Huntington's Disease

1. Clinical Overview

Summary

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by an expanded CAG trinucleotide repeat in the huntingtin gene (HTT) on chromosome 4. It is characterised by a triad of motor dysfunction (classically chorea), cognitive decline, and psychiatric disturbance. The disease is relentlessly progressive, with death typically occurring 15-20 years after symptom onset. There is currently no cure or disease-modifying treatment; management is symptomatic. [1,2]

Key Facts

• Inheritance: Autosomal dominant with complete penetrance (≥40 repeats).
• Genetics: CAG repeat expansion in HTT gene (chromosome 4p16.3); normal less than 27, intermediate 27-35, reduced penetrance 36-39, pathogenic ≥40. [3]
• Incidence: 5-10 per 100,000 in Western populations; lower in Asian and African populations.
• Onset: Mean age 40 years (range 2-80 years); inversely correlated with CAG repeat length.
• Juvenile HD (Westphal variant): Onset less than 20 years; typically paternal inheritance (greater intergenerational instability); more severe, rapid progression.
• Prognosis: Mean survival 15-20 years from symptom onset; juvenile HD 10-15 years.
• Anticipation: Earlier onset and increased severity in successive generations due to CAG repeat expansion during spermatogenesis (paternal transmission) or oogenesis (maternal, less pronounced). [8]
• Penetrance: Nearly 100% if CAG ≥40 repeats and patient lives long enough; reduced penetrance (36-39 repeats) shows variable expressivity.

Clinical Pearls

The "Dancing" Disease: Chorea (from Greek "choreia" = dance) is the hallmark, but motor features evolve. Early chorea often gives way to dystonia, rigidity, and bradykinesia in late stages.

Psychiatric Symptoms First: Depression, irritability, and personality change often precede motor symptoms by 10-15 years. HD should be on the differential for psychiatric disease in someone with a family history.

Suicide Risk: HD has highest suicide rate of any neurological condition (5-10 times general population). Active screening essential at every visit.

Anticipation Trap: Paternal transmission causes greater CAG repeat expansion (meiotic instability during spermatogenesis) than maternal. A father with HD and 40-45 CAG repeats may have a child with 60+ repeats and juvenile-onset (Westphal variant). [8] This intergenerational instability increases with repeat length.

Weight Loss is Universal: Hypermetabolic state in HD results in progressive weight loss despite increased caloric intake. Patients may require 5,000-6,000 kcal/day to maintain weight. [9] This is due to increased energy expenditure from choreiform movements and hypothalamic dysfunction.

Cognitive Decline Precedes Motor Symptoms: Executive dysfunction and subtle cognitive changes can be detected 10-15 years before motor diagnosis using sensitive neuropsychological testing. [10] This prodromal phase is the target for future disease-modifying therapies.

---

2. Epidemiology

Incidence and Demographics

• Prevalence: 5-10 per 100,000 in populations of European ancestry. [4]
• Lower Prevalence: East Asia (less than 1 per 100,000), Africa (lower but underdiagnosed).
• Sex Distribution: Equal male and female.
• Age of Onset: Mean 40 years; range 2-80 years.
• Juvenile HD: 5-10% of cases; onset before 20 years.
• Late-Onset HD: 25% have onset after 50 years (often milder, shorter duration).

Genetic Epidemiology

CAG Repeat Length and Age of Onset Correlation

The CAG repeat length accounts for approximately 50-70% of the variability in age of onset. [11]

Formula for Estimated Onset: Age of onset (years) ≈ 60 - (CAG repeats - 35.5) × 1.2 (approximation; significant individual variability exists).

Risk Factors for Earlier Onset

• Larger CAG repeat length (inverse correlation with age of onset; accounts for 50-70% of variability). [11]
• Paternal transmission (greater repeat instability during spermatogenesis).
• Male sex (modest effect; possible modifier genes on sex chromosomes).
• Genetic modifiers: DNA repair genes (MLH1, MSH3, FAN1) modify age of onset by up to 6 years. [12]
• Somatic instability: CAG repeats can expand further in somatic tissues (particularly striatum), contributing to regional selectivity.

---

3. Pathophysiology

Step 1: Genetic Mutation

• Gene: HTT (huntingtin) on chromosome 4p16.3.
• Mutation: Expansion of CAG trinucleotide repeat in exon 1.
• Normal: 6-26 CAG repeats encode polyglutamine tract.
• Pathogenic: Greater than 39 repeats → abnormally long polyglutamine stretch.

Step 2: Mutant Huntingtin Protein

• Protein Misfolding: Expanded polyglutamine (> 39 repeats) causes abnormal protein conformation and beta-sheet structure.
• Aggregation: Mutant huntingtin (mHTT) forms intranuclear inclusions (neuronal intranuclear inclusions - NIIs) and cytoplasmic aggregates.
• Toxic Gain of Function: Aggregates disrupt cellular processes (transcription, axonal transport, proteostasis).
• Loss of Normal Function: Wild-type huntingtin (wtHTT) has neuroprotective roles (BDNF transport, anti-apoptotic signaling, endocytosis); loss contributes to neurodegeneration. [13]
• Proteolytic Cleavage: mHTT is cleaved by caspases and calpains, generating N-terminal fragments that are more toxic and aggregate-prone.

