Abstract
Spinal muscular atrophy (SMA) is an autosomal recessive genetic disorder leading to paralysis, muscle atrophy, and death. Significant advances in antisense oligonucleotide treatment and gene therapy have made it possible for SMA patients to benefit from improvements in many aspects of the once devastating natural history of the disease. How the depletion of survival motor neuron (SMN) protein, the product of the gene implicated in the disease, leads to the consequent pathogenic changes remains unresolved. Over the past few years, evidence toward a potential contribution of gastrointestinal, metabolic, and endocrine defects to disease phenotype has surfaced. These findings ranged from disrupted body composition, gastrointestinal tract, fatty acid, glucose, amino acid, and hormonal regulation. Together, these changes could have a meaningful clinical impact on disease traits. However, it is currently unclear whether these findings are secondary to widespread denervation or unique to the SMA phenotype. This review provides an in-depth account of metabolism-related research available to date, with a discussion of unique features compared to other motor neuron and related disorders.
Highlights
In Spinal muscular atrophy (SMA), a homozygous deletion or point mutation in the Survival motor neuron 1 (SMN1) gene leads to loss of survival motor neuron (SMN) production from this gene [4]
These changes in the pancreas are thought to contribute to the development of non-alcoholic fatty liver disease (NAFLD) in Smn2B/− mice, as hyperglucagonemia and increased CREB phosphorylation could be driving a surge of energetic substrates in the bloodstream [31]
Advances in this area were generated in preclinical models of SMA, where most discoveries have been made, with some translational studies corroborating many of the basic research findings in human patients
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Spinal muscular atrophy (SMA) is a degenerative neuromuscular disease of the lower motor neurons in the anterior horn of the spinal cord. It should be noted that a clear mechanism linking SMN depletion and the various metabolic abnormalities is currently lacking Such defects could have serious clinical implications for SMA patients. The “2B/- model” (Smn2B/ − ) contains an engineered three-nucleotide substitution mutation within the exon splice enhancer in exon 7 of the mouse Smn gene and has a median survival of 28 days [45]. This comprehensive review aims to highlight the current evidence concerning metabolic dysfunction in SMA. We put forward some speculative mechanisms to explain the SMA metabolic presentation and provide future avenues of research in this area
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