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Page last updated 28th November 2022

For information on the symptoms and support, see our page: Distal SMA.

Distal SMA is caused by mutations in several different genes, by far the best studied of which is called GARS1. Mutations in GARS1 cause distal SMA type-V (also known as dSMA-V), which results in muscle weakness and wasting predominantly in the hands and feet due to deterioration of the connections between motor neurons and muscles1. In addition to motor symptoms, mutations in GARS1 can also affect the sensory nerves, impairing their ability to detect stimuli in the external environment. When this happens, there will be a diagnosis of Charcot-Marie-Tooth disease type 2D (CMT2D), as opposed to dSMA-V1.

Despite mutations in GARS1 being very rare, many studies have used flies and mice to model distal SMA and CMT2D in order to better understand how the mutations cause deterioration of the motor and sensory nerves2-5. These studies and others have led to the development of several treatment strategies that have proven beneficial in animal models6-8.

However, the most promising therapeutic approach to treat GARS1 mutations that affect motor and sensory nerves came from a large, collaborative approach from several different groups across the world9-10. Through studying fly and mouse models, an important mechanism was identified that links the GARS1 mutations to the symptoms observed in patients. These findings allowed the researchers to identify a treatment strategy, in which a key protein was increased throughout the body, that was able to fully treat both the flies and mice modelling GARS1 mutations9-10. It is very likely that this therapeutic approach can be adapted to a virus-mediated gene therapy that may prove beneficial to patients in the future.

1. Antonellis et al. (2003) Glycyl tRNA synthetase mutations in CMT2D and dSMAV. Am J Hum Genet 72: 1293-1299.

2. Seburn et al. (2006) An active dominant mutation of glycyl-tRNA synthetase causes neuropathy in a Charcot-Marie-Tooth 2D mouse model. Neuron 51: 715-726.

3. He et al. (2015) CMT2D neuropathy is linked to the neomorphic binding activity of glycyl-tRNA synthetase. Nature 526: 710-714.

4. Niehues et al. (2015) Impaired protein translation in Drosophila models for Charcot–Marie–Tooth neuropathy caused by mutant tRNA synthetases. Nat Comm 6: 7520.

5. Sleigh et al. (2017) Trk receptor signaling and sensory neuron fate are perturbed in human neuropathy caused by Gars mutations. Proc Natl Acad Sci U S A 114: E3324-E3333.

6. Benoy et al. (2018) HDAC6 is a therapeutic target in mutant GARS-induced Charcot-Marie-Tooth disease. Brain 141: 673–687.

7. Morelli et al. (2019) Allele-specific RNA interference prevents neuropathy in Charcot-Marie-Tooth disease type 2D mouse models. J Clin Invest 129: 5568–5583.

8. Ozes et al. (2021) AAV1.NT-3 gene therapy in a CMT2D model. Brain Commun 3: fcab252.

9. Spaulding et al. (2021) The integrated stress response contributes to tRNA synthetase–associated peripheral neuropathy. Science 373: 1156–1161.

10. Zuko et al. (2021) tRNA overexpression rescues peripheral neuropathy caused by mutations in tRNA synthetase. Science 373: 1161–1166.