HUNTINGTON’S DISEASE: GENETIC BASIS, CLINICAL MANIFESTATIONS, AND EMERGING THERAPEUTIC APPROACHES

Tamilselvan S.*, Archana B.

Huntington’s disease (HD) is a hereditary, autosomal-dominant neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the huntingtin (HTT) gene on chromosome 4. The mutation leads to the production of mutant huntingtin protein (mHTT) with an abnormally long polyglutamine sequence, resulting in neuronal toxicity, particularly in the striatum and cerebral cortex. Clinically, HD manifests with progressive motor disturbances such as chorea and dystonia, along with cognitive decline and psychiatric symptoms, including depression and anxiety. The disease can appear as adult-onset, typically between 35 and 50 years, or as a more aggressive juvenile-onset form. Diagnosis involves genetic testing for CAG expansion, supported by neuroimaging to identify striatal atrophy. Although there is no cure, management focuses on symptom control using dopamine modulators like tetrabenazine, antidepressants, and supportive therapy. Current research emphasizes disease-modifying strategies such as RNA/DNA-targeting therapies, antisense oligonucleotides (e.g., tominersen), gene therapy (AMT-130), and neuroprotective agents, including minocycline and cannabinoids. Investigational treatments targeting mutant huntingtin reduction and enhancing autophagy offer potential future benefits. Despite advances in understanding its complex pathogenesis involving transcriptional dysregulation, protein aggregation, and neuroinflammation, HD remains a fatal disorder with a typical survival of 15–20 years post-onset. Continued exploration of molecular mechanisms and targeted therapies provides hope for delaying progression and improving the quality of life for affected individuals.