A 35-year-old man presents to the neurology clinic with progressive involuntary movements of the face and limbs over the past 2 years, along with declining work performance due to difficulty concentrating. His father died at age 42 with a similar presentation. Genetic testing confirms the diagnosis of Huntington disease. The inheritance pattern marked **B** in the diagram shows autosomal dominant inheritance with anticipation and paternal expansion bias. Which of the following molecular mechanisms BEST explains why this patient's symptoms began earlier and are more severe than his father's?

Question

Accepted Answer

A. Expansion of the CAG trinucleotide repeat in the HTT gene during spermatogenesis in the paternal germline, resulting in a larger repeat number in the son than in the father at the time of inheritance. ## Why option 1 is correct

The clinical anchor is that Huntington disease shows **anticipation** — progressively earlier onset and increased severity in successive generations — due to **CAG repeat expansion during spermatogenesis**. The CAG trinucleotide repeat in exon 1 of the HTT gene on chromosome 4p16.3 is unstable during DNA replication in germ cells, and this expansion is **much more pronounced during spermatogenesis than oogenesis** (paternal expansion bias). Therefore, when an affected father passes the mutant allele to his son, the son typically inherits a **larger CAG repeat number**, which directly correlates with **earlier age of onset and more severe disease** (inverse correlation between repeat length and age of onset). This explains why the patient's symptoms began at age 35 while his father's began at age 42 — the son inherited an expanded repeat from his father. [Harrison's Principles of Internal Medicine 21e — Neurodegenerative Diseases]

## Why each distractor is wrong

- **Option 2**: De novo mutations do occur in HD, but they do not explain the **paternal inheritance pattern** or the **anticipation phenomenon** observed in this family. The patient clearly inherited the mutation from his affected father, not acquired it de novo.
- **Option 3**: Epigenetic silencing of the normal allele is not the mechanism of anticipation in HD. The disease is caused by a toxic gain-of-function of the mutant huntingtin protein, not loss of function of the normal allele. HTT is not subject to parent-of-origin-dependent imprinting.
- **Option 4**: Huntington disease is **autosomal dominant**, not mitochondrial. Mitochondrial inheritance would show maternal transmission exclusively, and the patient inherited the disease from his father, ruling out mitochondrial inheritance entirely.

**High-Yield:** Paternal CAG expansion during spermatogenesis → larger repeats in offspring → earlier HD onset (anticipation). Juvenile HD (>60 repeats) almost always comes from an affected father.

[cite: Harrison's Principles of Internal Medicine 21e — Neurodegenerative Diseases]

Answer

B. Spontaneous de novo mutation in the patient's HTT gene that occurred during early embryogenesis, independent of paternal inheritance

Answer

C. Mitochondrial inheritance of a defective HTT gene variant from the maternal lineage, causing cumulative toxic effects across generations

Answer

D. Epigenetic silencing of the normal HTT allele inherited from the mother, preventing compensatory gene expression

Explanation

Why option 1 is correct

Why each distractor is wrong

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Explanation

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