Huntington Disease: Diagnosis and Management

Introduction

Huntington disease (HD) is an autosomal dominant, fully penetrant neurodegenerative disorder caused by an expanded CAG trinucleotide repeat in the huntingtin (HTT) gene on chromosome 4, leading to progressive neuronal loss, most prominently in the striatum (caudate and putamen).³¹

It classically produces a triad of movement disorder (chorea), cognitive decline, and psychiatric disturbance, though these need not all be present together or appear in the same order², which is one reason presentation can be misleading, especially early in the disease when psychiatric symptoms alone may dominate.

HD is a compact but rich exam topic: it is one of the clearest examples of a trinucleotide repeat disorder with genetic anticipation, it raises important questions about predictive genetic testing and counselling, and its symptomatic management (particularly of chorea and psychiatric risk) is frequently tested.

Prevalence is roughly 10-12 per 100,000 in populations of European ancestry, with considerable geographical variation. Because inheritance is autosomal dominant with full penetrance at expanded repeat lengths, each child of an affected parent has a 50% risk, and the disease characteristically affects several generations of the same family - a pattern that shapes not only the genetics but the psychological and social context in which patients present, since many will have watched a parent decline from the same condition.

Genetics

HD is caused by an expanded CAG repeat within the HTT gene, encoding an abnormally long polyglutamine tract in the huntingtin protein, which becomes toxic and aggregates within neurons, particularly medium spiny neurones of the striatum.

The selective vulnerability of striatal medium spiny neurones explains the movement disorder and, importantly, why it changes over time. These neurones form the indirect pathway of the basal ganglia, which normally suppresses unwanted movement. Losing them removes that brake, releasing the excess involuntary movement seen as chorea. As the disease advances and the direct pathway is also lost, the capacity to initiate movement fails as well, so chorea gives way to bradykinesia and rigidity - which is also why juvenile-onset disease, with more widespread early degeneration, is akinetic-rigid from the outset.

Damage is not confined to the striatum. Cortical involvement, particularly frontal, produces the executive dysfunction and behavioural change, and accounts for the subcortical-frontal pattern of dementia and the impaired insight that makes long-term planning so difficult for families.

An important consequence of the CAG repeat mechanism is that repeat length and age of onset are inversely correlated - longer expansions produce earlier disease. The relationship is strong at the extremes but too imprecise to predict onset in an individual, which matters enormously in counselling. A person who has tested positive cannot be told when they will become symptomatic, and offering a number based on repeat length alone would be misleading.

This uncertainty is one reason the uptake of predictive testing among at-risk individuals is relatively low, and why testing protocols are built around extended counselling rather than a single consent conversation. Testing is not offered to asymptomatic children, since it removes their future autonomy to choose and there is no intervention that would alter the outcome.

Clinical features

Onset is typically in the 30s to 50s, though a juvenile-onset form (the Westphal variant, presenting before age 20 with rigidity and bradykinesia rather than chorea, plus seizures) and a later-onset form both occur.

Movement disorder

• Chorea - the hallmark movement abnormality: brief, irregular, unpredictable, dance-like involuntary movements that can affect the face, trunk and limbs, and which patients sometimes incorporate into a seemingly purposeful gesture ('parakinesia') to mask them
• Motor impersistence - difficulty sustaining a voluntary action, such as protruding the tongue or maintaining a tight grip ('milkmaid's grip')
• Oculomotor abnormalities - slowed voluntary saccades are an early and sensitive sign
• Dysarthria and dysphagia, worsening as the disease progresses
• Gait disturbance - a broad-based, unsteady, dance-like gait
• In later disease, chorea often gives way to bradykinesia and rigidity (a parkinsonian phenotype), particularly in juvenile-onset and late-stage disease

Cognitive decline

HD causes a subcortical dementia: predominant impairment of executive function, processing speed and attention, with relative preservation of memory and language until later, distinguishing it from the cortical pattern of Alzheimer's disease. Impaired insight into the illness is common, which complicates both diagnosis and safety planning.

Driving is a specific and frequently overlooked issue. Chorea, impaired reaction time and reduced insight together make driving hazardous well before the patient recognises any difficulty, and the DVLA must be informed at diagnosis. Because insight is often impaired, this conversation is usually best had with a family member present, and it should be revisited rather than treated as settled after a single discussion.

