A 10-year-old child has progressive ataxia, dysarthria, hyporeflexia, and Babinski signs developing since age 7. Echocardiography shows hypertrophic cardiomyopathy. Nerve conduction studies show mixed sensorimotor neuropathy. Frataxin protein is markedly reduced. The genetic mechanism involves:
- A GAA trinucleotide repeat expansion in intron 1 of FXN gene causing transcriptional silencing of frataxin ✓
- B Point mutation in frataxin (FXN) gene causing premature stop codon
- C Deletion of chromosome 9q13 encompassing the entire FXN gene
- D X-linked trinucleotide repeat expansion causing repeat instability
Explanation
Friedreich's ataxia (FA) is the most common inherited ataxia. It is caused by homozygous GAA trinucleotide repeat expansions within intron 1 of the frataxin (FXN) gene on chromosome 9q13. The expanded GAA repeats form triple-helical DNA structures (triplexes) that silence FXN transcription via heterochromatin formation. Frataxin deficiency impairs mitochondrial iron-sulphur cluster assembly, leading to iron accumulation in mitochondria, oxidative damage, and cell death in dorsal root ganglia, spinocerebellar tracts, and heart. FA is autosomal recessive and is the most common recessive ataxia.
Reference: Ghai Essential Pediatrics, 10th ed.
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Written and medically reviewed by the StethoPrep medical team.