Dystonia is a clinically and genetically highly heterogeneous neurological disorder characterized by abnormal movements and postures caused by involuntary sustained or intermittent muscle contractions. A number of groundbreaking genetic and molecular insights have recently been gained. While they enable genetic testing and counseling, their translation into new therapies is still limited. However, we are beginning to understand shared pathophysiological pathways and molecular mechanisms. It has become clear that dystonia results from a dysfunctional network involving the basal ganglia, cerebellum, thalamus, and cortex. On the molecular level, more than a handful of, often intertwined, pathways have been linked to pathogenic variants in dystonia genes, including gene transcription during neurodevelopment (e.g., KMT2B, THAP1), calcium homeostasis (e.g., ANO3, HPCA), striatal dopamine signaling (e.g., GNAL), endoplasmic reticulum stress response (e.g., EIF2AK2, PRKRA, TOR1A), autophagy (e.g., VPS16), and others. Thus, different forms of dystonia can be molecularly grouped, which may facilitate treatment development in the future.

中文翻译：

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肌张力障碍的遗传学和发病机制


肌张力障碍是一种临床和遗传高度异质性的神经系统疾病，其特征是由不自主的持续或间歇性肌肉收缩引起的异常运动和姿势。最近获得了许多开创性的遗传和分子见解。虽然它们能够进行基因检测和咨询，但它们转化为新疗法仍然有限。然而，我们开始了解共同的病理生理途径和分子机制。很明显，肌张力障碍是由涉及基底神经节、小脑、丘脑和皮质的功能障碍网络引起的。在分子水平上，超过少数通常交织在一起的通路与肌张力障碍基因的致病性变异有关，包括神经发育过程中的基因转录（例如 KMT2B、THAP1）、钙稳态（例如 ANO3、HPCA）、纹状体多巴胺信号转导（例如 GNAL）、内质网应激反应（例如 EIF2AK2、PRKRA、TOR1A）、自噬（例如 VPS16）等。因此，可以将不同形式的肌张力障碍进行分子分组，这可能有助于未来的治疗开发。