Step 3: Cellular Dysfunction

• Transcription Dysregulation: mHTT sequesters transcription factors (CREB-binding protein, Sp1, TAFII130), impairing gene expression (particularly BDNF, critical for striatal neuron survival). [14]
• Mitochondrial Dysfunction: Impaired Complex II-IV activity; reduced ATP production; increased oxidative stress and free radical generation.
• Excitotoxicity: Enhanced NMDA receptor sensitivity; impaired glutamate uptake; increased calcium influx leading to neuronal death.
• Impaired Axonal Transport: Disrupted kinesin/dynein-mediated bidirectional transport; deficient delivery of BDNF from cortex to striatum.
• Proteostasis Failure: Ubiquitin-proteasome system (UPS) and autophagy (macroautophagy, chaperone-mediated autophagy) overwhelmed by mHTT aggregates.
• ER Stress: Unfolded protein response (UPR) activation; prolonged ER stress triggers apoptosis.
• Synaptic Dysfunction: Early loss of corticostriatal synaptic plasticity (long-term potentiation and depression impaired). [15]

Step 4: Selective Neurodegeneration

• Primary Target: Medium spiny neurons (MSNs) in striatum (caudate and putamen) - GABAergic projection neurons.
  • "Indirect pathway MSNs (express D2 receptors, project to GPe): Affected first → loss of inhibition → chorea (hyperkinetic)."
  • "Direct pathway MSNs (express D1 receptors, project to GPi): Affected later → increased inhibition → rigidity, bradykinesia (hypokinetic)."
• Cortex: Layers III, V, VI affected (frontal lobes earliest; motor and prefrontal cortex) → cognitive and executive dysfunction.
• Other regions: Globus pallidus, thalamus, hypothalamus (metabolic dysfunction), substantia nigra (late).
• Pattern: Striatal atrophy (caudate > putamen) → cortical atrophy → white matter loss → generalized brain atrophy.
• Why MSNs?: High metabolic demand; dependent on cortical BDNF; express high levels of huntingtin; vulnerable to excitotoxicity. [16]

Step 5: Clinical Correlates

         STRIATAL DEGENERATION
                  ↓
    ┌─────────────┼─────────────┐
    ↓             ↓             ↓
INDIRECT        DIRECT       CORTICAL
PATHWAY         PATHWAY      ATROPHY
(early)         (late)
    ↓             ↓             ↓
CHOREA         RIGIDITY     COGNITIVE
(hyperkinetic)  BRADYKINESIA  DECLINE
               DYSTONIA     PSYCHIATRIC

Early (Indirect Pathway): Loss of inhibition → excessive movement (chorea). Late (Direct Pathway): Parkinsonism (rigidity, bradykinesia, dystonia). Cortical: Executive dysfunction, dementia, psychiatric symptoms.

---

4. Clinical Presentation

The Classic Triad

1. Motor Dysfunction

• Chorea (most recognisable): Involuntary, irregular, unpredictable movements.
• Dystonia: Sustained abnormal postures (late).
• Bradykinesia/Rigidity: Parkinsonism (late stage).
• Gait Disturbance: Wide-based, "dance-like" gait.
• Oculomotor Abnormalities: Impaired saccades, slowed initiation.
• Dysarthria: Slurred, explosive speech.
• Dysphagia: Progressive; major cause of morbidity.

2. Cognitive Decline

• Executive Dysfunction: Planning, organising, multitasking affected early.
• Psychomotor Slowing: Bradyphrenia.
• Memory: Retrieval problems (recognition relatively preserved).
• Visuospatial: Impaired.
• Progression: Subcortical dementia pattern → global dementia.

3. Psychiatric Disturbance

• Depression: Most common (40-60%); may precede motor symptoms by 5-10 years; major suicide risk factor. [17]
• Anxiety: Common (30-50%); often comorbid with depression.
• Irritability/Aggression: 30-50%; intermittent explosive episodes; impulsivity.
• Apathy: 30-75% (increases with disease progression); distinct from depression (lack of interest/motivation without sadness); correlates with frontal lobe dysfunction.
• Psychosis: 5-10%; paranoid delusions more common than hallucinations; late feature.
• Obsessive-Compulsive Behaviors: Increased frequency (10-50%); perseverative thoughts and behaviors.
• Suicide Risk: Lifetime rate 5-10 times general population; peak risk around time of diagnosis and during early symptomatic phase. [18]

Symptoms by Stage

Juvenile Huntington's Disease (Westphal Variant)

• Onset less than 20 years (some define as less than 10 years for "childhood-onset").
• Differs from adult:
  • Akinetic-rigid phenotype (rigidity, bradykinesia, dystonia) predominates over chorea.
  • "Seizures: 30-50% (generalized tonic-clonic)."
  • "Cerebellar signs: Ataxia, dysmetria (more common than in adult-onset)."
  • "Rapid cognitive decline: More pronounced intellectual disability."
  • "Behavioral problems: Severe behavioral disturbances, aggression."
• Genetics: Usually paternal transmission (large CAG expansions ≥60); greater instability during spermatogenesis.
• Progression: More rapid; survival 10-15 years from onset (vs. 15-20 years in adult-onset).
• Differential diagnosis: Wilson's disease, neuroacanthocytosis, DRPLA (dentatorubral-pallidoluysian atrophy), mitochondrial disorders. [19]

Red Flags - "The Don't Miss" Signs

1. Suicidal ideation: Screen at every visit using validated tools (PHQ-9, C-SSRS); risk 5-10x higher than general population; peak at diagnosis and early disease. [18]
2. Severe weight loss: Hypermetabolic state (5,000-6,000 kcal/day may be needed) + dysphagia; BMI monitoring essential; PEG consideration when BMI less than 18 or 10% weight loss. [9]
3. Aspiration: Leading cause of death; speech-language pathology (SLP) swallow assessment; modified barium swallow study; consider PEG early.
4. Acute psychosis/aggression: May need psychiatric inpatient care; low-dose antipsychotics; ensure safety of patient and caregivers.
5. Falls: Major morbidity (fractures, head injuries); physiotherapy assessment; home modifications; hip protectors; may require wheelchair for safety.
6. Choking episodes: Severe dysphagia; dietary modifications (pureed diet, thickened fluids); SLP involvement; PEG feeding may be life-saving.

---

5. Clinical Examination

General Observations

• Restlessness, fidgeting, incorporation of chorea into purposeful movements.
• May try to disguise chorea (early insight).
• Weight loss often apparent.

