Natural history of lung function in spinal muscular atrophy

Abstract

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.

Long-term follow-up of patients with type 2 and non-ambulant type 3 spinal muscular atrophy (SMA) treated with olesoxime in the OLEOS trial

“…OLEOS patients demonstrated a steady decline in FVC/TC during the study, which has also been reported looking at % estimated FVC values in untreated patients of this age range with Types 2 and 3 SMA [48] . However, FVC/TC values appeared more stable in older patients ( > 15 years) with Type 3 SMA in OLEOS.…”

The Identification of Novel Biomarkers Is Required to Improve Adult SMA Patient Stratification, Diagnosis and Treatment

“…The motor abilities can be monitored by a variety of measurements, spanning from scales assessing the general mobility or muscle function, to the more global walking analysis. Respiratory function is also frequently assessed in adult SMA patients, as respiratory failure is still the most frequent cause of morbidity in SMA patients [ 25 ]. In this section, we are documenting functional outcomes to assess (i) general mobility; (ii) motricity of the upper or lower limbs, in conjunction with muscle strength or fatigue; (iii) level of ambulation; and (iv) respiratory function in adult SMA patients.…”

“…Difficulty to cough can contribute to a reduced clearance and facilitate the onset of respiratory infections. This decline in the respiratory function is associated with mortality and morbidity in SMA patients of all types [ 14 , 25 ]. For this reason, many efforts have been devoted in the last few years to the search for appropriate parameters to assess this function.…”

“…The natural history study of lung function in SMA patients, reported by Wijngaarde et al [ 25 ], analyzed the Forced Expiratory Volume in 1 second (FEV ) in a cohort of 170 patients SMA types 1c to 4. Using these data, the authors were able to build age-dependent models of the evolution of this measure for 131 patients—subtypes 1c to 3b.…”

Relative hyperventilation in non-ventilated patients with spinal muscular atrophy

“…Reduced lung function in SMA is probably the most important cause of morbidity and mortality in patients with SMA [ 1 , 6 , 7 ] and is caused by a rather unique pattern of weakness that predominates in the intercostal muscles and relatively spares the diaphragm [ 8 ]. Both inefficient secretion clearance, leading to recurrent respiratory tract infections and lung damage, as well as hypoventilation, can occur from an early age [ 6 , 9 ].…”