Huntington'S Disease is a progressive neurodegenerative disorder characterized by the gradual loss of neuronal function. This page provides comprehensive information about the disease, including its pathophysiology, clinical presentation, diagnosis, and current therapeutic approaches.
Huntington's disease (HD) is a progressive neurodegenerative genetic disorder characterized by chorea (involuntary dance-like movements), psychiatric disturbances, and cognitive decline. It is caused by an autosomal dominant CAG trinucleotide repeat expansion in the HTT gene encoding huntingtin protein.
- Gene: HTT (Huntingtin) on chromosome 4p16.3
- Mutation: CAG trinucleotide repeat expansion in the first exon
- Normal repeats: 10-35
- Intermediate alleles: 36-39 (reduced penetrance)
- Disease-causing: ≥40 repeats (full penetrance)
- Anticipation: Earlier onset in successive generations (parenteral transmission)
-
Mutant Huntingtin Protein (mHTT)
- Expanded polyglutamine (polyQ) tract
- Toxic gain-of-function
- Protein aggregation into inclusion bodies
- Transcriptional dysregulation
- Impaired autophagy and mitochondrial dysfunction
-
Neuronal Vulnerability
- Striatal medium spiny neurons (MSNs) most affected
- Cortical neuron loss
- Substantia nigra pars compacta degeneration
- Selective vulnerability of GABAergic neurons
-
Key Pathogenic Mechanisms
- Transcriptional dysregulation (REST, BDNF)
- Mitochondrial dysfunction and energy deficits
- Excitotoxicity (glutamate receptor overactivation)
- Impaired axonal transport
- Synaptic dysfunction
- Neuroinflammation
- Chorea (involuntary movements)
- Dystonia
- Bradykinesia
- Rigidity
- Gait disturbance
- Dysarthria
- Dysphagia
- Depression
- Anxiety
- Irritability
- Aggression
- Apathy
- Psychosis
- Executive dysfunction
- Memory impairment
- Progressive dementia
- Impaired judgment
- Loss of impulse control
| Stage |
Features |
| Premanifest |
No symptoms, genetic diagnosis possible |
| Early |
Mild chorea, subtle cognitive changes |
| Moderate |
Functional impairment, chorea prominent |
| Advanced |
Severe motor disability, cognitive decline |
| End-stage |
Total care required, death typically from complications |
- Neuroimaging: Striatal atrophy on MRI, FDG-PET hypometabolism
- Fluid biomarkers: Neurofilament light chain (NfL), tau, mutant huntingtin
- Genetic testing: CAG repeat number
- Tetrabenazine - dopamine depleter for chorea
- Deutetrabenazine - deuterated tetrabenazine
- Valbenazine - VMAT2 inhibitor
- Antipsychotics: Haloperidol, olanzapine, risperidone
- Gene silencing: ASOs (tominersen, others), RNAi
- Mutant huntingtin lowering: Various approaches in development
- Neuroprotective agents: CoQ10, creatine, minocycline (failed in clinical trials)
- Cell replacement: Stem cell therapies
- Physical therapy
- Occupational therapy
- Speech therapy
- Nutritional support
- Psychiatric care
The study of Huntington'S Disease has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.
- The Huntington's Disease Collaborative Research Project. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. Cell. 1993.
- Ross CA, et al. Huntington disease: natural history, biomarkers and disease-modifying therapies. Nat Rev Neurol. 2023.
- Tabrizi SJ, et al. Huntington disease: new insights into molecular pathogenesis and treatment strategies. Lancet Neurol. 2022.
- Wild EJ, Tabrizi SJ. Therapies targeting DNA and RNA in Huntington's disease. Brain. 2023.
- Reilmann R, et al. Huntington's disease: therapeutic prospects and clinical trials. Nat Rev Drug Discov. 2023.