Motor Examination

Chorea Assessment

• Observe at rest, during conversation, during cognitive tasks (chorea worsens with distraction).
• Distribution: Face, trunk, limbs (proximal and distal).
• Ask patient to hold arms outstretched: "piano-playing" fingers, pronator drift with chorea.

Tone and Bradykinesia

• Early: Normal or hypotonic.
• Late: Rigidity, bradykinesia (parkinsonian features).

Dystonia

• Sustained posturing; may be painful.
• Late feature; can be axial or limb.

Gait

• Wide-based, irregular, lurch-like.
• May incorporate dance-like movements.
• Postural instability: positive pull test.

Eye Movements

• Impaired saccade initiation (often earliest sign).
• Hypometric saccades.
• Slowed pursuit.
• Blink initiation of saccades (compensatory).

Cognitive Assessment

• MMSE or MoCA: Detects moderate-severe impairment.
• Executive function tests: Trail-Making, verbal fluency.
• Stroop test: Impaired.
• Formal neuropsychology: Detailed characterisation.

Psychiatric Assessment

• PHQ-9 or HADS for depression.
• Suicide risk assessment: ESSENTIAL at every visit.
• Irritability/aggression screening.
• Assess insight (often preserved early; lost later).

Standardised Assessments

Unified Huntington's Disease Rating Scale (UHDRS) [20]

• Gold standard assessment tool; used in clinical trials and specialist clinics.
• Motor Assessment (TMS - Total Motor Score): 0-124 (higher = worse).
  • 31 items: oculomotor, bradykinesia, chorea, dystonia, gait, postural stability.
  • "Progression: Mean 5-10 points/year in manifest HD."
• Cognitive Assessment: Verbal fluency, Stroop test, Symbol Digit Modalities Test (SDMT).
• Behavioral Assessment: 11-item scale (depression, anxiety, irritability, apathy, obsessive-compulsive).
• Functional Assessment (TFC - Total Functional Capacity): 0-13 scale.
  • "Assesses: Occupation, finances, domestic chores, ADLs, level of care."
  • "Stage 1 (TFC 11-13): Mild impairment."
  • "Stage 2 (TFC 7-10): Moderate impairment."
  • "Stage 3 (TFC 3-6): Severe impairment."
  • "Stage 4 (TFC 1-2): Profound impairment."
  • "Stage 5 (TFC 0): Total care."
• Independence Scale: 100-point scale assessing functional independence.

Problem Behaviors Assessment (PBA-s): Short version for behavioral symptoms in HD (11 items).

Montreal Cognitive Assessment (MoCA): Useful screening (sensitive to executive dysfunction); HD patients typically score 18-24/30 at early-mid stage.

---

6. Investigations

Genetic Testing (Definitive Diagnosis)

Indications

• Symptomatic individual with family history of HD.
• Symptomatic individual without known family history (de novo mutation rare; consider unknown paternity, early death of parent before manifestation).
• Predictive (presymptomatic) testing: At-risk asymptomatic individual (50% risk if one parent affected); requires extensive genetic counseling per international guidelines.

Pre-test Requirements

• Genetic counseling: Mandatory; discuss implications, penetrance, no treatment available.
• Psychological assessment: Assess coping mechanisms, support systems, risk of adverse psychological reactions.
• Informed consent: Written consent after full discussion.
• Age requirement: Generally > 18 years (some centers offer testing from age 16 with rigorous safeguards); testing of minors discouraged except in exceptional circumstances.

Method: PCR-based CAG repeat sizing in HTT gene (blood sample).

Interpretation

Post-test Counseling

• Result disclosure: In person, with genetic counselor and support person.
• Positive result: Discuss prognosis, CAG-dependent age of onset (approximate), family implications, reproductive options, advance care planning, suicide risk assessment.
• Negative result: Discuss survivor guilt, family dynamics, still at risk for other conditions.
• Follow-up: Psychological support, referral to HD specialist center, family cascade testing offered.

Neuroimaging

MRI Brain

• Classic Finding: Caudate atrophy with "box-car" shaped lateral ventricles.
• Putaminal Atrophy: Later.
• Cortical Atrophy: Frontal lobes early; generalised later.
• Exclude Differentials: Inflammatory, vascular causes.

Volumetric MRI

• Used in research; can detect atrophy in premanifest carriers.

PET/SPECT (Research)

• Reduced striatal metabolism (FDG-PET).
• Reduced dopamine receptors (D1 and D2).

Blood Tests

• Routine bloods to exclude secondary causes of chorea.
• Consider Wilson's disease screen in young patient (copper, caeruloplasmin, 24h urine copper).
• Thyroid function.
• Acanthocytes (blood film) if neuroacanthocytosis suspected.

Differential Diagnosis of Chorea

---

7. Management

Management Algorithm

          SUSPECTED HUNTINGTON'S DISEASE
                      ↓
┌─────────────────────────────────────────┐
│         GENETIC TESTING                 │
│  (After appropriate counselling)        │
└─────────────────────────────────────────┘
                      ↓
             HD CONFIRMED
                      ↓
┌─────────────────────────────────────────┐
│       MULTIDISCIPLINARY TEAM            │
│  Neurology, Psychiatry, PT/OT/SLT,      │
│  Psychology, Genetics, Palliative Care  │
└─────────────────────────────────────────┘
                      ↓
       ┌──────────────┼──────────────┐
       ↓              ↓              ↓
    MOTOR         PSYCHIATRIC    COGNITIVE
   SYMPTOMS        SYMPTOMS       DECLINE
       ↓              ↓              ↓
┌───────────┐  ┌───────────┐  ┌───────────┐
│Tetrabenazine│ │SSRIs      │ │Cognitive  │
│Deutetrabenz│ │Mirtazapine│ │strategies │
│Antipsychotics│Antipsychotics│Support    │
│Amantadine │ │Mood       │ │Plan for   │
│           │ │stabilisers│ │capacity   │
└───────────┘  └───────────┘  └───────────┘

Symptomatic Treatment - Motor

Chorea

Principles:

• Start low, titrate slow ("go low, go slow").
• Monitor for depression/suicidality at every visit (especially with tetrabenazine).
• Chorea often does not bother patient as much as family; treat only if functionally impairing or requested.
• Antichorea medications may worsen cognition and gait (balance risk/benefit).
• Combination therapy rarely beneficial; prefer monotherapy at adequate dose.

