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Background Spinal muscular atrophy type 1 (SMA1) is a motor neuron disease associated with progressive muscle weakness, ventilatory failure, and reduced survival. Objective: To report the evaluation of the nusinersen, an antisense oligonucleotide, on the motor function of SMA1. Methods This was a longitudinal and observational study to assess the outcomes of nusinersen therapy in SMA1 patients using the HINE-2 and CHOP-INTEND scales. Results Twenty-one SMA1 patients (52.4% males) were included; the mean age at first symptoms was 2.7 months (SD =±1.5), and the mean disease duration at first dose was 34.1 (SD =±36.0) months. During posttreatment, the mean gain on the CHOP-INTEND was 4.9, 5.9, 6.6, and 14 points after 6, 12, 18, and 24 months, respectively. Starting medication with a disease duration of less than 12 months and/or without invasive ventilation were predictors of response on CHOP-INTEND. Of the patients, 28.6% acquired a motor milestone or gained at least three points on the HINE-2. The daily time for ventilatory support was reduced after treatment in most of the patients with noninvasive ventilation at baseline. No change in the daytime use of ventilation was observed in most of the patients using invasive ventilation at baseline. Conclusions Nusinersen produces improvements in motor and respiratory functions, even in long-term SMA1 patients. However, patients under invasive ventilation at the beginning of the treatment experience little benefit.

Background Spinal muscular atrophy (SMA) is a motor neuron disease associated with progressive muscle weakness and motor disability. Objective This study aims to report the evaluation of nusinersen, an antisense oligonucleotide, on motor function in patients with SMA types 2 and 3. Methods This single-center retrospective observational study assessed nusinersen therapy outcomes, measured by HSMFSE or CHOP-INTEND scales, in patients with SMA types 2 and 3, compared to untreated patients, for at least 24 months. Results In 30 patients with SMA types 2 and 3 (mean age: 10.6 years; 14 with SMA type 2) under nusinersen treatment, the mean change in HFMSE scores was +1.47 points (SD = 0.4) and +1.60 points (SD = 0.6) after 12 and 24 months of treatment, respectively. In contrast, the control group (N = 37) (mean age: 10.2 years; 20 with SMA type 2) presented a mean change of −1.71 points (SD = 0.02) and −3.93 points (SD = 0.55) after 12 and 24 months of follow-up, respectively. The most severe patients (N = 11) showed a change of +2.37 (SD = 1.13) on the CHOP-INTEND scale after 12 months of follow-up. Disease duration at the beginning of treatment was the main predictor of functional improvement. Despite functional gain and motor stabilization, treatment with nusinersen did not prevent the progression of scoliosis. Conclusions Our data provide evidence for the long-term safety and efficacy of nusinersen use in the treatment of later-onset SMA, and patients with shorter disease duration showed better response to treatment.

ObjectiveThe aim of the study was to report the proportion of homozygous and compound heterozygous variants in the survival motor neuron 1 (SMN1) gene in a large population of patients with spinal muscular atrophy (SMA) and to correlate the severity of the disease with the presence of specific intragenic variants in SMN1 and with the SMN2 copy number.MethodsFour hundred fifty Brazilian patients with SMA were included in a retrospective study, and clinical data were analyzed compared with genetic data; the SMN2 copy number was obtained by multiplex ligation-dependent probe amplification and pathogenic variants in SMN1 by next-generation sequencing.ResultsFour hundred two patients (89.3%) presented homozygous exon 7-SMN1 deletion, and 48 (10.7%) were compound heterozygous for the common deletion in one allele and a point mutation in the other allele. Recurrent variants in exons 3 and 6 (c.460C>T, c.770_780dup and c.734_735insC) accounted for almost 80% of compound heterozygous patients. Another recurrent pathogenic variant was c.5C>G at exon 1. Patients with c.770_780dup and c.734_735insC had a clinical phenotype correlated with SMN2 copy number, whereas the variants c.460C>T and c.5C>G determined a milder phenotype independently of the SMN2 copies.ConclusionsPatients with specific pathogenic variants (c.460C>T and c.5C>G) presented a milder phenotype, and the SMN2 copy number did not correlate with disease severity in this group.

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