A 4-year-old girl developed clumsiness and difficulty ambulating over 6 months. On physical examination, she showed difficulty with balance while walking, dysarthria, poor hand coordination, absent deep tendon reflexes, and a bilateral Babinski sign. Light touch and vibratory sensation were greatly diminished. There was no muscular weakness. Over the next 5 years, she developed congestive heart failure from hypertrophic cardiomyopathy. She also had hyperglycemia. At autopsy, there was increased perinuclear iron deposition within cardiac myocytes. Which of the following genetic abnormalities with trinucleotide repeat expansions was most likely present in this patient?
A 4-year-old girl developed clumsiness and difficulty ambulating over 6 months. On physical examination, she showed difficulty with balance while walking, dysarthria, poor hand coordination, absent deep tendon reflexes, and a bilateral Babinski sign. Light touch and vibratory sensation were greatly diminished. There was no muscular weakness. Over the next 5 years, she developed congestive heart failure from hypertrophic cardiomyopathy. She also had hyperglycemia. At autopsy, there was increased perinuclear iron deposition within cardiac myocytes. Which of the following genetic abnormalities with trinucleotide repeat expansions was most likely present in this patient?
💡 Explanation
**Core Concept**
The question describes a patient with a complex clinical presentation involving neurological and cardiac features, ultimately leading to hypertrophic cardiomyopathy and hyperglycemia. This constellation of symptoms is suggestive of a multisystem disorder caused by an expansion of trinucleotide repeats in a specific gene.
**Why the Correct Answer is Right**
The patient's symptoms, including clumsiness, difficulty ambulating, dysarthria, poor hand coordination, absent deep tendon reflexes, and diminished light touch and vibratory sensation, are consistent with Friedreich's ataxia. This condition is caused by an expansion of GAA trinucleotide repeats in the FXN gene, leading to impaired function of the frataxin protein. Frataxin plays a crucial role in mitochondrial iron homeostasis, and its deficiency results in increased perinuclear iron deposition within cardiac myocytes, contributing to hypertrophic cardiomyopathy. Additionally, frataxin deficiency is associated with hyperglycemia due to impaired insulin secretion.
**Why Each Wrong Option is Incorrect**
* **Option A:** Huntington's disease is caused by an expansion of CAG trinucleotide repeats in the HTT gene, leading to chorea, psychiatric symptoms, and cognitive decline. It does not typically present with hypertrophic cardiomyopathy or hyperglycemia.
* **Option B:** Spinocerebellar ataxia type 3 (Machado-Joseph disease) is caused by an expansion of CAG trinucleotide repeats in the ATXN3 gene, leading to ataxia, dysarthria, and extrapyramidal symptoms. While it shares some clinical features with Friedreich's ataxia, it does not typically involve hypertrophic cardiomyopathy or hyperglycemia.
* **Option D:** There is no well-established genetic disorder with trinucleotide repeat expansions that matches the clinical presentation described.
**Clinical Pearl / High-Yield Fact**
Friedreich's ataxia is a classic example of a multisystem disorder caused by a trinucleotide repeat expansion, highlighting the importance of considering genetic etiologies in patients with complex clinical presentations.
**Correct Answer: C.**
✓ Correct Answer: D. GAA repeats in the frataxin gene
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