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Neuromuscular junction involvement in inherited motor neuropathies: genetic heterogeneity and effect of oral salbutamol treatment

Lookup NU author(s): Professor Roger Whittaker, Ruth Wake

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

© 2023, The Author(s).Objectives: Inherited defects of the neuromuscular junction (NMJ) comprise an increasingly diverse range of diseases. Several recently identified genes highlight the overlap between peripheral neuropathies and congenital myasthenic syndromes (CMS). The beta-2 adrenergic receptor agonist salbutamol has been shown to provide symptomatic benefit in CMS, while improving structural defects at the NMJ. Based on these findings, we identified cases of motor neuropathy with NMJ dysfunction and assessed the effect of salbutamol on motor function. Methods: Cases of motor neuropathy with significant NMJ dysfunction, were identified using repetitive nerve stimulation and single fibre electromyography. Oral salbutamol was administered for 12 months. Repeat neurophysiological and clinical assessments were undertaken at baseline, 6 months and 12 months. Results: Significant defects of neuromuscular transmission were identified in 15 patients harbouring a range of genetic defects, including mutations in GARS1, DNM2, SYT2 and DYNC1H. No clear benefit on motor function was seen following the administration of 12 months of oral salbutamol; however, there was a significant improvement in patient reported fatigue. In addition, no clear effect on neurophysiological parameters was seen in patients treated with salbutamol. Side-effects due to off-target beta-adrenergic effects were significant in the patient cohort. Conclusion: These results highlight the involvement of the NMJ in several subtypes of motor neuropathies, including subtypes of neuropathy due to deficits in mitochondrial fusion-fission, synaptic vesicle transport, calcium channels and tRNA synthetases. Whether the NMJ dysfunction is simply due to muscle reinnervation or a pathology unrelated to denervation is unknown. The involvement of the NMJ may represent a novel therapeutic target in these conditions. However, treatment regimens will need to be more targeted for patients with primary inherited defects of neuromuscular transmission.


Publication metadata

Author(s): McMacken G, Whittaker RG, Wake R, Lochmuller H, Horvath R

Publication type: Article

Publication status: Published

Journal: Journal of Neurology

Year: 2023

Volume: 270

Pages: 3112-3119

Online publication date: 04/03/2023

Acceptance date: 22/02/2023

Date deposited: 20/03/2023

ISSN (print): 0340-5354

ISSN (electronic): 1432-1459

Publisher: Springer Science and Business Media Deutschland GmbH

URL: https://doi.org/10.1007/s00415-023-11643-z

DOI: 10.1007/s00415-023-11643-z


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Funding

Funder referenceFunder name
201064/Z/16/ZWellcome Trust
109915/Z/15/ZWellcome Trust
305444
309548
779257European Commission
950-232279
CFI-JELF 38412
BRC-1215-20014
EJP RD COFUND-EJP N°825575
EJP-RD
FP7/2007-2013
G100142
FDN-167281
INB/ELIXIR-ES
MR/N025431/1Medical Research Council (MRC)
MR/N027302/1Medical Research Council (MRC)
MR/S005021/1Medical Research Council (MRC)
MR/V009346/1
NMD4C

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