Huntington's Disease
Summary
Huntington's Disease (HD) is a progressive, fatal, autosomal dominant neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the HTT gene on Chromosome 4. The resultant toxic Huntingtin protein aggregates in neurons, causing selective degeneration of the Striatum (Caudate & Putamen). The classic triad consists of Movement Disorder (Chorea), Cognitive Decline (Subcortical Dementia), and Psychiatric Disturbance (Depression/Aggression). Symptoms typically begin in mid-life (30-50 years). "Juvenile HD" presents differently with rigidity (Westphal variant). Diagnosis is genetic. There is no cure; management focuses on symptom control (Tetrabenazine for chorea) and palliative care. [1,2]
Key Facts
- Prevalence: 10-12 per 100,000 (Western populations).
- Inheritance: Autosomal Dominant (50% risk to offspring).
- Gene: HTT (Chr 4p16.3).
- Mutational Mechanism: CAG Repeat Expansion (>36 repeats is pathogenic).
- Anticipation: Disease occurs earlier in subsequent generations, typically with Paternal Transmission (sperm instability).
- Pathology: Atrophy of Caudate Nucleus ("Boxcar Ventricles").
- Death: Usually 15-20 years after onset (Pneumonia/Suicide).
Clinical Pearls
"It's not just Chorea": The psychiatric symptoms (Apathy, Irritability, Suicide) often precede the movement disorder by years. A "personality change" in a 35-year-old with a family history is a red flag.
"The Milkmaid's Grip": A classic sign where the patient cannot maintain a constant grip; they squeeze and relax rhythmically due to chorea.
"Can't stick tongue out": Motor impersistence. They can protrude it but cannot keep it out (Trumpet player's sign).
"Suicide Risk": The risk is significantly elevated, especially just before or just after diagnosis (when insight is preserved).
Incidence and Prevalence
- Western Europe: High prevalence (10-12/100k).
- East Asia/Africa: Much lower (1/100k).
- Age of Onset: Mean 40 years.
- Juvenile HD (<20y): 5-10%.
- Late onset (>60y): 20%.
The Genetic Bomb (CAG)
- Normal: The HTT gene contains a CAG repeat segment (glutamine). Normal is <27 repeats.
- Expansion: In HD, this segment expands.
- 27-35: Intermediate (Will not get disease, but risk to children).
- 36-39: Reduced Penetrance (May or may not get disease).
- >40: Full Penetrance (100% will get disease).
- >60: Juvenile HD.
- Mechanism: The expanded "Polyglutamine tract" makes the Huntingtin protein sticky.
- Aggregation: Mutant Huntingtin forms intracellular inclusions (aggregates).
- Toxicity:
- Transcription interference.
- Mitochondrial dysfunction.
- BDNF (Brain Derived Neurotrophic Factor) depletion.
The Striatal Death
- Main Target: GABAergic Medium Spiny Neurons in the Caudate and Putamen.
- Circuitry:
- Loss of GABA neurons -> Loss of inhibition on the Thalamus.
- Thalamus becomes overactive -> Excites Cortex -> Chorea (Hyperkinetic).
- Late Stage: Direct pathway also degenerates -> Rigidity/Bradykinesia (Hypokinetic).
A. Motor Symptoms
- Chorea:
- Brief, involuntary, irregular movements. "Dance-like".
- Initially incorporated into voluntary movements (parakinesia - e.g. touching face to hide a twitch).
- Flows from one body part to another.
- Dystonia: Sustained posturing (more common in late/juvenile HD).
- Saccadic Dysfunction:
- Slow saccades.
- Difficulty initiating saccades (Head thrusts - "Ocular Apraxia").
- Dysphagia/Dysarthria: Major cause of mortality (Aspiration).
B. Cognitive Symptoms (Subcortical Dementia)
C. Psychiatric Symptoms
D. Juvenile HD (Westphal Variant)
Genetic Testing (The Gold Standard)
- PCR: Measures CAG repeat length.
- Diagnostic Testing: For symptomatic patients. Requires consent.
- Predictive Testing: For asymptomatic at-risk relatives. Needs strict protocol (Counseling, Cooling-off period).
Imaging
- MRI Brain:
- Caudate Atrophy: Flattening of the caudate head leads to enlargement of the frontal horns of the lateral ventricles ("Boxcar Ventricles").
- Putaminal atrophy.
- Global atrophy (late).
- PET: Striatal hypometabolism (precedes atrophy).
3. Deep Dive: Juvenile Huntington's Disease (JHD)
"The Westphal Variant."
