What is Huntington disease?

Huntington's Disease

Huntington's disease (HD) is an inherited neurodegenerative disorder caused by an abnormal expansion of CAG trinucleotide repeats in the Huntingtin gene (HTT) located on chromosome 4, characterized by motor dysfunction, cognitive decline, and emotional disturbances that inevitably progresses toward a fatal outcome. 1

Genetic Basis and Epidemiology

• HD is transmitted in an autosomal dominant manner, meaning a child of an affected parent has a 50% chance of inheriting the disease 1
• The disease is caused by expansion of CAG repeats in the HTT gene on chromosome 4p16.3 1, 2
  • Normal individuals: 9-35 CAG repeats
  • HD patients: >35 CAG repeats
  • 36-39 repeats: reduced penetrance
  • ≥40 repeats: full penetrance (will definitely develop the disease) 3
• Global prevalence is approximately 2.71 per 100,000 people, with higher rates (10.6-13.7 per 100,000) in Western countries 1
• Caucasian population prevalence is estimated at 1/10,000-1/20,000 2

Clinical Presentation

Classic Triad of Symptoms

1. Motor Dysfunction:

   • Chorea (involuntary, flowing, non-stereotyped movements with a writhing quality) is the most recognizable motor symptom 4
   • Progressive motor impairment eventually affects all muscles 2
   • Juvenile-onset HD (before age 20) presents with rigidity and spasticity rather than chorea 4

2. Cognitive Decline:

   • Progressive impairment of executive functions, attention, and memory 4
   • All psychomotor processes become severely retarded as the disease progresses 2

3. Psychiatric/Behavioral Disturbances:

   • Personality changes, impulsivity, depression, and aggression 4
   • Often present early in the disease course and may precede motor symptoms 4

Disease Progression

• Mean age of onset is typically 30-50 years 2
• Juvenile onset (before age 20) is associated with more rapid progression 4
• Disease progression typically spans 15-20 years from symptom onset to death 1, 2
• CAG repeat length correlates inversely with age of onset and directly with disease severity 1
  • Longer repeats (>55) often result in juvenile-onset HD 1
• The most common cause of death is pneumonia, followed by suicide 2

Diagnosis

• Definitive diagnosis is based on:
  • Clinical symptoms in an individual with a family history of HD
  • Confirmed by genetic testing for CAG repeat expansion in the HTT gene 4
• MRI findings include progressive atrophy of the neostriatum, particularly the head of the caudate nuclei 4
• Imaging may be normal early in the disease course, even when genetic testing is positive 4

Diagnostic Challenges

• Early psychiatric symptoms may be misattributed to primary psychiatric disorders 4
• Subtle motor symptoms might be overlooked in early stages 4
• Juvenile-onset HD can be misdiagnosed due to its different presentation (rigidity rather than chorea) 4
• Family history may be absent or unknown in some cases 4

Management

• Currently, there is no curative treatment for HD 1, 2
• Management is multidisciplinary and focuses on symptom relief to improve quality of life 1

Pharmacological Approaches

• Chorea: Treated with dopamine receptor blocking or depleting agents 2
• Psychiatric symptoms: Targeted medication for depression, aggression, and other behavioral disturbances 2

Non-pharmacological Approaches

• Physical, occupational, and speech therapy to maintain function 5
• Social work intervention to assist with practical difficulties 5
• Support from voluntary organizations for patients and families 5

Genetic Counseling and Testing

• Genetic counseling is essential before testing symptomatic patients 5
• Predictive testing in asymptomatic at-risk individuals requires comprehensive genetic counseling 5
• Prenatal diagnosis is possible through chorionic villus sampling or amniocentesis 2
• Preimplantation diagnosis with in vitro fertilization is available in several countries 2

Future Directions

• Innovative gene and cell therapy strategies are being actively researched 1
• Potential disease-modifying therapies are entering clinical trials 6
• Gene silencing approaches show promise for neuroprotection and prevention 3

Prognosis

• Progressive disease leads to complete dependency in daily life 2
• Eventually requires full-time care until death 2
• Aspiration pneumonia is a common fatal complication 1

HD is a devastating neurodegenerative disorder with profound impacts on patients and families. While current management is limited to symptomatic treatment, ongoing research into gene therapies offers hope for future disease-modifying interventions.