Huntington's Disease

• inherited disorder; autosomal dominant (50% probability of any child having disorder)
• Mutated gene coding for Huntington (Htt) protein - due to a CAG trinucleotide repeat (>38 CAG repeats)
• Htt is required for normal functioning of 6/19 classes of cell's organelles - mutant Htt leads to iron upregulation of Htt causing iron accumulation in Huntington's Disease
• involves the progressive brain atrophy (shrinking) and degeneration of GABAergic neurons of basal ganglia (area of the brain responsible for regulating motor movements) and frontal cortex (involved in motor movement signaling to the spinal cord and, in turn, to the limbs)
• average age of onset of 30-40 years
• Prevalence increased in Caucasians
• Juvenile rigid early onset form - paternally inherited
• diagnostic test can be performed (good?, bad?)
  

Clinical Features

• chorea (flailing, jerky limbs)
• dementia
• bradykinesia (slow movement)
• depression

Potential Treatments

• Gene therapy
• RNA - antisense
• Protein
  • interferring with abnormal aggregation
  • Htt binding proteins
  • Up-regulation of chaperone proteins
  • decreasing transglutaminase activity
  • cystamine
• Indirect
  • Upregulation of mitochondrial function
  • Coenzyme Q10
  • Metabolism trehalose
  • decreasing excitotoxicity/NMDA antagonist
  • Remacemide
  • Recently : Minocycline, a second generation tetracycline antibiotic, shows promising results, as it decreases caspase and cytochrome c expression leading to apoptotic cell death, decreases TNF-alpha, and acts as anti-inflammatory; also diminishes microglial and astrocyte activation