Late-Stage Motor (Rigidity/Dystonia)

• Reduce or stop anti-chorea medications (chorea diminishes in late stage; rigidity predominates).
• Botulinum toxin for focal dystonia (cervical dystonia, foot dystonia, jaw dystonia causing trismus).
• Physiotherapy for spasticity, contracture prevention, passive range of motion exercises.
• Baclofen 5-80mg/day (divided TDS) if severe spasticity; intrathecal baclofen for refractory cases.
• Benzodiazepines (diazepam, clonazepam) for dystonia/spasticity (use cautiously due to sedation, cognitive impairment).
• Avoid levodopa/dopamine agonists (generally ineffective; may worsen chorea if residual).

Symptomatic Treatment - Psychiatric

Depression

• SSRIs first-line: Citalopram 10-40mg OD, sertraline 50-200mg OD, escitalopram 10-20mg OD.
• Mirtazapine 15-45mg ON: Also helps sleep, appetite, weight (beneficial in HD); α2-antagonist/5-HT2/5-HT3 antagonist.
• SNRIs: Venlafaxine 75-225mg/day for severe depression; may cause agitation (use cautiously).
• ECT (electroconvulsive therapy): Consider in refractory depression, severe suicidality; effective and safe in HD (Level C evidence).
• CRUCIAL: Active suicide risk assessment at every visit using validated tools (Columbia-Suicide Severity Rating Scale [C-SSRS], PHQ-9 item 9).
• Avoid tricyclics (anticholinergic effects worsen cognition).

Irritability/Aggression

• SSRIs: First-line; sertraline, citalopram (may take 4-8 weeks for full effect).
• Low-dose antipsychotics: Risperidone 0.5-3mg/day, olanzapine 2.5-10mg/day, quetiapine 25-200mg/day.
• Mood stabilizers: Valproate 500-1500mg/day, carbamazepine 200-800mg/day (if mood instability, cyclic aggression); monitor LFTs and drug levels.
• Beta-blockers: Propranolol 40-120mg/day for impulse control (off-label; limited evidence).
• Avoid benzodiazepines long-term (dependence, disinhibition, cognitive impairment); short-term use only for acute agitation.
• Non-pharmacological: Behavioral strategies, environmental modification, caregiver education (de-escalation techniques).

Psychosis

• Low-dose atypical antipsychotics: Risperidone 1-4mg/day, olanzapine 5-10mg/day, quetiapine 50-300mg/day.
• Avoid clozapine (requires regular blood monitoring; impractical in HD due to compliance/venipuncture difficulties).
• Avoid high-potency typicals (haloperidol) except in refractory, severe psychosis (high EPS risk).
• Monitor for extrapyramidal side effects (may worsen motor symptoms).

Apathy

• Difficult to treat; often refractory to pharmacotherapy.
• Trial of: Methylphenidate 10-40mg/day (divided BD; stimulant), bupropion 150-300mg/day (dopamine/noradrenaline reuptake inhibitor).
• Limited evidence: Amantadine may help (anecdotal).
• Non-pharmacological: Structured daily routines, occupational therapy, caregiver education (apathy ≠ laziness; neurological symptom).
• Distinguish from depression (apathy = lack of motivation without sadness; depression = low mood, anhedonia).

Multidisciplinary Care

Genetic Counselling

Presymptomatic (Predictive) Testing [21]

• Must be offered by accredited genetic counselors per international guidelines (IHA-EHDN, HDSA).
• Pre-test counseling: Minimum 2 sessions (ideally 3-6 months apart).
  • "Discuss: HD natural history, test implications (no cure/prevention), insurance/employment discrimination, family implications, right not to know."
  • "Psychological assessment: Evaluate coping mechanisms, psychiatric history, support systems."
  • "Exclusion criteria: Age less than 18, acute psychiatric illness, coercion by family/third party, inadequate support."
• Testing process: Blood sample for CAG repeat analysis; results in 2-4 weeks.
• Result disclosure: In person (never by phone/mail); genetic counselor + support person present; allocated time for reaction.
• Post-test support:
  • "Positive result: Psychological support, HD clinic referral, discuss reproductive options, suicidal ideation screening."
  • "Negative result: Address survivor guilt, family dynamics, continued at-risk for other conditions."
  • Follow-up at 1 week, 1 month, 6 months, 12 months.
• Uptake: Only ~15-20% of at-risk individuals choose predictive testing (majority prefer "not knowing").
• Adverse events: Depression (30%), suicide risk (2-5% attempt; highest in first year post-positive result), relationship breakdown.

Reproductive Options

• Prenatal testing: Chorionic villus sampling (CVS) at 10-13 weeks or amniocentesis at 15-20 weeks; CAG repeat analysis on fetal DNA.
• Preimplantation genetic diagnosis (PGD): IVF + embryo biopsy (day 3 or 5); only unaffected embryos transferred; avoids termination decision.
• Non-disclosure prenatal testing: Pregnancy continues only if fetus unaffected; parent never learns own genetic status (controversial; limited availability).
• Exclusion testing: Tests whether fetus inherited grandparental chromosome (without revealing parent's status); available in some centers.
• Sperm/egg donation: Eliminates HD risk entirely.
• Adoption: Alternative to biological children.
• Ethical considerations: Autonomy, right to open future (testing children), selective termination, disability perspectives.

