Huntington’s disease (HD) is a debilitating inherited neurodegenerative disorder resulting from an autosomal dominant genetic mutation that progressively destroys nerve cells in the brain1. It impairs movement, cognition, and mental health, which ultimately leads to severe disability and death. First described by George Huntington in 1872, HD is rare but occurs worldwide, with one mutated gene copy guaranteeing development of this disease. There is no cure at present; current therapies merely alleviate symptoms.
Genetics and inheritance of Huntington’s disease
The hallmark of HD is the expansion of a CAG trinucleotide repeat in exon 1 of the huntingtin (HTT) gene on the shorter arm of chromosome 41. Normally, people have 10–26 repeats; expansions beyond 36 increase disease risk1.
This mutation causes “genetic anticipation,” which is an acceleration of disease onset and symptom severity linked to an increase in the CAG repeat length2. This acceleration is often most pronounced when the mutation is passed from father to child, leading to increasingly severe symptoms in subsequent generations. HD is inherited in an autosomal dominant manner: each affected parent has a 50% chance of passing it to each child. Genetic studies confirm that the appearance of a truly de novo mutations is very rare1.
Pathophysiology of Huntington’s disease
The expanded CAG sequence produces an abnormally long polyglutamine tract in the Huntingtin protein, giving rise to a mutant huntingtin (mHTT)1. This mutant protein gains new toxic properties, which is the primary cause of the disease, rather than simply losing its normal function.
Misfolded mHTT proteins aggregate inside neurons and form nuclear and cytoplasmic inclusions that disrupt cellular processes. Neuronal loss is seen to be most significant in the striatum—the caudate and putamen, which are key for motor control, cognition, and emotion3. As disease progresses, degeneration spreads to the cerebral cortex, thalamus, and cerebellum.
At the molecular level, mHTT toxicity involves several converging mechanisms that together drive progressive neuronal damage and brain dysfunction4:
- Impaired gene regulation that disrupts essential proteins
- Mitochondrial dysfunction that reduces energy and increases oxidative stress
- Excitotoxicity from glutamate overstimulation harming neurons
- Failures in protein folding and clearance (proteostasis)5
- Disrupted axonal transport and synaptic signaling
- Chronic neuroinflammation activated by glial cells6
Clinical manifestations of Huntington’s disease
HD’s hallmark symptom is chorea—involuntary, irregular jerky movements that worsen over time7. Patients also develop dystonia (sustained muscle contractions), slowed or absent movements (bradykinesia/akinesia), speech slurring, swallowing difficulties, gait instability, and abnormal eye movements1, 8, 9.
Cognitive decline typically involves impaired planning, executive function, memory retrieval, and slowed processing speed. Patients often lack insight into their deficits which complicates care.
Psychiatric symptoms arise early or before motor signs, including depression (with heightened suicide risk), irritability, anxiety, apathy, obsessive-compulsive behaviors, psychosis, impulsivity, and aggression10. These profoundly affect their quality of life.
Stages of Huntington’s disease progression
Huntington’s typically unfolds over 15–20 years after onset:
- Premanifest: Gene carriers show no obvious symptoms, but sensitive testing may reveal subtle cognitive or psychiatric changes.
- Early stage: Mild motor symptoms like chorea or mood changes appear but do not impair daily functioning. Diagnosis is usually made in this stage.
- Middle stage: Motor symptoms worsen, which seriously impacts daily tasks and independence. Caregiver assistance becomes necessary as cognitive and psychiatric symptoms become more severe.
- Late stage: At this stage, severe motor impairment is present, including rigidity, dystonia, loss of communication abilities, and marked cognitive decline. Patients become fully dependent for support and are at extensive risk for complications such as aspiration and pneumonia.
Diagnosis of Huntington’s disease
Diagnosis involves clinical evaluation of characteristic motor signs alongside cognitive and psychiatric assessments.
- A family history is crucial because of its strong hereditary influence8.
- Definitive confirmation comes from genetic testing, which quantifes CAG repeats via blood analysis11, 12.
- Pre-symptomatic testing is also available but it requires intensive counseling due to psychological and ethical complexities13.
