A 12-year-old boy from rural Rajasthan presents with progressive gait ataxia, areflexia at the knees and ankles with extensor plantar responses, and pes cavus deformity. Genetic testing reveals homozygous expansion of the structure marked **C** in the pedigree diagram. His echocardiogram shows concentric left ventricular hypertrophy. Which of the following best describes the molecular pathology underlying his cardiac involvement?

Explanation

## Why option 1 is correct The structure marked **C** in the pedigree is the GAA trinucleotide repeat expansion in the frataxin gene (FXN) on chromosome 9q13, which is the molecular hallmark of Friedreich ataxia. Frataxin deficiency leads to impaired mitochondrial iron-sulfur cluster assembly and iron accumulation within mitochondria, causing oxidative damage. In cardiac myocytes, this results in hypertrophic cardiomyopathy (present in 60–90% of FRDA patients), which is the leading cause of mortality in this condition. The patient's clinical presentation—progressive ataxia with areflexia and extensor plantar responses (the pathognomonic combination), pes cavus, and concentric left ventricular hypertrophy—is entirely consistent with FRDA caused by this specific genetic defect (Harrison 21e, Ch 444). ## Why each distractor is wrong - **Option 2 (CAG repeat in huntingtin)**: This causes Huntington disease, an autosomal dominant disorder with chorea, cognitive decline, and psychiatric features—not the recessive inheritance, ataxia-areflexia-Babinski combination, or hypertrophic cardiomyopathy seen here. - **Option 3 (Dystrophin point mutation)**: This causes Duchenne or Becker muscular dystrophy, which presents with proximal muscle weakness and elevated CK, not cerebellar ataxia or the distinctive neurologic signs of FRDA. Cardiomyopathy in DMD is typically dilated, not hypertrophic. - **Option 4 (Androgen receptor CAG repeat)**: This causes Kennedy disease (X-linked spinal and bulbar muscular atrophy), which presents with lower motor neuron signs and gynecomastia, not the upper motor neuron signs (Babinski), cerebellar ataxia, or autosomal recessive inheritance pattern evident in this pedigree. **High-Yield:** Friedreich ataxia = GAA repeat in FXN gene → frataxin deficiency → mitochondrial iron accumulation → the pathognomonic triad of cerebellar ataxia + areflexia + extensor plantars + hypertrophic cardiomyopathy (leading cause of death). [cite: Harrison 21e, Ch 444]