homozygous for SMN1 deletion. In 2016, nusinersen was the first drug approved for treatment of SMA in the United States. Two other drugs were subsequently approved: onasemnogene abeparvovec and risdiplam. Clinical trials with these drugs targeting patients with pre-symptomatic SMA (those who were diagnosed by genetic testing but showed no symptoms) revealed that such patients could achieve the milestones of independent sitting and/or walking. Following the great success of these trials, population-based newborn screening programs for SMA (more precisely, SMN1-deleted SMA) have been increasingly implemented worldwide. Early detection by newborn screening and early treatment with new drugs are expected to soon become the standards in the field of SMA.

Spinal muscular atrophy type I associated with a novel SMN1 splicing variant that disrupts the expression of the functional transcript

“…At the same time, another group reported this variant for the first time ( 10 ) in Chinese patients. Intragenic variants usually account for 5% of SMA cases according to recent literature ( 1 , 9 , 25 ). With the two variants identified recently (the frameshift and the currently reported novel splice site), under the hypothesis that there are no other Cypriot cases that have been diagnosed by a foreign country centre, this percentage is ~19% in our population, which is probably much higher than in other populations To our knowledge, expect for a recent study in Brazil referring to a percentage of 10.7% of compound heterozygous intragenic variants identified by next generation sequencing without excluding the SMN2 interference ( 26 ), the reported percentages in other populations do not exceed 5% [i.e.…”

Autophagy in spinal muscular atrophy: from pathogenic mechanisms to therapeutic approaches

“…Various in vitro and in vivo models have been used to understand the molecular and cellular mechanisms underlying SMA pathogenesis ( Monani et al, 2000 ; Edens et al, 2015 ; O’Hern et al, 2017 ; Nishio et al, 2023 ). Although a detailed report on SMA pathogenesis is beyond the scope of this review, a few important aspects are discussed below.…”

Newborn Screening for Spinal Muscular Atrophy: A 2.5-Year Experience in Hyogo Prefecture, Japan

“…Spinal muscular atrophy (SMA) is a lower motor neuron disease with an autosomal recessive inheritance. Patients exhibit progressive muscular weakness and muscular atrophy [1]. The clinical forms of SMA are classified into five types, from type 0 to type IV, according to the timing of onset and motor developmental achievement.…”

“…Approximately 95% of patients have homozygous deletion of SMN1, and 5% of patients retain SMN1 with an intragenic mutation. The SMN2 gene, a paralog of SMN1, was recognized to be the disease-modifying gene for SMA, since an inverse correlation was observed between the SMN2 copy number and phenotype [1,2]. Hence, SMN2 copy number is used as a predictor of disease severity [3].…”