Mortality of symptomatic children with spinal muscular atrophy in the era of disease-modifying therapies.

With the availability of novel disease-modifying therapies (DMT), survival in spinal muscular atrophy (SMA) has significantly increased, but mortality is not rare in severely affected cases. To improve care further, we aimed to characterise causes of mortality in children with SMA over the last five years since the introduction of DMT. This was a retrospective review of all patients with SMA registered on SMA REACH UK database, who died between 2019 and 2023. In the last 5 years, 533 patients were registered with SMA REACH (6 pre-symptomatic; 1-SMA0; 247-SMA1; 188-SMA2; 91-SMA3). Twenty-five paediatric patients with SMA died in this period: 1 SMA0(4 %;1 copy-SMN2), 20 SMA1(80%;17 patients-2 copies of SMN2 and 1 with 3 copies of SMN2) and 4 SMA2(16%). In SMA 1 cohort, 7/20(35%) patients were treatment naïve (5 ineligible; 1 died prior to commencement; 1 declined). Twelve patients received nusinersen; median age at treatment initiation of 6 months (range:1 month-12.3 years old) and median treatment duration of 6 months (range:1 month-6.5 years). One patient switched from nusinersen to risdiplam at age 4 years (died 19 months later) and 1 received onasemnogene abeparvovec at 2 years old (died 10 months later). The median age of death was 10.5 months(range:8 weeks-13 years), and 80%(16/20) died from respiratory-related causes. In SMA 2 cohort, 2/4 patients were not eligible for DMT and one received risdiplam at age 13 years for duration of 2.7 years and died as result of traumatic brain injury. The median age of death was 18 years 4 months (range:16-21 years). Two deaths were respiratory-related and one of sudden cardiac arrest. In conclusion, over the last 5 years, 5% of SMA patients registered with SMA REACH died. The majority had symptomatic SMA1 with 2 SMN2 copies at the severe end of the spectrum and were either treatment naïve or had initiation of DMT after significant disease progression. Respiratory-related deaths occurred in 72% of known causes of death. Standard of care for respiratory management and ceiling of care discussions should continue to be a key part of the overall management particularly in those with severe disease at onset. These outcomes will be considerably improved once newborn screening will be available also in the UK.