Trinucleotide Repeat Expansion Diseases

Fragile X Syndrome

• Inheritance pattern
  • X-linked dominant 
• Repeat expansion
  • CGG repeat on FMR1 gene
• Presentation
  • mental retardation
  • autism
  • long face large jaw
  • large ears
• large testicles (macroorchidism)

Friedrich’s Ataxia

• Inheritance pattern
  • autosomal recessive
• Repeat expansion
  • GAA repeat on chromosome 9
    • results in
      • defect in frataxin (an iron binding protein) that leads to impaired mitochondrial function
      • degeneration of various spinal cord tracts
• Presentation
  • neurological findings
    • muscle weakness
    • loss of deep tendon reflexes
    • loss of vibratory sensation and proprioception
    • clumsy gait with falls, nystagmus
  • other findings
    • pes cavus
    • diabetes mellitus
• hypertrophic cardiomyopathy

Huntington’s Disease

• Inheritance pattern 
  •  autosomal dominant
• Repeat expansion
  • CAG repeat on chromosome 4
• Presentation
  • neurologic findings
    • caudate atrophy with enlarged ventricles on head CT
    • decreased GABA and Ach
    • increased dopamine
    • NMDA mediated excitotoxicity
    • movement disorder
    • aggression/pyschosis
    • depression
    • dementia
    • occurs typically a young patient (age 20 – 50)
• mnemonic
• HUNT 4 an animal, put it in a CAGe

Myotonic Dystrophy – Type 1

• Inheritance pattern
  • autosomal dominant
• Repeat expansion
  • CTG repeat on DMPK gene
    • results in
      • abnormal expression of myotonin protein kinase
• Presentation
  • myotonia
  • muscle wasting
  • cataracts
  • testicular atrophy
  • arrhythmia
  • frontal balding
• classically “can’t release a doorknob/handshake”