Type 1 spinal muscular atrophy without treatment is a disease in which most children die or need permanent ventilation before their second birthday, and none sit unaided. The FIREFISH open-label extension reports five-year outcomes in the 62 children enrolled at 1 to 7 months of age with two SMN2 copies, across 17 centres in 12 countries. Fifty-five continued into the three-year extension and 52 (84%) completed five years of treatment.
Survival first, because it is the outcome that reframes the disease: 56 children (90%) were alive at year 5, and 50 (80%) were alive without permanent ventilation. In the pivotal-dose group of 58, 17 (29%) needed no respiratory support at all and 13 (22%) had never been hospitalised during the study.
Motor function improved and then held. By year 5, 36 children (62%) could sit unsupported for at least 5 seconds and 34 (59%) for 30 seconds. Mean CHOP-INTEND score rose from 22.47 at baseline to around 50 and plateaued, with 29 children (50%) scoring 50 or above. Four children (7%) could stand without support and six (10%) were cruising; none walked independently. Mean HINE-2 score rose from 0.93 at baseline to 14.22 by year 4 and stayed there.
The bulbar outcomes deserve as much attention as the motor ones, because they determine daily life. Forty-two children (72%) still fed orally and 46 (79%) retained swallowing — meaning most of these children were not tube-fed, which is not the natural history of this condition.
The safety picture is dominated by infection, and it is not incidental. Pneumonia occurred in 31 children (50%) and was the commonest serious adverse event, affecting 28 (45%). Pyrexia and upper respiratory infection were near-universal. These children survive with substantial residual weakness, and respiratory infection remains the thing that kills them. For Indian practice, where newborn screening for SMA is not routine and diagnosis is often made after significant motor loss, the message is about timing: these outcomes come from starting treatment between 1 and 7 months of age. The window matters more than the drug. Alongside it, aggressive respiratory prophylaxis — immunisation, physiotherapy, early treatment of chest infection — is not an optional extra.
- Push for early genetic diagnosis; these outcomes come from treatment started at 1 to 7 months of age.
- Set expectations honestly: most children sit, few stand, none walked independently at five years.
- Bulbar function is largely preserved — most children continued to feed and swallow orally.
- Plan intensive respiratory prophylaxis; pneumonia affected half the cohort and was the main serious adverse event.
- Motor gains accrued over years 1 to 4 and then plateaued, so counsel families about a ceiling rather than continued improvement.
The statistics, in plain English
This is an open-label extension with no control group, so every comparison is against the historical natural history of untreated type 1 spinal muscular atrophy rather than against a randomised comparator. That is legitimate here because the untreated course is so uniformly poor that a 90% five-year survival cannot be explained by selection or secular improvement. Two cautions on the numbers: the confidence intervals reported are 90% rather than the usual 95%, and denominators shift between analyses — survival is reported for all 62 enrolled, while motor outcomes come from the 58 on the pivotal dose. Children who died or withdrew cannot contribute to motor scores, which flatters later time points.
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