A 42-year-old man presents with progressive involuntary movements, cognitive decline, and psychiatric symptoms. His father died at age 55 with similar manifestations. Examination reveals widespread chorea, motor impersistence, abnormal saccades, and gait instability. MRI shows bilateral caudate atrophy with widening of the frontal horns. Genetic testing reveals a heterozygous CAG repeat expansion (47 repeats) in exon 1 of the HTT gene on the structure marked **A** in the diagram. Which of the following best explains the pathophysiology of the movement disorder in this patient?
A. Mutation in the FXN gene causing mitochondrial dysfunction and selective loss of Purkinje cells in the cerebellum
B. Loss of dopaminergic neurons in the substantia nigra pars compacta, resulting in reduced dopamine availability in the striatum
C. Selective degeneration of medium spiny neurons in the striatum, leading to loss of GABAergic/enkephalinergic inhibition of the indirect pathway and disinhibition of thalamocortical projections
D. Expansion of CTG repeats in the DMPK gene leading to myotonic dystrophy with secondary chorea
Explanation
Why option 1 is correct
The HTT CAG expansion (≥40 repeats) on chromosome 4p16.3 encodes a mutant huntingtin protein with an expanded polyglutamine tract that causes selective degeneration of medium spiny neurons in the striatum (caudate > putamen). These neurons normally provide GABAergic and enkephalinergic inhibition via the indirect pathway. Their loss leads to disinhibition of thalamocortical projections, resulting in the characteristic chorea seen in this patient. This is the core pathophysiologic mechanism of Huntington disease and directly explains the movement disorder observed on examination (Harrison 21e Ch 436; Caron GeneReviews 2023).
Why each distractor is wrong
Option 2: Loss of dopaminergic neurons in the substantia nigra is the hallmark of Parkinson disease, not Huntington disease. While Huntington disease may show bradykinesia and parkinsonism in later stages, the primary pathology is striatal medium spiny neuron degeneration, not substantia nigra pathology. The prominent chorea in this patient is inconsistent with primary dopaminergic loss.
Option 3: Mutation in the FXN gene (chromosome 9) causes Friedreich ataxia, not Huntington disease. Friedreich ataxia presents with progressive ataxia, sensory loss, and cardiomyopathy—not chorea, cognitive decline, and psychiatric symptoms. The selective loss of Purkinje cells occurs in cerebellar ataxias, not HD.
Option 4: CTG repeat expansion in the DMPK gene on chromosome 19 causes myotonic dystrophy (DM1), not Huntington disease. Myotonic dystrophy presents with myotonia, muscle weakness, and cataracts—not the chorea, caudate atrophy, and executive dysfunction seen in this patient. The genetic locus and clinical phenotype are entirely distinct.
High-YieldNEET PG
Huntington disease = CAG expansion on chromosome 4p16.3 → mutant huntingtin → striatal medium spiny neuron degeneration → loss of indirect pathway inhibition → chorea + cognitive decline + psychiatric features.
Harrison 21e Ch 436; Caron GeneReviews Huntington Disease 2023
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