A 9-year-old boy of Japanese descent presents with intractable generalized tonic-clonic seizures, myoclonus, progressive intellectual decline, and cerebellar ataxia since age 6. His father developed chorea, dementia, and gait ataxia at age 38 and is now wheelchair-bound. MRI shows atrophy of the cerebellum, brainstem, and cerebral white matter. Genetic testing reveals a heterozygous CAG repeat expansion (75 repeats) in the ATN1 gene on the structure marked **A** in the diagram. Which of the following best describes the chromosomal location and pathogenic threshold for this mutation?
A. Chromosome 6 with pathogenic threshold ≥39 CAG repeats (SCA1)
B. Chromosome 12p13.31 with pathogenic threshold ≥48 CAG repeats (DRPLA)
C. Chromosome 4 with pathogenic threshold ≥40 CAG repeats (Huntington disease)
D. Chromosome 14 with pathogenic threshold ≥52 CAG repeats (SCA3)
Explanation
Why Chromosome 12p13.31 with pathogenic threshold ≥48 CAG repeats (DRPLA) is right
The clinical presentation—juvenile-onset progressive myoclonus epilepsy with myoclonus, seizures, intellectual decline, ataxia, and MRI findings of dentate nucleus, brainstem, and white matter atrophy in a Japanese patient with paternal anticipation—is pathognomonic for DRPLA. The mutation resides in exon 5 of the ATN1 gene on chromosome 12p13.31. The pathogenic threshold is ≥48 CAG repeats; the patient's 75 repeats fall in the juvenile-onset range (>60), consistent with his early presentation and severe phenotype. His father's 60 repeats and the 15-repeat expansion between generations exemplify the marked anticipation characteristic of paternal transmission in DRPLA (up to ~26 units per generation possible). [Harrison 21e Ch 436; Tsuji GeneReviews DRPLA 2023]
Why each distractor is wrong
Chromosome 4 with pathogenic threshold ≥40 CAG repeats (Huntington disease): While adult-onset DRPLA can mimic Huntington disease (HD) clinically, this patient's juvenile-onset myoclonus epilepsy phenotype, Japanese ancestry, and MRI pattern of dentatorubral-pallidoluysian atrophy are not typical of HD. The HTT gene on chromosome 4 has a lower pathogenic threshold (≥40 repeats) and does not typically present with myoclonus epilepsy in childhood. The paternal anticipation is also more pronounced in DRPLA.
Chromosome 6 with pathogenic threshold ≥39 CAG repeats (SCA1): SCA1 (ATXN1 on chromosome 6) presents with pure cerebellar ataxia and does not typically cause myoclonus epilepsy or the marked intellectual decline seen here. The clinical phenotype and MRI findings (brainstem and white matter involvement) are inconsistent with SCA1.
Chromosome 14 with pathogenic threshold ≥52 CAG repeats (SCA3): SCA3 (ATXN3 on chromosome 14) is the most common SCA worldwide but typically presents with progressive ataxia, ophthalmoplegia, and pyramidal signs—not with juvenile-onset myoclonus epilepsy. The pathogenic threshold (≥52) and clinical features do not match this patient's presentation.
High-YieldNEET PG
DRPLA is relatively common in Japan (1:200,000), rare in Europeans, presents as juvenile myoclonus epilepsy (>60 repeats) or adult chorea-dementia (48–60 repeats), and shows marked paternal anticipation—always consider it in HD-negative chorea/dementia or progressive myoclonus epilepsy patients, especially with Japanese ancestry.
Harrison 21e Ch 436; Tsuji GeneReviews DRPLA 2023
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