Huntington Disease

Huntington disease is a progressive, autosomal dominant neurodegenerative disorder caused by an expanded trinucleotide (CAG) repeat in the huntingtin gene. It produces a mutant huntingtin protein with toxic gain of function. Neuronal loss is progressive, with early, disproportionate involvement of the striatum (caudate nucleus and putamen).

The clinical triad is progressive chorea (or, in some presentations, other movement disorder), cognitive decline, and psychiatric disturbance. Age of onset and severity correlate inversely with the length of the CAG repeat expansion.

The disease shows genetic anticipation. The repeat tends to expand further across successive generations, so age of onset decreases and severity increases. This occurs particularly, though not exclusively, with paternal transmission of the affected allele.

Pathophysiology and genetics

• The huntingtin gene contains a CAG trinucleotide repeat. Repeat lengths of 36 or greater are generally considered pathological.
• Repeat lengths of 40 or greater give essentially full disease penetrance. Intermediate lengths of 36 to 39 give reduced, though still significant, penetrance and generally later, more variable age of onset.
• The expanded repeat produces a mutant huntingtin protein with an abnormally elongated polyglutamine tract. Its toxic gain of function drives progressive neuronal dysfunction and death, with early vulnerability of the medium spiny neurons within the striatum.
• Progressive striatal neuronal loss disrupts basal ganglia circuitry and produces the movement disorder. Chorea is typical in the common adult onset presentation. Bradykinesia and rigidity, resembling parkinsonism, can predominate in some presentations, particularly the rarer, more severe juvenile onset form, termed the Westphal variant.
• Cognitive decline reflects direct striatal pathology, given the role of the striatum in executive function and cognitive processing, together with more widespread cortical involvement as the disease advances. Psychiatric disturbance also occurs.
• Genetic anticipation reflects the instability of this trinucleotide repeat during spermatogenesis. It is clinically relevant to genetic counselling about likely age of onset in affected offspring, particularly where the disease has been transmitted through the paternal line.

• Progressive chorea is the characteristic presenting movement disorder in the common, adult onset form. It comprises involuntary, irregular, unpredictable, dance-like movements affecting the face, trunk and limbs. It develops insidiously and progresses gradually.
• In later, more advanced disease, chorea frequently gives way to progressive bradykinesia, rigidity and dystonia, reflecting the evolving pattern of neurodegeneration.
• Progressive cognitive decline initially affects predominantly executive function (including planning, organisation, and cognitive flexibility) and processing speed. Episodic memory is relatively preserved in the earlier stages, which distinguishes it from the typical early presentation of Alzheimer disease. In advanced disease it progresses to global, severe cognitive impairment (major neurocognitive disorder).
• Psychiatric disturbance frequently precedes the movement disorder by a number of years and is sometimes the initial presenting feature. It includes depression, irritability, anxiety, obsessive compulsive symptoms, and, in some patients, psychotic symptoms.
• Depression carries a substantially elevated suicide risk in this population and warrants careful, ongoing clinical vigilance. The psychiatric component is frequently significant and sometimes underrecognised.
• The disease is relentlessly progressive over a typical duration of fifteen to twenty years from symptom onset to death. Functional decline across all three core domains (motor, cognitive, and psychiatric) results in complete dependency for care.
• Death frequently results from complications of advanced disease, including aspiration pneumonia and other intercurrent illness related to the severely debilitated state.

• Genetic testing for the expanded CAG repeat in the huntingtin gene gives definitive diagnostic confirmation, in the context of a compatible clinical presentation.
• Predictive, presymptomatic testing in an at risk, asymptomatic individual with a relevant family history is an entirely distinct scenario. It requires structured genetic counselling protocols, given its profound psychological and practical implications.
• Clinical assessment includes a detailed history, with a thorough family history given the autosomal dominant inheritance. Some cases arise from new, de novo expansion of an intermediate, previously non-pathological repeat length. Others reflect lack of awareness of family history, given historical underdiagnosis or non-disclosure within affected families.
• Formal assessment of the movement disorder, cognitive function, and psychiatric symptoms is the essential clinical foundation supporting the diagnosis alongside genetic confirmation.
• Structural neuroimaging characteristically shows progressive caudate and putaminal atrophy, with resulting enlargement of the frontal horns of the lateral ventricles. This supports the clinical diagnosis, though genetic testing remains the definitive investigation.
• Predictive genetic testing in an asymptomatic, at risk individual needs full, structured pre-test genetic counselling. It must address the profound psychological, social, and practical implications of a positive result, including implications for future family planning, insurance, and employment.
• A positive result also carries a substantial psychological burden. The individual remains, and for some years will remain, entirely asymptomatic, and no disease modifying or preventive treatment is currently available.
• This testing context needs a fundamentally different, more extensive and carefully structured approach than genetic testing in an already symptomatic individual.

• There is currently no available disease modifying or curative treatment for Huntington disease. Management is entirely symptomatic, addressing the motor, cognitive and psychiatric manifestations in the individual patient.
• Give structured psychosocial support to the patient and family, given the severe, progressive, and life limiting nature of the condition.
• Chorea is managed with vesicular monoamine transporter 2 inhibitors (tetrabenazine or deutetrabenazine), specifically approved, effective options for this symptom.
• Certain antipsychotic medications also benefit chorea. They are particularly relevant where coexisting psychotic or significant behavioural disturbance warrants antipsychotic treatment in its own right, allowing combined symptomatic benefit from a single agent.
• Depression and other psychiatric manifestations are managed according to standard principles for the presenting symptom.
• Be particularly vigilant about the substantially elevated suicide risk in this population. Carry out proactive, ongoing, systematic risk assessment throughout the illness.
• Multidisciplinary supportive care is an essential, central component throughout the disease course:
  • Physiotherapy and occupational therapy for the progressive motor impairment and functional decline.
  • Speech and language therapy, particularly for the significant, progressive dysarthria and, in more advanced disease, dysphagia with aspiration risk.
  • Nutritional support, given both the swallowing difficulty and the marked hypermetabolic state with weight loss. This often requires proactive, substantial caloric supplementation to maintain adequate nutritional status.
• Genetic counselling for the family is an essential component of family centred care, given the hereditary nature of the condition and its wide ranging implications for the affected family.
• It covers predictive testing for at risk relatives (following the structured protocol) and reproductive counselling about options for future pregnancies (including preimplantation genetic testing). Connect families to specialist Huntington disease services and patient support organisations.
• Involve palliative care as the disease progresses to its advanced stages, addressing symptom management, advance care planning, and family support.
• Provide ongoing, coordinated multidisciplinary specialist input throughout the entire course of this severe, progressive, currently incurable condition.