Friedreich's Ataxia

• autosomal recessive genetic disease that affects 1-2 people/100,000
• Onset occurs in 1st or 2nd decade; progressive

Clinical Features

• Gait ataxia (Wobbliness. Incoordination and unsteadiness due to the brain's failure to regulate the body's posture and regulate the strength and direction of limb movements), clumsiness, dysarthria (slurred, slow speech that is difficult to produce/understand due to paralysis, weakness, or inability to coordinate the muscles of the mouth)
• Scoliosis (S-shaped vertebral column), cardiomyopathy (problems associated with the heart muscle), diabetes mellitus
• Weakness in legs
• Hearing loss, optic atrophy
• Loss of vibration, position sense; Areflexia and Babinski sign (abnormal extension of toes upon tickling the sole of the foot, indicative of upper motor neuron damage)

Pathology

• Loss of large dorsal root ganglion cells (nodules of Nageotte)
  • Degeneration in dorsal columns and large diameter peripheral sensory neurons
• Clarke's column
  • Degeneration in dorsal spinocerebellar tract
• Corticospinal tract
• Cranial nerve nuclei (VIII, XI, XII), dentate nucleus (cerebellum) and purkinje cells
• Cuneate, Gracilis nuclei (transynaptic degeneration)

Genetics

• Linked to Chromosome 9q13
• Large GAA repeat expansion in the FRDA (Friedreich's receptor gene) or X25 gene (1st intron)
  • normal gene has 6-36 GAA repeats
  • abnormal gene has 90-1300 GAA repeats
• X25 codes for the 210 amino acid protein Frataxin
• Frataxin is expressed in the mitochondrial membrane
  • involved in iron transport, storage, antioxidant activity and biosynthesis of iron-sulphur centres (ISCs)
  • Frataxin defiiciency likely results in reduced ISC biosynthesis, increase in intramitochondrial iron and resulting oxidative stress
• Expansion mutation decreases transcription of X25
• Correlation between expansion size and severity (1/age of onset)
• Genetic Heterogeneity (non-9q13 Freidreich's)
• Unlike other diseases with expanded trinucleotide repeats, Freideich's does not involve "anticipation" (increase in disease severity in successive generations)
• Phenotypic heterogeneity (inter and intrafamilial)
• Mitochondria accumulate iron leading to oxidative stress, in turn, leading to the death of these neurons