Advance Care Planning

• Timing: Discuss early (at diagnosis or soon after) while patient has capacity; revisit regularly.
• Topics to address:
  • "Healthcare decisions: PEG feeding (yes/no; when), CPR/DNAR, hospital admission vs. home care, antibiotics for infections."
  • "Personal care: Preferred location of care (home, nursing home), preferred caregivers."
  • "End-of-life wishes: Palliative care approach, hospice, preferred place of death."
• Legal documents:
  • "Advance Directive (Living Will): Specifies treatment preferences if lose capacity."
  • "Lasting Power of Attorney for Health and Welfare (UK) / Healthcare Proxy (US): Appoints decision-maker."
  • "Lasting Power of Attorney for Property and Financial Affairs: Appoints financial decision-maker."
• Capacity assessment: Use Mental Capacity Act (UK) principles; assume capacity unless proven otherwise; capacity is decision-specific and time-specific.
• Common dilemmas:
  • "PEG feeding: Prolongs life but may not improve quality; discuss early before dysphagia crisis."
  • "Resuscitation: Most HD patients opt for DNAR given poor prognosis and advanced disease."
  • "Nursing home placement: Often necessary in late stage; address guilt and identify suitable facilities."
• Family involvement: Include family in discussions (with patient consent); address caregiver burden and respite needs.

---

8. Complications

Disease-Related Complications

Treatment Complications

---

9. Prognosis and Outcomes

Natural History

• Prodromal Phase: 10-15 years of subtle changes before diagnosis.
• Manifest Disease: Median survival 15-20 years from motor symptom onset.
• Juvenile HD: More rapid; survival 10-15 years.

Causes of Death

1. Pneumonia (most common): Aspiration, debility.
2. Suicide: 5-10% of deaths.
3. Cardiovascular disease.
4. Falls/injuries.
5. Choking.

Prognostic Factors

Worse Prognosis

• Larger CAG repeat length.
• Younger onset (especially juvenile).
• Prominent rigidity/bradykinesia (less chorea).
• Early weight loss.
• Psychiatric comorbidity.

Better Prognosis

• Later onset.
• Predominantly choreic phenotype.
• Good nutritional status.
• Strong social support.

Quality of Life

• Functional decline approximately 0.5-1 TFC (Total Functional Capacity) points/year.
• Nursing home admission typically 10-15 years after onset.
• End-of-life: Total dependence, mute, minimal movement.

Premanifest/Prodromal HD

• Gene-positive individuals are "at risk" before symptoms.
• Subtle cognitive and psychiatric changes may be detectable.
• Research into disease-modifying therapies targets this stage.

---

10. Evidence and Guidelines

Key Guidelines

Landmark Studies

1. TETRA-HD Trial (2006) [6]

• Question: Does tetrabenazine reduce chorea?
• N: 84 patients.
• Result: Significant reduction in chorea (TMS improved by 5 units).
• Impact: FDA approval; first drug specifically for HD chorea.
• PMID: 16510744.

2. FIRST-HD Trial (2017) [7]

• Question: Is deutetrabenazine effective and tolerable?
• N: 90 patients.
• Result: Similar efficacy to tetrabenazine; fewer neuropsychiatric side effects.
• Impact: Deutetrabenazine approved as alternative.
• PMID: 28668671.

3. TRACK-HD / TRACK-ON Studies (2011-2016)

• Question: Can we detect changes in premanifest HD?
• N: Longitudinal biomarker study.
• Result: Identified imaging and cognitive markers of early disease.
• Impact: Informs trial design for disease-modifying therapies.
• PMID: 23141659.

4. Ionis HTT-Rx (Tominersen) Trial (2021)

• Question: Can antisense oligonucleotide lower huntingtin protein?
• Result: Successfully lowered mutant huntingtin; Phase 3 halted due to lack of efficacy/safety concerns.
• Impact: Proof of concept; ongoing research into selective lowering.
• PMID: 30063248.

---

11. Exam-Focused Content

Common MRCP/FRACP Viva Questions

1. "Tell me about Huntington's disease."

Model Answer: "Huntington's disease is an autosomal dominant neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the huntingtin gene on chromosome 4. It is characterized by a triad of progressive motor dysfunction—classically chorea—cognitive decline, and psychiatric disturbance. The disease is fully penetrant with 40 or more CAG repeats, with onset typically in the fourth decade. It demonstrates anticipation, particularly with paternal transmission. The pathophysiology involves selective degeneration of medium spiny neurons in the striatum, with loss of indirect pathway neurons causing chorea. There is no disease-modifying treatment; management is symptomatic with tetrabenazine or deutetrabenazine for chorea, and multidisciplinary care is essential. Mean survival is 15-20 years from symptom onset."

---

2. "What is anticipation, and why does it occur in Huntington's disease?"

Model Answer: "Anticipation is the phenomenon of earlier age of onset and increased disease severity in successive generations. In Huntington's disease, this occurs due to meiotic instability of the CAG trinucleotide repeat during gametogenesis, particularly spermatogenesis. A parent with 40-45 CAG repeats may have a child with 60 or more repeats, leading to juvenile-onset disease—the Westphal variant. This intergenerational expansion is more pronounced with paternal transmission due to greater repeat instability during sperm formation. The CAG repeat length accounts for approximately 50-70% of the variability in age of onset, with longer repeats causing earlier onset."

---

3. "How would you counsel someone requesting predictive genetic testing for Huntington's disease?"

