Translating fatigability in spinal muscular atrophy to clinical trials and management

Fatigability and perceived fatigue are common and unrelated symptoms in spinal muscular atrophy (SMA). These symptoms distinguish this patient population from muscular dystrophies such as Duchenne muscular dystrophy and limb girdle muscular dystrophies, in which such symptoms are much less frequent. Fatigability is the decreased endurance to repeatedly perform functional motor tasks. It is measured using the 6-minute walk test (6MWT) by subtracting the distance walked in the sixth minute from the first minute. Perceived fatigue is a subjective feeling of tiredness and exhaustion. Numerous patient-reported outcome measures (PROMs) have been used to measure fatigue, such as the PedsQL Fatigue scale, the Multi-dimensional Fatigue Inventory (MFI), and the Ratings of Perceived Exertion (RPE), the latter of which was originally used to assess the perception of effort during a physical activity and subsequently became used as a proxy for fatigue. Using RPE, Cheng and colleagues make the important observation that perceived exertion is not associated with fatigability in SMA. Although a validated PROM for fatigability would be useful for clinical monitoring and research, this study suggests that RPE cannot be used as a surrogate for fatigability. The distinction between fatigability and perceived exertion suggests that these are different processes characterized by distinct pathophysiology in SMA. Distinguishing between the two may involve correlating with electrophysiology and/or muscle biopsy findings of mitochondrial enzyme activity. Neuromuscular junction dysfunction in SMA has been characterized by histology and also by electrophysiology. Fatigability, as measured by the 6MWT, correlates with neuromuscular junction dysfunction, as measured by repetitive nerve stimulation in type 3 SMA patients. Pyridostigmine is being tested in a clinical trial (SPACE trial) in The Netherlands on type 2 to 4 SMA patients. Mitochondria, which are involved in metabolism and energy production, are abnormal in SMA motor neurons and skeletal muscle. The mitochondrial protective agent olesoxime has been tested in clinical trials on type 2 and nonambulatory type 3 SMA patients, and results suggest that it may maintain motor function over 24 months. Perhaps to address perceived fatigue, albuterol, which has caffeine-like stimulant properties, continues to be prescribed to SMA patients even after the discovery of the three survival motor neuron (SMN) protein-augmenting innovative therapies. In addition, there are nuances to measuring perceived fatigue in SMA patients. Perceived fatigue as measured by the PedsQL Fatigue scale does not correlate with measures of motor function and may be confounded by obstructive sleep apnea, which is common in the adult population with SMA. Different types of perceived fatigue exist; the MFI measures general fatigue, physical fatigue, reduced activity, reduced motivation, and mental fatigue. Each of these measures may have different biological correlates. More robust and sensitive outcome measures for perceived fatigue and fatigability are needed for clinicians to better characterize our heterogeneous SMA population, predict response to treatment, and appropriately treat the patients most likely to respond. Measures would optimally be targeted to each patient group, as the etiology of fatigability and perceived fatigue may differ in children and adults; for example, the symptoms in children may be caused by neuromuscular junction dysfunction, whereas the symptoms in adults may be caused primarily by obstructive sleep apnea. In the era of innovative therapies, and to justify the costs of such expensive medicines, clinicians need first to prove treatment benefit in patients with SMA and second to have validated instruments to monitor therapeutic effects adequately over time. Motor function scales have captured remarkable and meaningful clinical improvement in treated infants and children with SMA. However, the same motor function scales show only stabilization or minimal clinical improvement in adults, who have more long-standing motor neuron loss and irreversible advanced disease. Nevertheless, treatment benefits are not trivial, and adults report more endurance and energy with treatment. Measures of perceived fatigue and fatigability probably could better measure clinical efficacy of treatment in this population. Other than PROMs, biomarkers relating to neuromuscular junction or mitochondrial dysfunction may be helpful. Clinical trials of drugs that target different pathways, particularly those that act on modulating the neuromuscular junction or mitochondrial pathways, should include reliable and validated outcome measures for perceived fatigue and fatigability.