- Definition: Onset before age 20. (Approx 5-10% of cases).
- Genetics: Usually >60 CAG repeats. Almost always Paternal Transmission (massive expansion in spermatogenesis).
- Phenotype:
- Rigidity (Not Chorea).
- Bradykinesia.
- Seizures (50% - rare in adult HD).
- Learning Difficulty (Decline in school performance is often the first sign).
- Prognosis: Rapidly progressive. Death often within 10 years.
4. Case Studies
Case A: The "Clumsy" Dad.
- 45-year-old man. Wife complains he is irritable and dropping things.
- Exam: Mild chorea in fingers (Piano playing).
- Diagnosis: HD (42 repeats).
- Family: His father died in a "psych ward" at 50.
- Issue: He has a 20-year-old daughter who wants to act. She decides NOT to test.
Case B: The Tragedy of Anticipation.
- A 60-year-old man is diagnosed with mild chorea (39 repeats). Late onset.
- His son (30 years old) says "I've been feeling shaky too". Test: 45 repeats. (Anticipation).
- His grandson (5 years old) has been having seizures and failing school. Test: 65 repeats. (Juvenile HD).
- Diagnosis: Three generations affected simultaneously.
Management Algorithm
(Renumbered)
DIAGNOSIS CONFIRMED
↓
┌───────────┼───────────────┐
CHOREA PSYCH SOCIAL/
MGMT MGMT SAFETY
↓ ↓ ↓
- Tetrabenazine - SSRIs - Dietician (High cal)
- Neuroleptics - Mood Stab - SALT (Dysphagia)
- Deutetra- - Antipsych - Advance Directives
benazine - Genetic Counselling
1. Pharmacological
- Chorea:
- Only treat if disabling.
- Tetrabenazine: VMAT2 inhibitor (depletes Dopamine).
- Side Effect: Depression/Suicidality, Parkinsonism.
- Olanzapine / Risperidone: Antipsychotics. Good if psych symptoms co-exist.
- Psychiatric:
- SSRIs (Citalopram) for depression/OCD.
- Mood stabilisers (Valproate) for irritability.
- Dementia:
- None proven. Rare use of Donepezil.
2. Multi-disciplinary
- SALT: Texture modification to prevent aspiration.
- Dietician: HD patients have massive calorie expenditure (chorea + metabolic state). They need 3000-5000 kcal/day to maintain weight.
- Physio: Falls prevention.
3. Future Therapies
- Huntingtin Lowering:
- ASO (Antisense Oligonucleotides): Tominersen. Injected intrathecally to degrade HTT mRNA. (Trials ongoing/halted due to efficacy issues).
- Viral Vectors: CRISPR/Cas9.
"Palliative Neuromodulation." While less effective than in Parkinson's, DBS is used for severe, drug-resistant chorea.
- Target: Globus Pallidus Internus (GPi).
- Rationale:
- In HD, the indirect pathway dies, leading to disinhibition of the thalamus (excess movement).
- Stimulating the GPi can restore the inhibitory tone.
- Outcome: Reduces chorea significantly. Does NOT improve dementia, psychiatric symptoms, or disease progression. In fact, it can worsen cognition.
- Indication: Purely for severe motor symptoms interfering with life (e.g. violent flailing).
8. Deep Dive: The Huntingtin Protein (HTT)
"The Sticky Toxic Blob."
- Normal Function:
- Huntingtin is a massive protein (348 kDa).
- Essential for embryonic development (Knockout mice die in utero).
- Involved in axonal transport (BDNF delivery) and synaptic function.
- The Mutant Protein (mHTT):
- The elongated Polyglutamine tail (PolyQ) changes the protein's shape.
- Gain of Function Toxicity:
- Aggregation: It clumps together into "Inclusion Bodies" inside the nucleus and cytoplasm.
- Sequestration: The sticky clumps trap other vital proteins (transcription factors like CBP), depleting the cell of essential tools.
- Mitochondrial Poisoning: It interferes with energy production.
- Selective Vulnerability:
- Why does the Striatum die first?
- Possible reason: The Striatum is heavily dependent on BDNF (Brain Derived Neurotrophic Factor) delivered from the cortex. mHTT blocks BDNF transport.
- Aspiration Pneumonia: Leading cause of death.
- Suicide: Second leading cause.
- Trauma: From falls (Safety helmet?).
- Malnutrition: Hypercatabolic state.
- Progressive: Inevitable decline.
- Duration: Death usually occurs 15-20 years after diagnosis.
- End of Life: Patient becomes bedbound, akinetic, mute.