Model Answer: "Predictive genetic testing for Huntington's disease must follow strict international guidelines. I would ensure the request is made by the individual themselves, not coerced by family. Testing requires pre-test genetic counseling over at least two sessions, ideally separated by several months. I would discuss the natural history of HD, the implications of a positive result—that there is no cure or prevention—and the psychological impact, including a 30% risk of depression and increased suicide risk in the first year after a positive result. I would arrange psychological assessment to evaluate coping strategies and support systems. The test itself analyzes CAG repeat length, and results are disclosed in person with counseling support. Post-test follow-up is essential, including suicide risk screening for positive results and addressing survivor guilt for negative results. I would also discuss reproductive options including PGD and prenatal testing."

---

4. "What is the mechanism of action of tetrabenazine, and what are the key adverse effects?"

Model Answer: "Tetrabenazine is a vesicular monoamine transporter 2 (VMAT2) inhibitor, which depletes presynaptic dopamine by blocking its packaging into synaptic vesicles. This reduces dopaminergic transmission in the striatum, thereby reducing chorea. The landmark TETRA-HD trial in 2006 demonstrated a significant reduction in chorea, with a decrease in Total Motor Score by approximately 5 units. However, tetrabenazine carries a black box warning for depression and suicidality, occurring in up to 30% of patients. Other adverse effects include drug-induced parkinsonism, akathisia, and sedation. Active suicide risk screening is mandatory at every visit. Deutetrabenazine, a deuterated form with longer half-life, has similar efficacy with reduced neuropsychiatric side effects and is preferred if depression or suicidal ideation is present."

---

5. "Why does Huntington's disease selectively affect the striatum?"

Model Answer: "The selective vulnerability of striatal medium spiny neurons in Huntington's disease is multifactorial. First, these neurons have high metabolic demands and are dependent on brain-derived neurotrophic factor (BDNF) from cortical neurons, which is impaired in HD due to disrupted axonal transport by mutant huntingtin. Second, mutant huntingtin is highly expressed in the striatum. Third, medium spiny neurons are particularly vulnerable to excitotoxicity via NMDA receptors, which is enhanced in HD. Fourth, within the striatum, indirect pathway neurons expressing D2 receptors are affected first, leading to loss of inhibition and chorea, while direct pathway neurons expressing D1 receptors are affected later, causing rigidity and bradykinesia. This differential vulnerability explains the evolution of motor symptoms from hyperkinetic to hypokinetic."

---

6. "Describe the differential diagnosis of chorea."

Model Answer: "Chorea is involuntary, irregular, unpredictable movements. The differential diagnosis includes:

• Huntington's disease: Family history, cognitive decline, genetic testing.
• Wilson's disease: Young onset (less than 40), Kayser-Fleischer rings, low ceruloplasmin; treatable.
• Sydenham's chorea: Post-streptococcal, pediatric, self-limiting.
• Neuroacanthocytosis: Lip/tongue biting, feeding dystonia, acanthocytes on blood film, elevated CK.
• Benign hereditary chorea: Non-progressive, normal cognition, TITF1 gene mutation.
• Drug-induced (tardive dyskinesia): History of dopamine antagonist use, orofacial dyskinesia.
• SLE (lupus chorea): Antiphospholipid antibodies, systemic features.
• Thyrotoxicosis: Thyroid function tests, tremor, weight loss.
• Cerebrovascular (post-stroke chorea): Acute onset, contralateral basal ganglia lesion on imaging.
• Polycythemia vera: Hyperviscosity, elevated hematocrit.

Key is to exclude Wilson's disease in young patients, as it is treatable."

---

Common Mistakes (What Gets You Failed)

❌ Mistake 1: Offering genetic testing without mentioning mandatory genetic counseling.

• Predictive testing MUST involve genetic counseling, psychological assessment, and informed consent per international guidelines.

❌ Mistake 2: Missing suicide risk assessment in a patient with Huntington's disease.

• Suicide risk is 5-10 times higher than general population; active screening is essential at every visit, especially around diagnosis and when starting tetrabenazine.

❌ Mistake 3: Stating that chorea always requires treatment.

• Chorea often does not bother the patient as much as family; treat only if functionally impairing or causing distress. Antichorea medications may worsen cognition and gait.

❌ Mistake 4: Confusing juvenile HD presentation with adult-onset.

• Juvenile HD (Westphal variant) presents with akinetic-rigid phenotype (rigidity, dystonia, bradykinesia), NOT chorea, plus seizures and rapid cognitive decline.

❌ Mistake 5: Not distinguishing apathy from depression.

• Apathy = lack of motivation/interest without sadness (frontal lobe dysfunction); Depression = low mood, anhedonia, guilt. Management differs.

❌ Mistake 6: Failing to recognize anticipation mechanism.

• Anticipation is due to CAG repeat expansion during gametogenesis (particularly spermatogenesis), NOT genomic imprinting.

❌ Mistake 7: Missing Wilson's disease in a young patient with chorea.

• Wilson's disease is treatable; must be excluded in any patient less than 40 with unexplained chorea (check ceruloplasmin, slit-lamp exam, 24h urine copper).

---

High-Yield Exam Facts

Genetics

• CAG repeat in HTT gene (chromosome 4p16.3); codes for polyglutamine tract.
• ≥40 repeats = full penetrance; 36-39 = reduced penetrance; 27-35 = intermediate (at-risk offspring).
• Anticipation more pronounced with paternal transmission (meiotic instability).
• CAG length inversely correlates with age of onset (accounts for 50-70% of variance).

Pathophysiology

• Selective loss of striatal medium spiny GABAergic neurons (indirect pathway first → chorea; direct pathway later → rigidity).
• Mechanisms: Protein aggregation, transcriptional dysregulation (reduced BDNF), mitochondrial dysfunction, excitotoxicity.

Clinical

• Triad: Motor (chorea, later rigidity), cognitive (executive dysfunction → dementia), psychiatric (depression, irritability, apathy).
• Suicide risk 5-10× general population (peak at diagnosis).
• Weight loss universal (hypermetabolic; may need 5,000-6,000 kcal/day).
• Aspiration pneumonia = leading cause of death.

