Autosomal dominant CAG trinucleotide repeat disorder producing chorea, psychiatric symptoms, and progressive cognitive decline.
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Question 1NeurologyMedium
A 48-year-old man with a family history of an autosomal dominant neurodegenerative disease presents with progressive chorea, irritability, and cognitive decline. Genetic testing reveals 44 CAG trinucleotide repeats in the HTT gene. As his disease progresses over the next decade, which of the following complications is he most likely to develop?
- AAcute myocardial infarction
- BIschemic stroke
- CStatus epilepticus
- DAspiration pneumonia
Reveal answer & full explanation
Correct answer: D — Aspiration pneumonia
- AAcute myocardial infarction
- BIschemic stroke
- CStatus epilepticus
- DAspiration pneumonia✓
Why Aspiration pneumonia is correct
- Huntington disease is an autosomal dominant disorder caused by CAG trinucleotide repeat expansion in the HTT gene, leading to neuronal loss in the striatum and cortex.
- Progressive motor dysfunction includes chorea, dystonia, and eventually bulbar involvement with dysphagia.
- Aspiration pneumonia is the most common cause of death in Huntington disease, driven by impaired swallowing and weakened cough.
Why the others are wrong
- Status epilepticus — Seizures and status epilepticus can occur in juvenile-onset Westphal variant but are uncommon in adult Huntington disease and are not the leading complication.
- Ischemic stroke — Ischemic stroke is not characteristic of Huntington disease, which is a primary neurodegenerative process rather than a vascular one.
- Acute myocardial infarction — Acute MI is not directly linked to the HTT mutation; cardiovascular disease occurs at baseline population rates and is not the predominant terminal event.
Question 2NeurologyMedium
A 42-year-old man is brought in by his wife for 8 months of involuntary writhing movements of his hands and face and a year of worsening irritability and apathy. His father died in a nursing home with dementia and a "movement problem." On exam he has brief, irregular, dance-like movements that flit between body parts, slow eye saccades, and inability to keep his tongue protruded. Mental status shows slowed processing and impaired executive function with relatively preserved memory. Which of the following is the most appropriate next diagnostic test?
- AHTT gene CAG repeat genetic testing
- BBrain MRI with caudate volumetry
- CAnti-streptolysin O antibody titer
- DSerum ceruloplasmin and urine copper
Reveal answer & full explanation
Correct answer: A — HTT gene CAG repeat genetic testing
- AHTT gene CAG repeat genetic testing✓
- BBrain MRI with caudate volumetry
- CAnti-streptolysin O antibody titer
- DSerum ceruloplasmin and urine copper
Why HTT gene CAG repeat genetic testing is correct
- The vignette is a textbook presentation of Huntington disease: adult-onset chorea, psychiatric change (irritability, apathy), subcortical dementia (executive dysfunction with preserved memory), slow saccades and motor impersistence, plus an autosomal dominant family history (father with dementia and a movement disorder).
- Diagnosis is confirmed by measuring the CAG trinucleotide repeat number in the huntingtin (HTT) gene: >=40 is fully penetrant and >=36 is diagnostic in a symptomatic patient. This is both the confirmatory and the definitive next study once HD is clinically suspected.
- Because the patient is symptomatic, this is diagnostic testing rather than presymptomatic predictive testing, though genetic counseling still accompanies it given implications for at-risk relatives.
Why the others are wrong
- Serum ceruloplasmin and urine copper screen for Wilson disease, a real chorea mimic, but Wilson typically presents in a younger patient with hepatic dysfunction and Kayser-Fleischer rings; here the dominant inheritance pattern and classic HD phenotype point elsewhere, making this a non-discriminating mimic workup rather than the confirmatory test.
- Brain MRI with caudate volumetry may show caudate atrophy with enlarged frontal horns, but this is a late, nonspecific finding and a normal MRI does not exclude HD; imaging does not establish the diagnosis the way the genetic test does.
- Anti-streptolysin O antibody titer evaluates for Sydenham chorea, a post-streptococcal disorder of children and young adults that is self-limited; it does not fit a 42-year-old with progressive dementia and dominant inheritance.
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Risk factors
- Affected parent (autosomal dominant inheritance; 50% risk to each offspring)
- Paternal transmission predisposes to anticipation — earlier onset and longer repeat in next generation
- CAG repeat length: ≥40 fully penetrant; 36-39 reduced penetrance; 27-35 intermediate (no disease but risk of expansion); ≤26 normal
Pathophysiology
Expanded CAG repeats produce mutant huntingtin protein with an elongated polyglutamine tract that misfolds, aggregates, and causes selective neuronal degeneration. Medium spiny GABAergic neurons of the striatum are preferentially lost, particularly those projecting to the lateral globus pallidus (indirect pathway), producing disinhibition of thalamocortical drive and chorea. Cortical neurodegeneration contributes to cognitive decline.
