Genetic basis of Friedreich’s ataxia

Notes

• Friedreich’s ataxia (FRDA) is a progressive genetic disorder affecting nerves and heart, typically manifesting between ages 5 and 15.
• Symptoms include impaired coordination, slurred speech, difficulty swallowing, sensory loss, and spinal curvature; death often results from heart disease.
• FRDA is caused by mutations in the FXN gene, which codes for the protein frataxin, essential for mitochondrial function and ATP production.
• Low frataxin levels lead to mitochondrial dysfunction and toxic by-product accumulation in high-energy cells like those in the heart and nervous system.
• The mutation involves an expansion of DNA repeats in the FXN gene intron; normal variants have 5-33 repeats, while disease-causing variants have 100-1,500 repeats.
• Expanded variants force the chromosome into a closed structure, reducing frataxin expression.
• FRDA is an autosomal recessive disorder; individuals must inherit two expanded variants to develop the disease.
• Consanguineous marriages significantly increase the prevalence of FRDA in affected communities.
• The disease is primarily found in populations of European, North African, West Asian, and South Asian descent; it is absent in East Asia, sub-Saharan Africa, and North America.
• Research indicates 95% of expanded variants originated from two 'protomutations' that occurred in Eurasia at least 9,000 years ago.
• Protomutations evolved into pre-mutations (abnormally high repeats but functional frataxin) before undergoing sudden expansion into disease-causing variants.
• Pre-mutations acted as 'reservoirs' that replenished the population's pool of expanded variants over time.