Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.
J Neurol Neurosurg Psychiatry. 2020 Oct;91(10):1085-1091. doi: 10.1136/jnnp-2020-322949.
Spinal and bulbar muscular atrophy (SBMA) is a hereditary neuromuscular disorder caused by CAG trinucleotide expansion in the gene encoding the androgen receptor (). 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.
脊髓延髓肌肉萎缩症（SBMA）是一种遗传性神经肌肉疾病，由雄激素受体（）基因中编码的 CAG 三核苷酸扩展引起。在中枢神经系统中，下运动神经元被选择性地影响，而患者和动物模型的病理学也表明骨骼肌的参与，包括快肌 II 型纤维的丧失和慢肌 I 型纤维的增加，以及糖酵解到氧化代谢的转换。使用 MRI 评估肌肉和脂肪，以及血清肌酐水平等生化指标，是跟踪疾病进展的有前途的生物标志物。血清肌酐水平在肌肉无力出现之前开始下降，随后出现手部震颤，这是疾病的前驱症状。雄激素依赖性核内聚谷氨酰胺扩展的 AR 积累是发病机制中的一个重要步骤，通过激素操作和反义寡核苷酸的基因沉默提供了治疗机会。动物研究还表明，Src 的过度激活、自噬的改变和线粒体缺陷是 SBMA 中神经肌肉退化的基础，并提供了替代的治疗靶点。
