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 (greater than 40 repeats).
• Genetics: CAG repeat expansion in HTT gene; normal less than 27, pathogenic greater than 39. [3]
• Incidence: 5-10 per 100,000 in Western populations.
• Onset: Mean age 40 years (range 2-80 years).
• Juvenile HD: Onset before 20 years; typically paternal inheritance; more severe.
• Prognosis: Mean survival 15-20 years from symptom onset.
• Anticipation: Earlier onset and more severe disease in successive generations (especially paternal).

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 than maternal. A father with HD may have a child with juvenile onset (Westphal variant).

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)

• Motor, cognitive, behavioural, functional subscales.
• Used in clinical trials and specialist clinics.
• Total Motor Score (TMS): 0-124.

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.

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.

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