Movement Disorders: Parkinson & Huntington
A Step 1 pairing of Parkinson and Huntington disease as opposite ends of the basal ganglia circuit — pathophysiology, TRAP vs chorea presentation, Lewy bodies vs caudate atrophy, and levodopa vs VMAT2-inhibitor management, with next-best-step vignette logic and a side-by-side comparison.
Two Ends of One Circuit
The basal ganglia tune movement through two loops leaving the striatum. The direct pathway (dopamine acts on excitatory D1 receptors) promotes movement; the indirect pathway (dopamine acts on inhibitory D2 receptors) suppresses movement. Net effect: dopamine from the substantia nigra pars compacta facilitates movement.
Movement disorders fall into two camps:
- Hypokinetic — too little movement. Prototype: Parkinson disease (loss of nigral dopamine).
- Hyperkinetic — too much movement. Prototype: Huntington disease (loss of striatal GABAergic neurons → chorea).
Both are neurodegenerative and both wound the basal ganglia, but from opposite ends of the same wiring — which is exactly why Step 1 pairs them. Parkinson strips the dopaminergic input; Huntington destroys the striatal output neurons of the indirect (movement-suppressing) pathway first, releasing excess movement.
- Lesion: degeneration of dopaminergic neurons in the substantia nigra pars compacta → dopamine depletion → hypokinesia. Grossly, the SNc loses its pigment (depigmentation).
- Histology: Lewy bodies = round eosinophilic intracytoplasmic inclusions of α-synuclein.
- Cardinal motor signs — TRAP: resting tremor ("pill-rolling," 4–6 Hz, worst at rest, improves with action), cogwheel rigidity, akinesia/bradykinesia, postural instability (late). Onset is characteristically asymmetric.
- Also: masked facies, micrographia, shuffling/festinating gait, stooped posture, hypophonia.
- Non-motor prodrome (early clues): anosmia, REM sleep behavior disorder, constipation, depression — may precede motor signs by years.
- Mostly sporadic; dementia is a late feature. Contrast dementia with Lewy bodies, where cognitive decline + visual hallucinations occur before/within 1 yr of parkinsonism.
- Levodopa + carbidopa — most effective symptomatic therapy. Levodopa crosses the BBB (dopamine can't); carbidopa inhibits peripheral DOPA decarboxylase → less nausea/hypotension, more central delivery. Chronic use → "on–off" fluctuations, wearing-off, dyskinesias.
- Dopamine agonists (pramipexole, ropinirole) — often preferred in younger patients to delay levodopa; beware impulse-control disorders (gambling, hypersexuality) and somnolence.
- MAO-B inhibitors (selegiline, rasagiline) and COMT inhibitors (entacapone, tolcapone) — block dopamine breakdown / prolong levodopa.
- Amantadine — reduces levodopa-induced dyskinesias.
- Anticholinergics (benztropine, trihexyphenidyl) — tremor-predominant young patients; avoid in elderly (confusion).
- Deep brain stimulation of the subthalamic nucleus or GPi — refractory motor fluctuations.
Board rule of thumb: disabling symptoms + older patient → start levodopa; younger/mild → dopamine agonist first.
Vignette: A 68-year-old man has 1 year of a right-hand tremor that is worst when the hand rests in his lap and disappears when he reaches for a cup. His wife reports smaller handwriting, a softer voice, and a "blank" expression. Exam: cogwheel rigidity, reduced right arm swing, and a shuffling gait.
Diagnosis: Parkinson disease (asymmetric resting tremor + bradykinesia + rigidity).
Next best step:
- Clinical diagnosis — no imaging needed in classic cases; MRI is normal. If atypical, a DaTscan (dopamine-transporter SPECT) shows reduced striatal uptake.
- A sustained response to levodopa both supports the diagnosis and is the most effective therapy.
Buzzword traps:
- Action/postural tremor that improves with alcohol + family history → essential tremor (treat with propranolol).
- Symmetric parkinsonism after an antipsychotic or metoclopramide → drug-induced parkinsonism (stop the D2 blocker).
- Genetics: autosomal dominant CAG trinucleotide-repeat expansion in the HTT gene on chromosome 4p. 36–39 repeats = reduced penetrance; ≥40 → full penetrance; onset typically 30–50 yrs.
- Anticipation: repeats expand across generations → earlier, more severe disease, especially with paternal transmission (expansion in spermatogenesis).
- Pathophysiology: loss of GABAergic medium spiny neurons in the striatum (caudate > putamen) — indirect pathway first → chorea. ↓GABA and ↓ACh; glutamate/NMDA excitotoxicity and mutant huntingtin (polyglutamine) aggregates contribute.
- Imaging: caudate atrophy → "boxcar" ventricles (dilated frontal horns of the lateral ventricles).
- Clinical triad: chorea + psychiatric/behavioral change (depression, irritability, ↑ suicide risk) + progressive dementia.
- Juvenile (Westphal) variant: rigidity/bradykinesia rather than chorea; paternal inheritance, largest repeat expansions.
Vignette: A 42-year-old woman is brought in for 8 months of irritability, depression, and "fidgety," dance-like movements of her hands and face that she cannot suppress. Her father developed similar movements and dementia in his 40s and died by suicide. Cognition is mildly impaired.
Diagnosis: Huntington disease (mid-adult chorea + psychiatric change + dementia + autosomal-dominant family history).
Next best step:
- Genetic testing for the CAG repeat count in HTT is confirmatory — offer genetic counseling first.
- MRI may show caudate atrophy / boxcar ventricles but is supportive, not diagnostic.
Management (symptomatic only — no disease-modifying therapy):
- Chorea → VMAT2 inhibitors: tetrabenazine or deutetrabenazine (monitor for depression/suicidality); dopamine antagonists (e.g., risperidone) help when psychosis/agitation coexists.
- Treat depression (SSRIs) and screen suicide risk at every visit.
- TRAP = Parkinson's four cardinal signs: Tremor (resting) · Rigidity (cogwheel) · Akinesia/bradykinesia · Postural instability.
- CAG repeats tell you what Huntington's caudate loses: Caudate (atrophies) · ACh ↓ · GABA ↓.
- "Hunt 4 an animal" → Huntington = chromosome 4 (CAG expansion).
- "Park your Mercedes-Benz" → benztropine (anticholinergic) for Parkinson tremor.
Parkinson vs Huntington — Side by Side
| Feature | Parkinson disease | Huntington disease |
|---|---|---|
| Movement | Hypokinetic (slow, rigid) | Hyperkinetic (chorea) |
| Core lesion | Dopaminergic neurons, substantia nigra pars compacta | GABAergic medium spiny neurons, striatum (caudate) |
| Neurotransmitter | ↓ Dopamine | ↓ GABA, ↓ ACh (relative ↑ dopamine) |
| Inheritance | Mostly sporadic | Autosomal dominant — CAG on chr 4; anticipation |
| Histology | Lewy bodies (α-synuclein) | Neuronal huntingtin (polyQ) inclusions |
| Typical onset | ~60s | 30–50s |
| Imaging | Normal MRI; ↓ DaTscan uptake | Caudate atrophy, boxcar ventricles |
| Hallmark | TRAP, masked facies | Chorea + dementia + psychiatric change |
| First-line Rx | Levodopa/carbidopa | VMAT2 inhibitor (tetrabenazine) |
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