A 12-year-old boy is brought to the pediatric neurology clinic with a 2-year history of progressive rigidity, cognitive decline, and seizures. His father was diagnosed with Huntington disease at age 42 and is now severely affected. Genetic testing in the boy reveals 68 CAG repeats in the HTT gene. The pedigree pattern marked **D** in the diagram shows anticipation in paternal transmission resulting in the juvenile form. Which of the following BEST explains why this patient's presentation differs from the typical adult-onset form of Huntington disease?

Explanation

## Why option 1 is correct Anticipation in Huntington disease is a hallmark feature of paternal transmission. The HTT CAG repeat expansion is more unstable during spermatogenesis than oogenesis, leading to larger repeat expansions in successive generations when inherited paternally. This patient's 68 repeats (far exceeding the ≥40 fully penetrant threshold) and age of onset at 12 years are consistent with juvenile-onset HD, which typically occurs when repeats exceed 60 and is usually paternally inherited. The atypical rigid phenotype (Westphal variant) with seizures and cognitive decline, rather than classic chorea, is characteristic of juvenile HD and reflects the severity conferred by very large repeat expansions. This directly illustrates the phenomenon marked **D** in the pedigree — anticipation with paternal transmission producing the juvenile form. ## Why each distractor is wrong - **Option 2**: Maternal transmission does NOT show anticipation in HD; paternal transmission is responsible for the larger repeat expansions and earlier onset. Maternal transmission typically shows stable or only modest repeat expansion. Skipped generations do not occur in autosomal dominant HD. - **Option 3**: A de novo mutation is possible but would not explain the father's documented HD diagnosis at age 42 or the family history. The pedigree clearly shows paternal inheritance, not a sporadic de novo event. - **Option 4**: Compound heterozygosity (two mutant alleles) is not a recognized mechanism in HD pathogenesis. HD is caused by a single expanded HTT allele; individuals are heterozygous, not homozygous or compound heterozygous. **High-Yield:** Paternal transmission of HD → larger CAG repeats → earlier onset + atypical Westphal variant (rigidity, seizures) in juvenile HD; maternal transmission shows stability or minimal expansion. [cite: Harrison 21e Ch 444 — Huntington Disease: Anticipation and Paternal Transmission]