A 12-year-old boy of South Indian descent presents with progressive gait ataxia, dysarthria, and loss of ankle reflexes over the past 2 years. Examination reveals extensor plantar responses, pes cavus, and loss of vibration sense in the lower limbs. Genetic testing confirms the diagnosis shown at **A** in the diagram. Which of the following best describes the molecular basis of this condition?

Question

Accepted Answer

C. Homozygous GAA trinucleotide repeat expansion (≥66 repeats) in intron 1 of the FXN gene on chromosome 9q13.11, causing epigenetic silencing and frataxin deficiency. ## Why option 1 is correct

The structure marked **A** represents autosomal recessive Friedreich ataxia (FRDA), which is caused by homozygous GAA trinucleotide repeat expansion (≥66 repeats, typically several hundred to over a thousand) in intron 1 of the FXN gene on chromosome 9q21.11. The expansion forms a stable triple-helical "sticky DNA" structure that epigenetically silences FXN transcription, reducing frataxin protein to 5–30% of normal. Frataxin is a mitochondrial matrix protein essential for iron–sulphur cluster biogenesis; its deficiency impairs mitochondrial iron handling and disables Fe-S-cluster-containing enzymes, causing progressive neuronal and cardiomyocyte death. This is the prototype autosomal recessive trinucleotide-repeat disorder and the most common inherited ataxia in people of European ancestry (Harrison's 21e Ch 433; Adams & Victor 12e).

## Why each distractor is wrong

- **Option 2**: CAG repeats in the huntingtin gene cause Huntington disease, which is autosomal *dominant*, not recessive. The inheritance pattern and gene are both incorrect for FRDA.
- **Option 3**: PRNP point mutations cause familial Creutzfeldt–Jakob disease (fCJD), not ataxia with the stereotyped FRDA phenotype of gait ataxia, loss of reflexes, and extensor plantar responses. The molecular mechanism (prion misfolding) is unrelated to trinucleotide repeats.
- **Option 4**: ARX gene deletions cause infantile spasms and developmental delay, not the late-childhood-onset progressive ataxia with cardiomyopathy seen in FRDA. The inheritance is X-linked recessive, not autosomal recessive.

**High-Yield:** FRDA = homozygous GAA repeats in FXN intron 1 → frataxin loss → mitochondrial iron accumulation and Fe-S cluster enzyme failure → progressive ataxia + cardiomyopathy (leading cause of death).

[cite: Harrison's 21e Ch 433; Adams & Victor 12e]

Answer

A. Homozygous point mutations in the PRNP gene on chromosome 20, causing prion protein misfolding and neurodegeneration

Answer

B. Heterozygous CAG trinucleotide repeat expansion in the huntingtin gene on chromosome 4, inherited in an autosomal dominant pattern

Answer

D. Hemizygous deletion of the ARX gene on the X chromosome, leading to developmental delay and seizures

Explanation

Why option 1 is correct

Why each distractor is wrong

Practice similar questions