- Juvenile HD: Faster progression (death in 10 years).
- EHDN (European Huntington's Disease Network) Guidelines.
- AAN Guidelines on Chorea treatment.
What is Huntington's?
It is a disease of the brain that affects movement, thinking, and mood. It is passed down in families.
What causes it?
It is caused by a "stutter" in the genetic code. A specific gene (HTT) has a section that repeats too many times. This produces a sticky protein that clogs up brain cells.
Can we test for it?
Yes, a blood test can count the repeats. If you have a parent with HD, you have a 50/50 chance. We offer a special testing programme for people who want to know their status before symptoms start.
Is there a cure?
Not yet. But we have medicines to calm the movements and help with mood. Research into "gene silencing" drugs is very active.
- Walker FO. Huntington's disease. Lancet. 2007;369:218-28.
- Ross CA, Tabrizi SJ. Huntington's disease: from molecular pathogenesis to clinical treatment. Lancet Neurol. 2011;10:83-98.
Common Exam Questions
1. Genetics:
- Q: What is Anticipation?
- A: The phenomenon where the disease appears earlier and more severely in successive generations due to expansion of the CAG repeat. It is most prominent in Paternal transmission.
2. Management:
- Q: What is the mechanism of Tetrabenazine?
- A: It inhibits VMAT2 (Vesicular Monoamine Transporter 2), preventing packaging of dopamine into vesicles. This depletes presynaptic dopamine.
3. Signs:
- Q: How do you demonstrate "Motor Impersistence"?
- A: Ask the patient to stick their tongue out and KEEP it out. In HD, they cannot sustain it; it darts in and out ("Jack-in-the-box" tongue).
| CAG Repeats | Classification | Phenotype | Offspring Risk |
|---|---|---|---|
| < 26 | Normal | Unaffected | None |
| 27 - 35 | Intermediate | Unaffected | Risk of Expansion. Children might get HD if male transmission. |
| 36 - 39 | Reduced Penetrance | May or may not get HD | 50% risk. |
| 40+ | Full Penetrance | Will get HD | 50% risk. |
| 60+ | Juvenile | Juvenile HD (<20y) | 50% risk. |
Important: A repeat count of 28 is normal for the patient, but unstable. It can expand to 40 in the next generation. This explains sporadic cases ("New mutations").
"The Right Not to Know." Testing an asymptomatic person for a fatal, incurable disease requires a rigorous protocol (International Guidelines).
- session 1 (Pre-test): Discuss motivation, impact on insurance/career/family. "What will you do if it's positive?". Check suicide risk.
- Cooling Off Period: usually 4-6 weeks. Patient reflects.
- Session 2 (The Test): Blood is drawn ONLY if patient persists.
- Session 3 (The Result): Must be given in person. Never over phone. Support person must be present.
- Post-test Support: Psychology follow-up.
Forbidden: Testing minors (<18). Children have a "right to an open future". Parents cannot test their kids "just to know". (Unless symptomatic).
"Nursing the Rigid Phase." In advanced HD, chorea fades and is replaced by Parkinsonism/Dystonia.
- Nutrition: PEG feeding is often discussed. High calorie feed.
- Communication: Patient is often anarthric (unable to speak) but comprehension may be preserved. Use eye-gaze technology.
- Skin: High risk of pressure sores due to immobility + dystonic posturing.
- Palliative Care: Managing terminal agitation and secretions.
Advanced Viva Questions
1. Genetics:
- Q: What is the "Sherman Paradox"?
- A: An old term for Anticipation (before we knew about CAG repeats). It described how the disease worsened in subsequent generations.
2. Pathology:
- Q: Which neurones consistute the Striatum?
- A: GABAergic Medium Spiny Neurons (95%). These are the ones that die in HD. Interneurons are spared.
3. Pharmacology:
- Q: What is Deutetrabenazine?
- A: A deuterated form of Tetrabenazine. The deuterium gives it a longer half-life and smoother pharmacokinetic profile, reducing peak-dose side effects (less depression/sedation).
17. Reproductive Options (Expanded)
- PGD (Pre-implantation Genetic Diagnosis):
- IVF. Embryos are tested at day 5. Only "CAG-normal" embryos are implanted.
- "Exclusion Testing": You can do PGD without knowing your own status. (e.g. Ensure the baby doesn't have the grandparent's chromosome, without testing the parent).
- Prenatal Testing:
- CVS/Amnio at 11-15 weeks.
- Dilemma: If positive, will you terminate? You must decide this before testing.
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