More work needed to understand SMA fatigue mechanisms: Review
More high-quality studies are needed to understand the mechanisms of fatigue in spinal muscular atrophy (SMA) and to identify which, if any, SMA therapies or interventions might be able to truly ease the common but often troublesome symptom.
That’s according to a new review study that found that “SMA fatigability is a major complaint” among people with the genetic condition — one that is “frequently reported in common daily activities and negatively impacts on the overall quality of life” of patients, the researchers wrote.
“The increasing awareness of fatigue as an important clinical constraint … particularly, in SMA, identifies it as [a] relevant research topic and a fundamental therapeutic target,” the team wrote.
Their review, “Fatigue in Spinal Muscular Atrophy: a fundamental open issue,” was published in Acta Myologica.
Motor tests are best for capturing effects of mechanisms of fatigue in SMA
In SMA, the progressive loss of nerve cells, which communicate with muscles to coordinate movement, leads to muscle weakness and wasting. Fatigue — referring to a constant lack of energy or easy burnout — also is a common complaint.
The intrusive symptom can significantly interrupt a person’s ability to go about daily activities like driving a wheelchair or eating, according to the authors. Still, the mechanisms that underlie fatigue in SMA — and the best way to treat it — are not fully understood.
“Further research is needed to better understand the specific effects of different … therapies on fatigue” in SMA, the researchers wrote.
According to the review, conducted by a team of researchers from Italy, fatigue in SMA presents as progressive reductions in motor responses during daily tasks like walking, using the upper limbs, and chewing.
The team noted that the physical aspects of fatigue, also referred to as performance fatigue, are best captured by clinical motor tests — like the six-minute walk test (6MWT) — as well as electrophysiological studies that look at muscle cell activity. As its name suggests, the 6MWT measures the distance a person can cover in six minutes of walking; it is commonly used to assess aerobic capacity and endurance.
Among SMA patients who retain their ability to walk, it has been shown that a person’s walking speed at the start of 6MWT is faster than it is by the end of the test — when the individual has become progressively more fatigued.
Correspondingly, electrophysiological studies demonstrate that muscle cells show lower and lower electrical responses with repeated input from a nerve cell, and that this diminished response strongly correlates with 6MWT performance.
Such diminished responses have been linked to muscle weakness associated with alterations at the neuromuscular junction, where nerve and muscle cells interact to coordinate voluntary movements.
Trying to measure the psychological facets of fatigue
Importantly, the researchers noted, it is hard to adequately measure the psychological aspects of fatigue, or how severely people perceive they are affected by fatigue.
Questionnaires designed to measure this don’t always align well with clinical performance observations, and researchers have indicated that they are “probably unfit to properly highlight fatigue in this condition,” the researchers wrote.
Indeed, analyses have indicated a need for more SMA-specific metrics for measuring perceived fatigue.
Interestingly, fatigue seems to be most commonly reported in SMA type 3 — though it’s not entirely clear why, given that “the underlying mechanisms that cause fatigue in SMA are not well understood,” the researchers wrote.
The team suggested that it might, in part, be because the available tools for measuring fatigue are better suited for these relatively less severely affected patients compared with those with more severe SMA types 1 and 2.
Moreover, “a greater impairment may be linked to a reduced overall functionality that may lead to a lower level of physical activity and, consequently, to lower fatigue,” the researchers wrote.
Trials needed to test treatments that can ‘really impact’ fatigue
Given the prevalence of fatigue in SMA and its substantial daily life impacts, as shown in the studies reviewed here, this symptom has been increasingly recognized as an important target for SMA medications and interventions.
Exercise programs to boost muscle strength have been proposed as a way of combating fatigue, but a consistent conclusion has not been reached as to their effectiveness.
Some — but not all — studies have found benefits with exercise in easing fatigue in SMA. Importantly, some types of exercise might make fatigue worse, some studies have shown. For example, a six-month endurance cycle training program was linked to worsening fatigue in one European study.
“As a whole, available data do not allow … safe conclusions on whether endurance or resistance type exercise is useful or not in SMA,” the researchers wrote. The team stressed that better quality studies are needed to identify optimal exercise interventions in SMA.
High quality experimental trials are needed to unravel whether therapies … are able to really impact … fatigability in … patients experiencing different levels of performance and perceived impairments.
Whether or not SMA medications have meaningful effects on fatigue also is still being unraveled.
One candidate that’s shown promise is a muscle strengthener called pyridostigmine, used to treat myasthenia gravis — an autoimmune disease that also leads to muscle weakness and fatigue. It has been shown in a small clinical trial to ease patient-reported fatigue and improve endurance among SMA patients.
“High quality experimental trials are needed to unravel whether therapies … are able to really impact … fatigability in … patients experiencing different levels of performance and perceived impairments,” the researchers concluded.
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