Background: Respiratory muscle weakness is an important feature of spinal muscular atrophy (SMA). Progressive lung function decline is the most important cause of mortality and morbidity in patients. The natural history of lung function in SMA has, however, not been studied in much detail. Results: We analysed 2098 measurements of lung function from 170 treatment-naïve patients with SMA types 1c-4, aged 4-74 years. All patients are participating in an ongoing population-based prevalence cohort study. We measured Forced Expiratory Volume in 1 s (FEV 1), Forced Vital Capacity (FVC), and Vital Capacity (VC). Longitudinal patterns of lung function were analysed using linear mixed-effects and non-linear models. Additionally, we also assessed postural effects on results of FEV 1 and FVC tests. In early-onset SMA types (1c-3a), we observed a progressive decline of lung function at younger ages with relative stabilisation during adulthood. Estimated baseline values were significantly lower in more severely affected patients: %FEV 1 ranged from 42% in SMA type 1c to 100% in type 3b, %FVC 50 to 109%, and %VC 44 to 96%. Average annual decline rates also differed significantly between SMA types, ranging from − 0.1% to − 1.4% for FEV 1 , − 0.2% to − 1.4% for FVC, and + 0.2% to − 1.7% for VC. In contrast to SMA types 1c-3a, we found normal values for all outcomes in later-onset SMA types 3b and 4 throughout life, although with some exceptions and based on limited available data. Finally, we found no important differences in FVC or FEV 1 values measured in either sitting or supine position. Conclusions: Our data illustrate the longitudinal course of lung function in patients with SMA, which is characterised by a progressive decline in childhood and stabilisation in early adulthood. The data do not support an additional benefit of measuring FEV 1 or FVC in both sitting and supine position. These data may serve as a reference to assess longer-term outcomes in clinical trials.

The aim of this study was to document upper leg involvement in spinal muscular atrophy (SMA) with quantitative MRI (qMRI) in a cross‐sectional cohort of patients of varying type, disease severity and age. Thirty‐one patients with SMA types 2 and 3 (aged 29.6 [7.6‐73.9] years) and 20 healthy controls (aged 37.9 [17.7‐71.6] years) were evaluated in a 3 T MRI with a protocol consisting of DIXON, T2 mapping and diffusion tensor imaging (DTI). qMRI measures were compared with clinical scores of motor function (Hammersmith Functional Motor Scale Expanded [HFMSE]) and muscle strength. Patients exhibited an increased fat fraction and fractional anisotropy (FA), and decreased mean diffusivity (MD) and T2 compared with controls (all P < .001). DTI parameters FA and MD manifest stronger effects than can be accounted for the effect of fatty replacement. Fat fraction, FA and MD show moderate correlation with muscle strength and motor function: FA is negatively associated with HFMSE and Medical Research Council sum score (τ = −0.56 and −0.59; both P < .001) whereas for fat fraction values are τ = −0.50 and −0.58, respectively (both P < .001). This study shows that DTI parameters correlate with muscle strength and motor function. DTI findings indirectly indicate cell atrophy and act as a measure independently of fat fraction. Combined these data suggest the potential of muscle DTI in monitoring disease progression and to study SMA pathogenesis in muscle.

Objective:We assessed longitudinal patterns of muscle strength, motor function and maximal compound muscle action potential amplitudes (CMAPMAX) in older patients with spinal muscular atrophy (SMA), hypothesizing a continued decline of motor function parameters throughout life.Methods:We measured muscle strength (Medical Research Council, MRC), motor function (Hammersmith Functional Motor Scale Expanded (HFMSE) and Motor Function Measure (MFM)), and CMAPMAX in treatment-naïve patients. We used both longitudinal and cross-sectional data in mixed-models to analyze natural history patterns.Results:We included 250 patients with SMA types 1c–4. Median patient age at assessment was 26.8 years, the number of assessments per patient ranged from 1 to 6. Baseline muscle strength and motor function scores differed significantly between SMA types, but annual rates of decline were largely similar and mostly linear. HFMSE floor effects were present for all patients with SMA type 1c, and adolescents and adults with types 2 and 3a. CMAPMAX differed significantly between SMA types, but did not decline significantly with increasing age. Muscle strength correlated very strongly with motor function (τ > 0.8), but only moderately with CMAPMAX (τ ≈ 0.5–0.6).Conclusion:Muscle strength and motor function decline in older patients with SMA are constant without periods of slower progression or a plateau phase. The floor effects of the HFMSE preclude its use for long-term follow-up of adult patients with SMA types 1c–3a. Muscle strength sum scores represent an alternative, feasible outcome measure for adolescent and adult patients with SMA.