Respiratory Trajectories in Type 2 and 3 Spinal Muscular Atrophy in the iSMAC Cohort Study

Abstract

Objective.To describe the respiratory trajectories and their correlation with motor function in an international paediatric cohort of patients with type 2 and non-ambulant type 3 spinal muscular atrophy (SMA).Methods.Eight-year retrospective observational study of patients in the iSMAc natural history study. We retrieved anthropometrics, forced vital capacity (FVC) absolute, FVC% predicted (FVC%P.), Non-Invasive ventilation (NIV) requirement. Hammersmith functional motor scale (HFMS) and Revised performance of upper limb (RULM) were correlated with respiratory function. We excluded patients in interventional clinical trials and on Nusinersen commercial therapy.Results.There were 437 patients with SMA: 348 type 2, 89 non-ambulant type 3. Mean age at first visit was 6.9(±4.4) and 11.1(±4) years. In SMA type 2 FVC%P declined by 4.2%/year from 5 to 13 years, followed by a slower decline (1.0%/year). In type 3 FVC%P declined by 6.3%/year between 8 and 13 years, followed by a slower decline (0.9%/year). 39% SMA type 2 and 9% type 3 required NIV at median age 5.0(1.8-16.6) and 15.1(13.8-16.3) years. 84% SMA type 2 and 80% type 3 had scoliosis, 54% and 46% required surgery, which did not significantly affect respiratory decline. FVC%P positively correlated with HFMS and RULM in both subtypes.Conclusions.In SMA type 2 and non-ambulant type 3 lung function declines differently, with a common levelling after age 13 years. Lung and motor function correlated in both subtypes. Our data further defines the milder SMA phenotypes and provides novel information to benchmark the long-term efficacy of new treatments for SMA.

Longitudinal changes in respiratory and upper limb function in a pediatric type III spinal muscular atrophy cohort after loss of ambulation

“…This respiratory function decline is in line with previous studies, but those studies included data mainly from type II patients 5,19 . Type II patients are considered more severely affected and yet their RULM scores are comparable with type III patients who have also lost ambulation 11,20 . The average FVC% decrease was a statistically significant 17% at 24 months.…”

“…These inconsistent descriptions are likely to complicate evaluation of treatment‐related clinical data and may in part be due to the limited scope of motor performance measures used in this group. Studies have suggested that SMA III individuals are less likely to develop scoliosis and have little respiratory muscle weakness compared with type II patients, yet newer evidence has shown respiratory complications in type III patients 1,6,11 . Nonambulant pediatric SMA III patients commonly develop contractures and scoliosis, which requires spinal fusion when the deformity is sufficiently severe 6 …”

Validation of motor and functional scales for the evaluation of adult patients with 5q spinal muscular atrophy

“…The convergent validity of FVC% has been previously assessed in a large cohort of SMA patients, mostly children. 39 This study confirms moderate correlations of FVC% with functional scales, albeit its discriminating ability and responsiveness was overall low. However, it may still be useful in non-sitters, in whom its responsiveness is higher and respiratory endpoints are particularly clinically meaningful.…”

“…The convergent validity of FVC% has been previously assessed in a large cohort of SMA patients, mostly children. 39 This study confirms moderate correlations of FVC% with functional scales, albeit its discriminating ability and responsiveness was overall All rights reserved. No reuse allowed without permission.…”

Pulmonary function testing in patients with neuromuscular disease

“…Similar to DMD, in spinal muscular atrophy (SMA) FVC is a viable parameter for longitudinal monitoring of progression in respiratory muscle weakness 6 . Baseline absolute FVC and FVC% predicted is lower in patients with SMA type 2 compared with patients with SMA type 3 and these decline between the ages of 5 and 13 years and more slowly thereafter 6–8 . In one of the largest and most comprehensive cohort studies of treatment—naïve patients with SMA, Wijngaarde et al 9 showed significant differences in baseline VC% predicted showed that the average rate of change in VC% predicted declined by 1.57% per year in type 2a, 1.65% in type 2b, and 1.06% in type 3a.…”