Spinal and bulbar muscular atrophy (SBMA) is a hereditary neuromuscular disorder caused by CAG trinucleotide expansion in the gene encoding the androgen receptor (AR). In the central nervous system, lower motor neurons are selectively affected, whereas pathology of patients and animal models also indicates involvement of skeletal muscle including loss of fast-twitch type 2 fibres and increased slow-twitch type 1 fibres, together with a glycolytic-to-oxidative metabolic switch. Evaluation of muscle and fat using MRI, in addition to biochemical indices such as serum creatinine level, are promising biomarkers to track the disease progression. The serum level of creatinine starts to decrease before the onset of muscle weakness, followed by the emergence of hand tremor, a prodromal sign of the disease. Androgen-dependent nuclear accumulation of the polyglutamine-expanded AR is an essential step in the pathogenesis, providing therapeutic opportunities via hormonal manipulation and gene silencing with antisense oligonucleotides. Animal studies also suggest that hyperactivation of Src, alteration of autophagy and a mitochondrial deficit underlie the neuromuscular degeneration in SBMA and provide alternative therapeutic targets.
- motor neuron disease
- molecular biology
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Contributors All authors drafted, reviewed and edited the manuscript.
Funding This work was funded by JSPS KAKENHI Gran Numbers JP17H04195 and JP20H00527 (to MK); a grant from the Japan Agency for Medical Research and Development (AMED) (No. 19ek0109359h0002 to MK), a grant from the Hori Sciences and Arts Foundation (to MK), Telethon-Italy (GGP19128 to MP), Association Française contre les Myopathies (22221 to MP), CNCCS Scarl Pomezia (to MP) and NIH-R21 (1R21NS111768-01 to MP), UK Medical Research Council (to PF), The Motor Neurone Disease Association (to PF), the NIHR UCLH Biomadical Research Centre (to PF), The Neuro Reserch Trust (to PF), The Rosetrees Foundation (to PF) and intramural research funds from the National Institute of Neurological Disorders and Stroke (to KHF).
Competing interests AH is supported by a JSPS KAKENHI Grant Number JP18K07523. PF has received honoraria from Nido Biosciences. MK is supported by a JSPS KAKENHI Grant Number JP17H04195, grants from the Japan Agency for Medical Research and Development (Nos. 19ek0109221h0003, 19ek0109359h0002, 19dk0207027h0004, 19lk0201101h0001 and 19dm0107155h0001) and a grant from the Hori Sciences and Arts Foundation. He received honoraria from Takeda Pharmaceutical Co Ltd, Alnylam Japan, Daiichi Sankyo Co Ltd, Otsuka Pharmaceutical Co Ltd, Novartis Pharma Co Ltd, Biogen Japan and UCB Japan and grants from Zenyaku Kogyo Co Ltd, Japan Blood Products Organization, Mitsubishi-Tanabe Pharma, CSL Behring Co Ltd, Dainippon Sumitomo Pharma Co Ltd, Otsuka Pharmaceutical Co Ltd and Daiichi Sankyo Co Ltd.
Patient consent for publication Not required.
Provenance and peer review Commissioned; externally peer reviewed.
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