Q-Bank Breakdown: Huntington disease — Why Every Answer Choice Matters

You can memorize Huntington disease in one line, but Q-banks won’t reward that. They’ll reward the pattern recognition—and the ability to explain why the wrong answers are wrong. Let’s do this the way test writers think: one classic vignette, then a rapid, high-yield teardown of every answer choice.

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Clinical Vignette (USMLE-style)

A 42-year-old man is brought in by his partner for “personality changes” and increasing clumsiness over 18 months. He has become irritable, impulsive, and has been written up at work for poor judgment. On exam, he has intermittent, nonrhythmic, “dance-like” movements of his face and distal upper extremities. He has difficulty with rapid alternating movements and displays motor impersistence (cannot sustain tongue protrusion). His father died in his 50s after years of progressive neurologic decline. MRI shows atrophy of the caudate nuclei with enlargement of the frontal horns of the lateral ventricles.

Question: What is the underlying genetic mechanism?

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The Correct Answer: CAG trinucleotide repeat expansion with anticipation

Why it’s Huntington disease

This stem screams Huntington disease (HD):

• Age: typically 30–50
• Neuropsychiatric changes (irritability, impulsivity, depression, executive dysfunction) often precede motor findings
• Chorea: nonrhythmic, flowing, dance-like movements
• Motor impersistence (classic: “milkmaid grip,” inability to keep tongue out)
• Family history consistent with autosomal dominant
• MRI: caudate atrophy $\rightarrow$ enlarged frontal horns (“boxcar ventricles”)

The genetic mechanism (the testable core)

• Mutation: CAG repeat expansion in the HTT gene on chromosome 4
• Product: expanded polyglutamine tract (CAG = glutamine)
• Inheritance: autosomal dominant
• Anticipation: repeats expand in successive generations, usually worse/earlier onset
  • Classically more prominent with paternal transmission (imperfect but high-yield)

Pathophysiology you’ll be asked to connect

• Degeneration of GABAergic medium spiny neurons in the striatum (especially caudate and putamen)
• Early effect: loss of inhibitory output $\rightarrow$ hyperkinesia (chorea)
• Later: more global basal ganglia dysfunction $\rightarrow$ parkinsonism/rigidity, dementia

High-yield clinical associations

• Psych: depression, irritability, impulsivity; suicide risk increased
• Cognition: executive dysfunction early
• Motor: chorea $\rightarrow$ later dystonia/rigidity
• Treatment is symptomatic:
  • Chorea: VMAT2 inhibitors (tetrabenazine, deutetrabenazine) or antipsychotics
  • Behavioral symptoms: SSRIs, atypical antipsychotics as appropriate

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Why Every Other Answer Choice Is Wrong (and How to Spot Them Fast)

Below are common distractors that test writers love to pair with Huntington disease. The trick is to anchor each distractor to age + movement type + key MRI/genetic clue.

Distractor 1: CGG repeat expansion in FMR1 (Fragile X)

Why they try it: both are trinucleotide repeats and both can show anticipation.

Why it’s wrong here:

• Fragile X presents with intellectual disability (often from childhood), autism features, and physical findings (e.g., macroorchidism, long face, large ears).
• Not a progressive midlife chorea + caudate atrophy syndrome.

High-yield pearl:
Fragile X = CGG expansion $\rightarrow$ methylation/silencing of FMR1 (X-linked).
Huntington = CAG expansion (AD).

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Distractor 2: GAA repeat expansion (Friedreich ataxia)

Why they try it: progressive neurodegeneration; may include gait issues.

Why it’s wrong here:

• Friedreich ataxia is typically childhood/adolescence onset
• Ataxia and loss of proprioception (dorsal column + spinocerebellar)
• Absent reflexes, positive Babinski, scoliosis; often hypertrophic cardiomyopathy and diabetes
• Not chorea, not caudate atrophy, not strong psych prodrome

High-yield pearl:
Friedreich = GAA on frataxin gene $\rightarrow$ mitochondrial dysfunction.

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Distractor 3: Deletion of DMD gene (Duchenne/Becker muscular dystrophy)

Why they try it: X-linked inherited disorder with progression.

Why it’s wrong here:

• Duchenne presents in early childhood with proximal weakness, Gowers sign, calf pseudohypertrophy, cardiomyopathy.
• Movement disorder + psychiatric changes + caudate atrophy is not a muscular dystrophy picture.

High-yield pearl:
Duchenne = out-of-frame deletion; Becker = in-frame. Both X-linked recessive.

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Distractor 4: Autoimmune demyelination with oligoclonal bands (Multiple sclerosis)

Why they try it: neurodegenerative/demyelinating category overlap; age can be similar.

Why it’s wrong here:

• MS classically has episodes separated in time and space (optic neuritis, INO, sensory changes, weakness) rather than a steadily progressive chorea syndrome.
• MRI in MS shows periventricular white matter lesions (e.g., Dawson fingers), not isolated caudate atrophy.

High-yield pearl:
MS = CNS demyelination, CSF oligoclonal IgG bands, often worse with heat (Uhthoff).

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Distractor 5: Loss of dopaminergic neurons in substantia nigra (Parkinson disease)

Why they try it: basal ganglia disease in similar age range; movement disorder.

Why it’s wrong here:

• Parkinsonism is hypokinetic: bradykinesia, rigidity, resting tremor, postural instability.
• Huntington is hyperkinetic early: chorea, fidgety movements, motor impersistence.
• Parkinson disease doesn’t classically give caudate atrophy with enlarged frontal horns.

Test-tip:
If you see dance-like movements + psych changes, think Huntington before Parkinson.

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Distractor 6: Copper accumulation due to ATP7B mutation (Wilson disease)

Why they try it: movement disorder + psychiatric symptoms + basal ganglia involvement in young adults.

Why it’s wrong here:

• Wilson is usually younger (teens to 20s, sometimes early 30s).
• Look for liver disease, Kayser–Fleischer rings, hemolysis, and mixed movement disorders (tremor, dystonia, parkinsonism).
• The stem’s MRI cue (caudate atrophy + enlarged frontal horns) is a Huntington classic, and family history points strongly to AD.

High-yield pearl:
Wilson labs: low ceruloplasmin, high urine copper. Treat with chelation (penicillamine, trientine) or zinc.

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Distractor 7: Prion disease (Creutzfeldt-Jakob disease)

Why they try it: neurodegenerative, rapidly progressive, can include movement abnormalities.

Why it’s wrong here:

• CJD is rapid (weeks to months), with rapidly progressive dementia and often myoclonus.
• EEG: periodic sharp wave complexes; MRI: cortical ribboning/basal ganglia hyperintensity—not the slow chorea + caudate atrophy story.

High-yield pearl:
CJD = spongiform changes, 14-3-3 protein in CSF (supportive), fatal quickly.

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One Table to Lock It In

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High-Yield Takeaways (What the Exam Wants)

• Huntington = CAG repeat expansion (polyglutamine) on chromosome 4, autosomal dominant, anticipation.
• Clinical triad to memorize:
  • Movement: chorea (hyperkinetic early)
  • Psych: irritability/depression/impulsivity
  • Cognition: executive dysfunction $\rightarrow$ dementia
• Imaging hallmark: caudate nucleus atrophy $\rightarrow$ enlarged frontal horns.
• Path: degeneration of GABAergic neurons in the striatum.