- Brain imaging such as MRI reveals striatal atrophy characteristics of HD as it advances14.
- Functional neuroimaging (PET, fMRI) can detect early metabolic changes before structural loss appears, which aids early detection15, 16.
Current treatments of Huntington’s disease
There is currently no cure for HD, nor has any therapy been proven to halt its progression. Treatment strategies therefore focus on managing symptoms and maximizing quality of life.
- For motor symptoms, VMAT2 inhibitors such as tetrabenazine and deutetrabenazine reduce dopamine release and suppress chorea17.
- Antipsychotic medications, for instance, haloperidol or olanzapine provide additional relief but may cause significant side effects18.
- Rigidity and dystonia can be alleviated with muscle relaxants19.
- Psychiatric symptoms are treated with antidepressants, or mood stabilizers20, 21.
- Non-pharmacological interventions play a critical role, with physical and occupational therapy used to support mobility and independence22.
- For swallowing difficulties, treatment includes speech therapy, dietary modifications, and sometimes feeding tubes in advanced disease22, 23.
Challenges in research and treatment
HD poses some unique obstacles, notably:
- Individuals with pathogenic CAG expansions most inevitably develop this disease, which raises ethical and psychological dilemmas about predictive testing and life planning4.
- Diagnosis often occurs late, after significant irreversible brain damage has already occurred. This often limits opportunities for protective intervention strategies24.
- Expression of the huntingtin gene throughout the body complicates targeted therapies without affecting normal protein function25.
- Lack of reliable early progression biomarkers hinders tracking and trial design, though neurofilament light chain is showing promise26.
- The long disease course, variability, and ethical challenges make clinical trials more difficult and slow down drug development27.
- Targeting mHTT selectively without impacting normal HTT function remains a daunting research barrier28.
Emerging research and future directions
Research into Huntington’s disease is accelerating with a focus on therapies that directly address the root cause. Gene-silencing approaches such as antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs) aim to lower mutant protein production29, 30. Tominersen, one such ASO, demonstrated potential yet highlighted the challenges of managing safety and efficacy29. Even more experimental are gene-editing strategies using tools like CRISPR, which could one day correct the expanded repeat itself31.
Other parallel approaches are aimed at neuroprotection: improving mitochondrial function, reducing excitotoxic glutamate activity, modulating inflammation, and enhancing cellular clearance systems like autophagy32. Small molecules designed to prevent mHTT aggregation are being developed. Regenerative medicine, including stem cell therapy, still remains in experimental stages but holds long-term potential to replace or protect vulnerable neurons33.
Equally important is progress in biomarker development. Blood-based markers such as neurofilament light chain may soon provide reliable metrics for neurodegeneration and treatment response34. Advances in artificial intelligence and machine learning promise to accelerate trial design, predict disease course, and analyze complex datasets for personalized intervention strategies35.
Socio-economic and psychosocial impact
The reach of Huntington’s disease extends beyond the patient to reshape families, relationships, and communities. The psychosocial burden begins even before onset, as individuals struggle with whether to undergo testing and confront their potential future36. Parents often carry the guilt of passing the gene to children, with the present stigma, symptoms and psychiatric changes deepening isolation. Depression, anxiety, and suicidal ideation are common both among patients and family members.
With worsening symptoms, patients require full-time assistance that leads to burnout and financial hardship for caregivers37. Personality changes and cognitive decline can also deeply affect bonds within families, which leads to profound emotional stress long before the physical end stage. Economically as well, the long-term care costs for HD are substantial, and require direct medical needs, specialized support, and indirect losses of productivity.
Conclusion
Huntington’s disease is a genetic disorder that seriously affects motor, cognitive, and emotional abilities of a person. Current therapies only address symptoms, however, its clear genetic cause enables novel approaches aimed at disease modification. Gene therapies, neuroprotective strategies, and advancements in biomarker detection provide tangible hope for future treatments that could slow or prevent progression. At the same time, compassionate multidisciplinary care remains of equal significance. The combined effort of scientific innovation and empathetic support offers hope for patients and families going through this devastating illness.