Diagnosis

• Genetic testing (CAG repeat analysis) = gold standard.
• MRI: Caudate atrophy ("box-car" ventricles), cortical atrophy.
• UHDRS (Unified Huntington's Disease Rating Scale): Motor, cognitive, behavioral, functional.

Management

• No disease-modifying therapy.
• Chorea: Tetrabenazine (VMAT2 inhibitor; BLACK BOX for depression), deutetrabenazine (better SE profile).
• Depression: SSRIs, mirtazapine; screen for suicide at every visit.
• MDT: Neurology, psychiatry, genetics, PT/OT/SLP, dietitian, palliative care.

Genetic Counseling

• Predictive testing: Mandatory pre-test counseling, psychological assessment, post-test support.
• Reproductive options: PGD (IVF + embryo selection), prenatal testing (CVS/amniocentesis).

---

12. Patient and Layperson Explanation

What is Huntington's Disease?

Huntington's disease (HD) is an inherited brain condition that causes gradual damage to nerve cells. It affects movement, thinking, and behaviour. It is caused by a faulty gene that everyone with the condition has from birth, but symptoms usually start in adulthood.

How is it Inherited?

• HD is passed down through families (autosomal dominant).
• If a parent has the HD gene, each child has a 50% chance of inheriting it.
• Everyone who inherits the gene will eventually develop HD if they live long enough.

What Are the Symptoms?

Movement Problems

• Involuntary jerky movements (chorea) - early stage.
• Stiffness and slowness - later stage.
• Difficulty walking, speaking, and swallowing.

Thinking Problems

• Difficulty concentrating, planning, and organising.
• Memory problems.
• Eventually, dementia.

Emotional and Behavioural Changes

• Depression and anxiety (often before other symptoms).
• Irritability or aggression.
• Apathy (lack of motivation).
• Rarely, psychosis (false beliefs, hearing things).

How is it Diagnosed?

• A blood test can detect the faulty gene (genetic test).
• This test is only done after careful counselling about what the result means.
• Brain scans may show typical changes but are not diagnostic.

Can it be Treated?

• There is currently no cure or way to slow HD.
• Medications can help manage symptoms:
  • "Movement: Tetrabenazine, deutetrabenazine, some antipsychotics."
  • "Mood: Antidepressants, anti-anxiety medications."
• A team of specialists (neurologist, psychiatrist, therapists, dietitian) provides ongoing support.
• Research into treatments that target the underlying gene is ongoing.

Planning for the Future

• Early planning while thinking is clear is important.
• Discuss wishes for future care with family and doctors.
• Consider Powers of Attorney and advance care plans.

Testing for Family Members

• At-risk relatives can choose to have genetic testing.
• This is a personal decision with major implications.
• Genetic counselling is essential before testing.

Support Resources

• Huntington's Disease Association (UK): hda.org.uk
• European Huntington's Disease Network: euro-hd.net
• HDSA (USA): hdsa.org

---

13. References

Primary Sources

1. Bates GP, Dorsey R, Gusella JF, et al. Huntington disease. Nat Rev Dis Primers. 2015;1:15005. doi:10.1038/nrdp.2015.5. PMID: 27188817.

   • Comprehensive review of HD pathogenesis, clinical features, and management.

2. Ross CA, Tabrizi SJ. Huntington's disease: from molecular pathogenesis to clinical treatment. Lancet Neurol. 2011;10(1):83-98. doi:10.1016/S1474-4422(10)70245-3. PMID: 21163446.

   • Authoritative review of HD molecular mechanisms and therapeutic approaches.

3. MacDonald ME, Ambrose CM, Duyao MP, et al. (The Huntington's Disease Collaborative Research Group). A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. Cell. 1993;72(6):971-983. doi:10.1016/0092-8674(93)90585-E. PMID: 8458085.

   • Landmark paper identifying the HTT gene and CAG repeat expansion.

4. Pringsheim T, Wiltshire K, Day L, Dykeman J, Steeves T, Jette N. The incidence and prevalence of Huntington's disease: a systematic review and meta-analysis. Mov Disord. 2012;27(9):1083-1091. doi:10.1002/mds.25075. PMID: 22692795.

   • Systematic review of HD epidemiology worldwide.

5. Armstrong MJ, Miyasaki JM; American Academy of Neurology. Evidence-based guideline: pharmacologic treatment of chorea in Huntington disease: report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology. 2012;79(6):597-603. doi:10.1212/WNL.0b013e318263c443. PMID: 22815556.

   • AAN practice guideline for chorea management; Level B evidence for tetrabenazine.

6. Huntington Study Group. Tetrabenazine as antichorea therapy in Huntington disease: a randomized controlled trial. Neurology. 2006;66(3):366-372. doi:10.1212/01.wnl.0000198586.85250.13. PMID: 16510744.

   • TETRA-HD trial; pivotal RCT leading to FDA approval of tetrabenazine for HD chorea.

7. Huntington Study Group; Frank S, Testa CM, Stamler D, et al. Effect of Deutetrabenazine on Chorea Among Patients With Huntington Disease: A Randomized Clinical Trial. JAMA. 2016;316(1):40-50. doi:10.1001/jama.2016.8655. PMID: 27380342.

   • FIRST-HD trial; demonstrated efficacy and improved tolerability of deutetrabenazine vs. tetrabenazine.

8. Duyao M, Ambrose C, Myers R, et al. Trinucleotide repeat length instability and age of onset in Huntington's disease. Nat Genet. 1993;4(4):387-392. doi:10.1038/ng0893-387. PMID: 8401587.

   • Demonstrated inverse correlation between CAG repeat length and age of onset; anticipation mechanism.

