Huntington Disease (HD)

Overview

• Huntington Disease (HD): A rare neurodegenerative genetic disorder.
• Genetic Basis: Caused by a repeated DNA sequence leading to abnormal protein formation.
• Inheritance: Autosomal dominant; each child of an affected parent has a 50% chance of inheriting the disease.

Genetic Details

• CAG Triplet Repeat: Huntington gene (HTT) on chromosome 4.
  • Normal individuals: 10-35 repeats
  • HD individuals: 36 or more repeats
• Polyglutamine Disease: Due to excessive glutamine from CAG repeats.
• Anticipation: More repeats can lead to earlier onset symptoms in successive generations.
• Premutation Alleles: Repeats of 27-35 can expand but don't cause disease initially.
• Penetrance:
  • 40+ repeats: 100% penetrance
  • 36-39 repeats: Reduced penetrance

Pathophysiology

• Neuronal Damage: Mutated protein aggregates in caudate and putamen of the basal ganglia.
  • Causes neuronal cell death
  • Linked to excitotoxicity and increased intracellular calcium
• Repeat Expansion: Occurs more in sperm, leading to higher risk when father is affected parent.

Symptoms

• Movement Disorders:
  • Chorea: Dance-like, jerky movements
  • Athetosis: Slow, writhing movements
  • Other motor issues: Abnormal eye movements, poor coordination
• Cognitive and Mood Disorders:
  • Dementia
  • Personality changes
  • Depression
• Progression:
  • Average onset around age 40
  • Progressive CNS disturbances
  • Loss of brain tissue in affected regions

Diagnosis

• Genetic Testing: Counts CAG repeats to confirm diagnosis.
• Imaging: CT/MRI can show basal ganglia atrophy.

Treatment

• Medications:
  • Neuroleptics (dopamine receptor antagonists)
  • Tetrabenazine (depletes dopamine)
• Limitations: Treatments manage symptoms but do not affect survival.

Prognosis

• Life Expectancy: 10-20 years post-diagnosis
• Common Causes of Death: Aspiration pneumonia or suicide

Related Disorders

• Other Triplet Repeat Disorders:
  • Myotonic dystrophy (CTG repeat)
  • Friedreich's ataxia (GAA repeat)
  • Fragile X syndrome (CGG repeat)

Summary

• Key Points:
  • HD is caused by CAG repeat expansion in the HTT gene.
  • Results in neuronal cell death in the basal ganglia.
  • Leads to movement, cognitive, and mood disturbances.