Spinal muscular atrophy: a motor neuron disorder or a multi‐organ disease?

Abstract

Spinal muscular atrophy (SMA) is an autosomal recessive disorder that is the leading genetic cause of infantile death. SMA is characterized by loss of motor neurons in the ventral horn of the spinal cord, leading to weakness and muscle atrophy. SMA occurs as a result of homozygous deletion or mutations in Survival Motor Neuron-1 (SMN1). Loss of SMN1 leads to a dramatic reduction in SMN protein, which is essential for motor neuron survival. SMA disease severity ranges from extremely severe to a relatively mild adult onset form of proximal muscle atrophy. Severe SMA patients typically die mostly within months or a few years as a consequence of respiratory insufficiency and bulbar paralysis. SMA is widely known as a motor neuron disease; however, there are numerous clinical reports indicating the involvement of additional peripheral organs contributing to the complete picture of the disease in severe cases. In this review, we have compiled clinical and experimental reports that demonstrate the association between the loss of SMN and peripheral organ deficiency and malfunction. Whether defective peripheral organs are a consequence of neuronal damage/ muscle atrophy or a direct result of SMN loss will be discussed.

Evidence for mast cells contributing to neuromuscular pathology in an inherited model of ALS

“…CNS microvascular pathology has been described in ALS (69) and could lead to local hypoxia further promoting recruitment of mast cells, as has been reported in ischemia-reperfusion of skeletal muscle (70). A similar microcirculation failure has been reported in other neuromuscular pathologies such as spinal muscle atrophy or muscular dystrophy (71,72).…”

Emerging therapies and challenges in spinal muscular atrophy

“…59, 60 For example, there is now experimental evidence suggesting a non‐cell‐autonomous contribution to motor neuron degeneration from astrocytes and Schwann cells 61, 62. Likewise, low levels of SMN in skeletal muscle have been implicated in SMA pathogenesis with significant disruption of the molecular composition of skeletal muscle evident in presymptomatic severe SMA mice in the absence of detectable changes in lower motor neurons 63.…”

Advances in Therapeutic Development for Spinal Muscular Atrophy

“…However, mice reach an SMN-refractory period after about 2 weeks of age where SMN depletion does not lead to early postnatal lethality, but much later in life abnormal NMJs are apparent [83]. While SMN is known to affect motor neurons, muscles and possibly other tissues are also affected independent of motor neuron defects [17,84]. Overall, these studies suggest that treatments for SMA patients should be given as early as possible to increase the SMN level and potentially ameliorate any abnormalities as much as possible.…”