9. Aziz NA, van der Burg JM, Landwehrmeyer GB, Brundin P, Stijnen T; EHDI Study Group. Weight loss in Huntington disease increases with higher CAG repeat number. Neurology. 2008;71(19):1506-1513. doi:10.1212/01.wnl.0000334276.09729.0e. PMID: 18981372.

   • Demonstrated universal progressive weight loss in HD; hypermetabolic state; correlation with CAG repeats.

10. Tabrizi SJ, Langbehn DR, Leavitt BR, et al.; TRACK-HD investigators. Biological and clinical manifestations of Huntington's disease in the longitudinal TRACK-HD study: cross-sectional analysis of baseline data. Lancet Neurol. 2009;8(9):791-801. doi:10.1016/S1474-4422(09)70170-X. PMID: 19646924.

    • TRACK-HD study; identified cognitive and imaging biomarkers in premanifest HD.

11. Lee JM, Ramos EM, Lee JH, et al.; PREDICT-HD study of the Huntington Study Group (HSG); REGISTRY study of the European Huntington's Disease Network; HD-MAPS Study Group. CAG repeat expansion in Huntington disease determines age at onset in a fully dominant fashion. Neurology. 2012;78(10):690-695. doi:10.1212/WNL.0b013e318249f683. PMID: 22323755.

    • Large study demonstrating CAG repeat accounts for 50-70% of variance in age of onset.

12. Genetic Modifiers of Huntington's Disease (GeM-HD) Consortium. Identification of Genetic Factors that Modify Clinical Onset of Huntington's Disease. Cell. 2015;162(3):516-526. doi:10.1016/j.cell.2015.07.003. PMID: 26232222.

    • Identified DNA repair genes (MLH1, MSH3, FAN1) as genetic modifiers of HD age of onset.

13. Zuccato C, Cattaneo E. Brain-derived neurotrophic factor in neurodegenerative diseases. Nat Rev Neurol. 2009;5(6):311-322. doi:10.1038/nrneurol.2009.54. PMID: 19498435.

    • Review of BDNF role in HD; mutant huntingtin disrupts BDNF transcription and transport.

14. Nucifora FC Jr, Sasaki M, Peters MF, et al. Interference by huntingtin and atrophin-1 with cbp-mediated transcription leading to cellular toxicity. Science. 2001;291(5512):2423-2428. doi:10.1126/science.1056784. PMID: 11264541.

    • Demonstrated mutant huntingtin sequesters CBP (CREB-binding protein), impairing transcription.

15. Raymond LA, André VM, Cepeda C, Gladding CM, Milnerwood AJ, Levine MS. Pathophysiology of Huntington's disease: time-dependent alterations in synaptic and receptor function. Neuroscience. 2011;198:252-273. doi:10.1016/j.neuroscience.2011.08.052. PMID: 21907762.

    • Review of synaptic dysfunction in HD corticostriatal circuits.

16. Vonsattel JP, Myers RH, Stevens TJ, Ferrante RJ, Bird ED, Richardson EP Jr. Neuropathological classification of Huntington's disease. J Neuropathol Exp Neurol. 1985;44(6):559-577. doi:10.1097/00005072-198511000-00003. PMID: 2932539.

    • Classic neuropathological grading system for HD; describes pattern of striatal degeneration.

17. Paulsen JS, Nehl C, Hoth KF, et al.; PREDICT-HD Investigators and Coordinators of Huntington Study Group. Depression and stages of Huntington's disease. J Neuropsychiatry Clin Neurosci. 2005;17(4):496-502. doi:10.1176/jnp.17.4.496. PMID: 16387989.

    • Demonstrated high prevalence of depression (40-60%) across all HD stages.

18. Hubers AA, van Duijn E, Roos RA, et al. Suicidal ideation in a European Huntington's disease population. J Affect Disord. 2013;151(1):248-258. doi:10.1016/j.jad.2013.06.001. PMID: 23806588.

    • Large European study of suicide risk in HD; 5-10× general population; peak at diagnosis.

19. Nance MA, Myers RH. Juvenile onset Huntington's disease--clinical and research perspectives. Ment Retard Dev Disabil Res Rev. 2001;7(3):153-157. doi:10.1002/mrdd.1022. PMID: 11553930.

    • Review of juvenile HD (Westphal variant); akinetic-rigid phenotype, seizures, rapid progression.

20. Huntington Study Group. Unified Huntington's Disease Rating Scale: reliability and consistency. Mov Disord. 1996;11(2):136-142. doi:10.1002/mds.870110204. PMID: 8684382.

    • Validation of UHDRS; gold standard assessment tool for HD.

21. MacLeod R, Tibben A, Frontali M, et al.; on behalf of the European Huntington Disease Network. Recommendations for the predictive genetic test in Huntington's disease. Clin Genet. 2013;83(3):221-231. doi:10.1111/j.1399-0004.2012.01900.x. PMID: 22642570.

    • International guidelines for predictive genetic testing in HD; counseling protocols.

22. Tabrizi SJ, Leavitt BR, Landwehrmeyer GB, et al. Targeting Huntingtin Expression in Patients with Huntington's Disease. N Engl J Med. 2019;380(24):2307-2316. doi:10.1056/NEJMoa1900907. PMID: 31059641.

    • Phase 1/2a trial of tominersen (antisense oligonucleotide); successfully lowered huntingtin but Phase 3 halted (lack of efficacy).

Key Guidelines

• American Academy of Neurology (AAN): Pharmacologic treatment of chorea in HD (2012). [5]
• European Huntington's Disease Network (EHDN): Predictive testing guidelines (2013). [21]
• International Huntington Association (IHA): Genetic counseling standards.
• National Institute for Health and Care Excellence (NICE): No specific HD guideline; refer to neurological rehabilitation guidelines.

---

Medical Disclaimer: MedVellum content is for educational purposes and clinical reference. Clinical decisions should account for individual patient circumstances. Always consult appropriate specialists.