A progressive, inherited neurodegenerative disorder
Huntington’s disease (HD) is an autosomal dominant, inherited neurodegenerative disorder characterized by motor dysfunction, cognitive decline, and psychiatric symptoms. It results from a pathogenic CAG trinucleotide repeat expansion in the HTT gene on chromosome 4, which encodes the huntingtin protein. The disorder is fully penetrant with ≥40 CAG repeats; reduced penetrance occurs between 36–39 repeats, and <35 repeats are non-pathogenic.
Epidemiology
- Global prevalence: 3–10 per 100,000 people in populations of European ancestry; rarer in Asian and African populations.
- Approximately 41,000 symptomatic individuals and 200,000 at risk in the U.S. alone (Huntington’s Disease Society of America, 2024).
- De novo mutations (i.e., no family history) account for 1–3% of cases, often through paternal germline instability.
Genetic Transmission
- HD is inherited in an autosomal dominant fashion.
- An individual with one affected parent has a 50% chance of inheriting the expanded allele.
- If an individual does not inherit the expanded HTT gene, they do not transmit HD to future generations.
- Anticipation (earlier age of onset in successive generations) is commonly seen, especially with paternal transmission due to CAG repeat instability.
Clinical Presentation
Age of Onset
- Most individuals develop symptoms between 30 and 50 years of age (adult-onset HD).
- Juvenile-onset HD (onset <20 years) occurs in ~5–10% of cases and progresses more rapidly.
Core Symptom Clusters
- Motor Symptoms:
- Chorea (initial hallmark)
- Dystonia
- Bradykinesia and rigidity (especially in juvenile cases)
- Gait disturbance, falls
- Dysarthria, dysphagia
- Oculomotor dysfunction
- Cognitive Decline:
- Executive dysfunction (early)
- Memory impairment
- Decreased processing speed
- Eventual progression to subcortical dementia
- Psychiatric and Behavioral Changes:
- Depression, irritability
- Apathy, anxiety
- Obsessive-compulsive behaviors
- Psychosis (less common)
Note: Depression often precedes motor symptoms and may be present in the prodromal phase.
Juvenile Huntington’s Disease
- Onset: <20 years
- Typically presents with:
- Rigidity over chorea
- Bradykinesia and tremor
- Seizures (30–50% of cases)
- School decline and behavioral changes
- Prognosis is poor: disease often progresses to death within 10 years.
Diagnosis
Clinical Assessment
- Progressive motor dysfunction (especially chorea), cognitive impairment, and behavioral symptoms in an individual with family history should raise clinical suspicion.
- No single biomarker definitively confirms HD aside from genetic testing.
Genetic Testing
- Gold standard for diagnosis: HTT gene testing for CAG repeat expansion.
- ≥40 CAG repeats: fully penetrant
- 36–39: reduced penetrance
- 27–35: intermediate (non-pathogenic, but potential for expansion in offspring)
Neuroimaging
- MRI and CT may show:
- Early atrophy of caudate nucleus and putamen (striatal volume loss)
- Cortical thinning in advanced disease
Other Investigations
- Psychiatric and neuropsychological assessments
- Rule out differential diagnoses (Wilson’s disease, chorea-acanthocytosis, lupus)
Management and Treatment
There is no disease-modifying treatment yet approved, but management is symptom-directed and multidisciplinary.
Motor Symptom Management:
- Chorea:
- Tetrabenazine or deutetrabenazine (VMAT2 inhibitors): FDA-approved
- Atypical antipsychotics (e.g., olanzapine, risperidone) can also help chorea and psychiatric symptoms
- Parkinsonian features: may require levodopa in some cases (especially in juvenile HD)
Psychiatric Symptoms:
- SSRIs or SNRIs: for depression and anxiety
- Antipsychotics: for irritability, aggression, psychosis
- Mood stabilizers (e.g., valproate, lithium) in select cases
Cognitive Decline:
- No approved treatment; cognitive rehabilitation and caregiver education recommended
Supportive Measures:
- Speech and language therapy
- Nutritional support (caloric needs increase with disease progression)
- Swallowing assessment to prevent aspiration
- Physical therapy to manage gait instability and reduce fall risk
- Occupational therapy for ADL support
Multidisciplinary care is the standard, involving neurology, psychiatry, genetics, nutrition, social work, and palliative care.
Ongoing Research and Trials (2024 Update)
Several disease-modifying therapies are under investigation, including:
- Huntingtin-lowering therapies (e.g., antisense oligonucleotides like tominersen)
- Gene silencing via RNAi
- Stem cell therapies
- CRISPR-based editing (still in preclinical phases)
No therapy has yet been shown to reverse or halt progression in phase III trials, though some have shown target engagement and biomarker shifts.
Prognosis and Mortality
- Life expectancy after onset: 15–20 years
- Common causes of death:
- Aspiration pneumonia
- Falls and trauma
- Nutritional complications
- Suicide (especially in early stages—screen regularly)
Conclusion
Huntington’s disease remains a devastating inherited neurodegenerative disorder with multisystem involvement. While a cure is not yet available, a multidisciplinary approach to care, early diagnosis through genetic testing, and ongoing clinical trials provide hope for disease modification in the near future. Early psychological support and advance care planning are essential components of holistic care.
Further Resources:
- Huntington’s Disease Society of America: https://hdsa.org
- Clinical trials database: https://clinicaltrials.gov (search: Huntington’s disease)