Clinical presentation
Symptoms
- Movement: chorea (early), dystonia, bradykinesia, dysarthria, dysphagia, gait impairment; rigidity in juvenile or late disease
- Psychiatric (often the first complaint): depression, irritability, apathy, anxiety, obsessive-compulsive features, psychosis; elevated suicide risk
- Cognitive: subcortical dementia with executive dysfunction, impaired attention, and slowed processing — memory relatively preserved until later
- Weight loss despite adequate caloric intake
Signs / physical exam
- Chorea — involuntary, brief, irregular, dance-like movements that flit from one body part to another
- Motor impersistence ('milkmaid grip' — inability to maintain sustained tongue protrusion or hand grip)
- Abnormal saccades — slow and hypometric, often the earliest motor sign
- Oculomotor apraxia (head thrust to initiate gaze)
- Hyperreflexia and gait instability
Classic findings
Adult with new chorea + family history of dementia or movement disorder + early personality change.
Differential diagnosis
- Sydenham chorea — Post-streptococcal, children/young adults, self-limited, jerking movements with hypotonia, anti-streptolysin O
- Wilson disease — Young adult with movement disorder + hepatic dysfunction, Kayser-Fleischer rings, low ceruloplasmin, high 24-h urinary copper
- Drug-induced chorea — Levodopa, neuroleptics (tardive), stimulants, cocaine, oral contraceptives, antiepileptics
- Neuroacanthocytosis — Chorea + acanthocytes on smear + elevated CK + self-mutilation behaviors
- Benign hereditary chorea — Childhood onset, non-progressive, TITF1 mutation
- C9orf72 expansion — Can produce HD phenocopy with motor and behavioral features
- SLE / antiphospholipid syndrome — Chorea in young woman with autoimmune features
Diagnostic workup
Diagnostic criteria
Clinical motor signs + positive genetic test (CAG ≥36, fully penetrant ≥40).
Labs
- Genetic testing for CAG repeat number in HTT (diagnostic and predictive)
- Pre-test and post-test counseling are mandatory for presymptomatic testing
- Rule out mimics: ceruloplasmin and 24-h urine copper, peripheral smear for acanthocytes, anti-streptolysin O, ANA/lupus serologies, TFTs
Imaging
- MRI brain — caudate atrophy with enlarged frontal horns of lateral ventricles ('boxcar ventricles'); later cortical atrophy
- FDG-PET shows striatal hypometabolism preceding atrophy
Treatment
First-line
- Tetrabenazine or deutetrabenazine — VMAT2 inhibitors that deplete presynaptic dopamine; reduce chorea. Monitor for depression/suicidality, parkinsonism, QT prolongation
- Valbenazine — newer VMAT2 inhibitor with similar efficacy and arguably better tolerability
- Atypical antipsychotics (olanzapine, risperidone, quetiapine, aripiprazole) — useful when chorea coexists with psychosis or aggression
- SSRIs (sertraline, citalopram, escitalopram) for depression and irritability
- Speech and swallow therapy; PT/OT; nutrition counseling for caloric intake
Juvenile-onset (Westphal)
- Rigidity and dystonia predominate over chorea — VMAT2 inhibitors often unhelpful
- Levodopa or dopamine agonists may help rigidity
- Seizure management with standard AEDs
Genetic counseling
- Presymptomatic testing reserved for adults with mature decision-making capacity after multidisciplinary counseling
- Prenatal and preimplantation genetic diagnosis available
- Address insurance and confidentiality concerns
Second-line / adjunct
- Amantadine for chorea (limited evidence)
- Botulinum toxin for focal dystonia
- Hospice/palliative care in advanced disease
Complications
- Aspiration pneumonia — most common cause of death
- Falls and traumatic injury
- Severe weight loss / malnutrition
- Suicide (substantially elevated risk, particularly around the time of genetic diagnosis and loss of independence)
- Loss of capacity for ADLs and need for institutional care
PANCE pearls
- VMAT2 inhibitors can precipitate or worsen depression and suicidality — screen psychiatric status at every visit.
- Anticipation is more pronounced with paternal inheritance — sons of an affected father may present earlier.
- Slow saccades and motor impersistence appear before frank chorea — examine eye movements and ask the patient to stick out the tongue.
- Avoid antidopaminergic agents for non-essential nausea/sedation when atypical agents are available — they can worsen parkinsonism in late disease.
- Caudate atrophy on MRI is a late finding; normal imaging does not exclude HD when CAG repeat is positive.
References
- AAN 2012 — Armstrong MJ, Miyasaki JM. Evidence-based guideline: Pharmacologic treatment of chorea in Huntington disease. Neurology 2012;79:597-603.
- EHDN — European Huntington's Disease Network guidelines on genetic testing (Mac Leod et al., Clin Genet 2013).
- TETRA-HD — Huntington Study Group. Tetrabenazine as antichorea therapy in Huntington disease. Neurology 2006;66:366-372.
- First-HD — Huntington Study Group. Effect of deutetrabenazine on chorea among patients with HD. JAMA 2016;316:40-50.