Generalized dystonia unraveled: Molecular mechanisms, diagnostic strategies, and treatment paradigms

Abstract

Background: Generalized dystonia is a complex and heterogeneous movement disorder characterized by sustained or intermittent muscle contractions that lead to abnormal postures and movements.

Pathophysiology: It primarily arises from dysfunction within basal ganglia circuits and involves a range of underlying pathophysiological mechanisms, including disrupted dopamine synthesis, altered calcium signaling, and impaired stress response pathways. Advances in genetics have identified key causative mutations-most notably in KMT2B, VPS16, EIF2AK2, PRKRA, and AOPEP- that contribute to disease onset and progression, with varying degrees of clinical penetrance. These genetic insights have clarified distinct molecular pathways, such as dopamine biosynthesis and synaptic vesicle trafficking, that underpin the disorder.

Diagnosis: Diagnostic evaluation integrates clinical phenotyping with genetic testing, including targeted gene panels or whole-exome sequencing, and is often supplemented by neuroimaging modalities, such as MRI for detecting structural or metabolic abnormalities.

Treatment: Treatment follows a stepwise strategy, beginning with oral pharmacologic agents like anticholinergics and levodopa (especially in dopamine-related dystonias), progressing to botulinum toxin injections and deep brain stimulation of the globus pallidus internus in refractory cases. Emerging approaches such as gene therapy offer promise for future disease-modifying interventions.

Conclusion: This review synthesizes current evidence to support a multidisciplinary approach in the diagnosis and management of generalized dystonia, while also identifying high-yield genetic targets and highlighting directions for future research.

Keywords: Calcium signaling; Deep brain stimulation; Dystonia genes; EIF2α pathway; Gene therapy; KMT2B gene.