A 38-year-old woman presents with 5 years of progressive gait instability, dysarthria, and clumsy hand movements. Family history reveals her father, paternal aunt, and paternal grandfather all developed similar symptoms in their 40s. Examination shows slowly progressive cerebellar ataxia with wide-based gait, bilateral appendicular dysmetria, dysdiadochokinesia, and scanning dysarthria, accompanied by hyperreflexia and extensor plantar responses. MRI brain demonstrates olivopontocerebellar atrophy. Genetic testing reveals a heterozygous CAG repeat expansion (52 repeats) in exon 8 of ATXN1 on **chromosome 6p23** (marked **A** in the diagram). Which of the following best describes the pathogenic mechanism of the mutation identified at this locus?
A. CAG repeat expansion in ATXN2 locus causing slow saccades and areflexia with relative preservation of pyramidal signs
B. Trinucleotide repeat expansion in HTT gene causing selective degeneration of striatal medium spiny neurons with prominent chorea
C. Abnormal polyglutamine tract that interacts aberrantly with transcriptional co-regulators and forms nuclear inclusions in cerebellar Purkinje cells, inferior olivary neurons, and pontine nuclei
D. Loss-of-function mutation causing deficiency of frataxin protein and mitochondrial iron accumulation in dorsal root ganglia
Explanation
Why option 1 is correct
The mutation at chromosome 6p23 (ATXN1) in SCA1 encodes ataxin-1 with an abnormally enlarged polyglutamine (polyQ) tract (≥39 CAG repeats). This expanded polyQ tract abnormally interacts with transcriptional co-regulators such as Capicua and RBM17, and forms pathogenic nuclear inclusions within Purkinje cells, inferior olivary neurons, and pontine nuclei. This selective neuronal degeneration drives the characteristic slowly progressive cerebellar ataxia with pyramidal signs (hyperreflexia, extensor plantar responses) and ophthalmoplegia seen in this patient. (Harrison 21e Ch 436; Opal GeneReviews SCA1 2024)
Why each distractor is wrong
Option 2: This describes Friedreich ataxia (FRDA), caused by GAA repeat expansion in the FXN gene on chromosome 9 (marked C in the diagram), not ATXN1. Friedreich ataxia presents with loss of frataxin and mitochondrial dysfunction, and typically features areflexia and cardiomyopathy—not the hyperreflexia and pyramidal signs seen here.
Option 3: This describes Huntington disease (HTT gene on chromosome 4, marked B in the diagram), which presents with prominent chorea, cognitive decline, and psychiatric symptoms. SCA1 is distinguished by cerebellar ataxia with pyramidal signs and ophthalmoplegia, not chorea.
Option 4: This describes SCA2 (ATXN2 on chromosome 12, marked D in the diagram), which classically presents with slow saccades and areflexia. The patient's hyperreflexia and extensor plantar responses are hallmarks of SCA1, not SCA2.
High-YieldNEET PG
SCA1 = polyQ expansion in ATXN1 (Chr 6p23) → nuclear inclusions in cerebellum + brainstem → cerebellar ataxia + pyramidal signs (distinguishes from SCA2/SCA6); autosomal dominant with anticipation.
Harrison 21e Ch 436; Opal GeneReviews SCA1 2024
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