International BEST-CLI Collaborative: next steps to create a coordinated global initiative to improve awareness and access while reducing mortality and amputation for patients with chronic limb-threat

Spinal muscular atrophy (SMA) is a hereditary neurogenerative disease caused by mutations in the SMN gene. SMA is a progressive disease that causes muscle weakness of the muscles in the extremities and trunk. SMA varies widely in severity, and the incidence is estimated to be 1 in 10,000 live births globally. SMA has historically been classified into five subtypes depending on onset and achieved motor function. Type I is characterized by onset before 6 month of age, and untreated children with this type will not sit independently. Type II is characterized by onset between 6 and 18 months, and untreated children with this type will not stand and walk independently. Type III is characterized by onset after 18 months, often after the children have achieved independent ambulation. Type 0 and IV are rare forms. The symptoms vary in extent depending on time of onset, but involve muscle weakness, delayed and impaired motor function, scoliosis, respiratory problems, and affected bulbar muscles that impair orofacial functions, including deficits in voice, articulation and swallowing. With the introduction of disease modifying therapies, there has been a dramatic positive change in survival, achievement of motor function, and in the overall progression of the disease, and consequently the prior classifications are phased out. Three therapies aiming at restoring the SMN protein have been approved for treatment. They can be divided into two groups: gene therapy, where the defective SMN1 gene is replaced (Onasemnogene abeparvovec), and splicing modifiers of SMN2 (Nusinersen and Risdiplam). The three disease modifying therapies were approved by FDA and EMA from 2016–2021. The disease modifying therapies are now available worldwide – however, their availability can vary according to type of SMA, age, and legislation and insurance coverage of the specific country. With disease modifying therapies, many countries have introduced newborn screening to ensure early diagnosis and treatment which are paramount to achieve favorable outcomes for the child with SMA. The first disease modifying therapy for SMA in Denmark was approved for SMA type I and II in 2018, and in 2024 the treatment was approved for all types of SMA. Newborn screening for SMA was introduced in Denmark in 2023.