Skip to content
Page last updated : 22nd January 2025

 

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

Distal SMA is caused by mutations in several different genes, but by far the best studied is GARS1. Mutations in GARS1 cause distalSMA 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 is 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 nerves2-7. These studies and others have led to the development of several treatment strategies that have proven beneficial in the animal models8-11.

These approaches have several common themes – the first is correction of an important process that occurs in nerve cells known as axonal transport. Axonal transport ensures that different substances are delivered throughout nerve cells to ensure that they function properly12. This process is known to go wrong in dSMA-V models, hence why correcting it has been a focus of research. The second theme is supporting muscles and nerves through delivery of survival molecules that are produced by muscles. Boosting the availability of these supportive molecules has a positive impact on the nervous system. A final successful strategy has been to target and degrade the mutant protein that causes the disease; by reducing the production of the disease protein, the symptoms become less severe.

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 world13-14. 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 mutations13-14. 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. Indeed, this strategy is the focus of a new spin-off company called XTRNA Bio B.V. that is currently trying to raise funds to develop their clinical candidate treatment.

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. Grice et al. (2015) Dominant, toxic gain-of-function mutations in gars lead to non-cell autonomous neuropathology. Hum Mol Genet 24: 4397-4406.

6. 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.

7. Sleigh et al. (2020) Developmental demands contribute to early neuromuscular degeneration in CMT2D mice. Cell Death Dis 11: 564.

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

9. 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.

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

11. Sleigh et al. (2023) Boosting peripheral BDNF rescues impaired in vivo axonal transport in CMT2D mice. JCI Insight 8: e157191.

12. Sleigh (2020) Axonal Transport: The Delivery System Keeping Nerve Alive. Front Young Minds 8:

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

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