Treatment of spinal muscular atrophy with Onasemnogene Abeparvovec in Switzerland: a prospective observational case series study.

BACKGROUND: Spinal muscular atrophy (SMA) is a rare neuromuscular disorder leading to early death in the majority of affected individuals without treatment. Recently, targeted treatment approaches including Onasemnogene Abeparvovec (OA) were introduced. This study describes the first real-world experience with OA in Switzerland. METHODS: Prospective observational case series study using data collected within the Swiss Registry for Neuromuscular Disorders from SMA patients treated with OA. Development of motor, bulbar and respiratory function, appearance of scoliosis, and safety data (platelet count, liver function, and cardiotoxicity) were analyzed. RESULTS: Nine individuals were treated with OA and followed for 383 ± 126 days: six SMA type 1 (of which two with nusinersen pretreatment), one SMA type 2, and two pre-symptomatic individuals. In SMA type 1, CHOP Intend score increased by 28.1 from a mean score of 20.5 ± 7.6 at baseline. At end of follow-up, 50% of SMA type 1 patients required nutritional support and 17% night-time ventilation; 67% developed scoliosis. The SMA type 2 patient and two pre-symptomatically treated individuals reached maximum CHOP Intend scores. No patient required adaptation of the concomitant prednisolone treatment, although transient decrease of platelet count and increase of transaminases were observed in all patients. Troponin-T was elevated prior to OA treatment in 100% and showed fluctuations in 57% thereafter. CONCLUSIONS: OA is a potent treatment for SMA leading to significant motor function improvements. However, the need for respiratory and especially nutritional support as well as the development of scoliosis must be thoroughly evaluated in SMA type 1 patients even in the short term after OA treatment.

Impact of respiratory tract infections on spinal muscular atrophy with focus on respiratory syncytial virus infections: a single-centre cohort study.

AIMS OF THE STUDY: Spinal muscular atrophy (SMA) is a degenerative neuromuscular disorder leading to muscle hypotonia, weakness, and respiratory and bulbar impairment. Infants with SMA have an increased risk of respiratory tract infections (RTI) including severe respiratory syncytial virus (RSV) infections. Therefore, guidelines for the treatment of SMA recommend RSV prophylaxis with palivizumab for patients aged below two years who have compromised motor functions ("non-sitters"). Since palivizumab is not approved for RSV prophylaxis in SMA patients in Switzerland, payers usually do not grant cost approvals for this indication. Therefore, this study aimed to investigate the frequency of severe RTI among SMA patients focusing on RSV infections requiring hospital treatment and to determine the long-term impact of RSV infections on the natural history of SMA. METHODS: A single-centre cohort study at the tertiary paediatric Neuromuscular Centre Zurich, Switzerland, including data of SMA patients with a genetic-based therapy initiated below two years of age between May 2019 and December 2022. All hospitalisations were analysed with a focus on severe RTI and especially RSV infections, and their impact on nutritional and respiratory function. The costs of inpatient treatment of RSV infections were determined and compared with estimated expenses for RSV prophylaxis with palivizumab. RESULTS: 12 SMA patients (median age at treatment initiation: 3.5 months, range: 0-17 months) were followed for a cumulative period of 25.75 years (7 SMA type 1; 5 SMA type 2 including one presymptomatic individual). With an incidence rate of 2.34 per patient-year, the risk of severe RTI was especially high in SMA type 1 (versus 0.1 in SMA type 2, p = 0.044). A total of 37 hospitalisations (279 hospital days) was necessary for the treatment of RTI in general; 9 of them were attributed to RSV infections (in 5 SMA type 1 patients; 84 hospital days). Only 3/12 SMA patients had received seasonal RSV prophylaxis with palivizumab. No RSV infections requiring hospital treatment occurred in patients while receiving seasonal RSV prophylaxis. During RTI, nutritional support had to be commonly initiated and continued after discharge. In 3/7 SMA type 1 patients, non-invasive ventilation was started during acute treatment for RTI and continued to the end of follow-up. CONCLUSION: We observed a high risk of RTI, especially RSV infections, among young SMA patients. Failure to adhere to established care protocols, for example by omitting RSV prophylaxis, may be linked to a heightened risk of morbidity in these children.

A Multicenter Cross-Sectional Study of the Swiss Cohort of LAMA2-Related Muscular Dystrophy.

Background: LAMA2-related muscular dystrophy (LAMA2-RD) is an autosomal-recessive disorder and one of the most common congenital muscular dystrophies. Due to promising therapies in preclinical development, there is an increasing effort to better define the epidemiology and natural history of this disease. Objective: The present study aimed to describe a well-characterized baseline cohort of patients with LAMA2-RD in Switzerland. Methods: The study used data collected by the Swiss Registry for Neuromuscular Disorders (Swiss-Reg-NMD). Diagnostic findings were derived from genetics, muscle biopsy, creatine kinase-level and electrophysiological testing, as well as from brain MRIs. Further clinical information included motor assessments (CHOP INTEND, MFM20/32), joint contractures, scoliosis, ophthalmoplegia, weight gain, feeding difficulties, respiratory function, cardiac investigations, EEG findings, IQ and schooling. Results: Eighteen patients with LAMA-RD were included in the Swiss-Reg-NMD as of May 2023 (age at inclusion into the registry: median age 8.7 years, range 1 month - 31 years F = 8, M = 10). Fourteen patients presented with the severe form of LAMA2-RD (were never able to walk; CMD), whereas four patients presented with the milder form (present or lost walking capability; LGMD). All patients classified as CMD had symptoms before 12 months of age and 11/14 before the age of six months. 15 carried homozygous or compound heterozygous pathogenic or likely pathogenic variants in LAMA2 and two were homozygous for a variant of unknown significance (one patient unknown). Brain MRI was available for 14 patients, 13 had white matter changes and 11 had additional structural abnormalities, including cobblestone malformations, pontine hypoplasia and an enlarged tegmento-vermial angle not reported before. Conclusion: This study describes the Swiss cohort of patients with LAMA2-RD and gives insights into measuring disease severity and disease progression, which is important for future clinical trials, as well as for a better clinical understanding and management of patients with LAMA2-RD.