Psychiatric disturbance

• Depression - very common and can precede motor symptoms by years; a major driver of the markedly increased suicide risk in HD
• Irritability, apathy and personality change
• Anxiety
• Obsessive-compulsive features
• Psychosis - in a minority, sometimes resembling schizophrenia
• Psychiatric symptoms can be the first manifestation of HD, sometimes years before chorea or clear cognitive decline become apparent, and are easily misattributed to a primary psychiatric disorder if the family history is not specifically sought

Clinical examination

• Observe for spontaneous chorea at rest and during conversation
• Test motor impersistence (sustained tongue protrusion, sustained grip)
• Assess voluntary saccades for slowing
• Cognitive screening focused on executive function and processing speed
• Screen explicitly for depression, anxiety, irritability and suicidal ideation
• Assess gait and functional independence
• Take a detailed three-generation family history, specifically asking about movement disorders, psychiatric illness and dementia in relatives, since the family history may not have been recognised as HD at the time

Differential diagnosis

• Huntington disease-like syndromes and other choreas - genocopies exist (HDL1-4) that are clinically indistinguishable but genetically distinct, relevant if standard HTT testing is negative despite a convincing phenotype and family history
• Drug-induced chorea - dopaminergic drugs, antipsychotics (tardive dyskinesia), or oral contraceptives
• Sydenham's chorea - post-streptococcal, in children, usually self-limiting
• Chorea gravidarum - chorea occurring in pregnancy, often in someone with an underlying predisposition
• Wilson's disease - movement disorder plus liver disease and psychiatric features in a younger patient
• Primary psychiatric disorder - if psychiatric symptoms dominate and family history is not elicited
• Vascular or autoimmune chorea - antiphospholipid syndrome, systemic lupus erythematosus

Investigations

The diagnosis is confirmed by genetic testing for the CAG repeat expansion in HTT. Because this is a predictive test with profound implications not just for the patient but for their at-risk relatives, testing (whether diagnostic in a symptomatic person, or predictive in an asymptomatic at-risk relative) should be preceded by formal genetic counselling.

• Genetic testing - confirms the diagnosis by identifying the expanded CAG repeat; distinguishes HD from phenocopies
• MRI brain - may show caudate and putamen atrophy with secondary enlargement of the frontal horns of the lateral ventricles in established disease, though this is a supportive rather than diagnostic finding, and imaging can be normal early in the disease
• Neuropsychological assessment - characterises the cognitive profile and helps with functional planning
• Screening bloods - to exclude alternative causes of chorea where the family history or genetic test is unclear

Management

There is currently no treatment that slows the underlying neurodegeneration in HD. Management is entirely symptomatic and, as with MND, depends heavily on proactive multidisciplinary input.

Chorea

• Tetrabenazine - a vesicular monoamine transporter inhibitor that depletes presynaptic dopamine; effective for chorea but can worsen or precipitate depression and suicidal ideation, so psychiatric status must be assessed before and during treatment
• Antipsychotics (e.g. olanzapine, risperidone) - can treat chorea and coexisting psychiatric symptoms simultaneously, useful when both are present
• Treatment is only started when chorea causes functional impairment, injury risk or distress - not simply because it is present

Psychiatric and cognitive management

• SSRIs for depression - first-line, alongside psychological support
• Antipsychotics for psychosis or severe irritability/aggression
• Active, ongoing suicide risk assessment at every contact, given the persistently elevated risk throughout the disease course
• Cognitive and behavioural strategies, and support for the family in managing personality change and impaired insight

Multidisciplinary supportive care

• Speech and language therapy - for dysarthria and, later, dysphagia
• Dietetics - chorea itself increases energy expenditure, and weight loss is common; nutritional support and texture-modified diets as swallowing declines
• Physiotherapy and occupational therapy - maintaining mobility, fall prevention, home adaptations
• Genetic counselling for the wider family - each child of an affected parent has a 50% chance of inheriting the expansion
• Advance care planning, initiated proactively while capacity and communication are preserved
• Social care and carer support - given the long disease course and heavy caregiving burden

Complications

• Progressive loss of independence and mobility
• Aspiration pneumonia from advancing dysphagia - a common cause of death
• Weight loss and malnutrition
• Suicide - a leading and preventable cause of death, at any stage of the illness including the presymptomatic period
• Significant psychological and practical burden on family members and carers, who may themselves be at risk of carrying the gene
• Falls and injury from chorea and gait disturbance

Red flags

Many of the most important safety issues in Huntington disease arise from impaired insight, meaning the patient may not recognise or report them. Actively asking the family, rather than relying on the patient's own account, is often what surfaces the problems below.

Prognosis

HD is relentlessly progressive, typically over 15-20 years from symptom onset to death, though this varies with age of onset and CAG repeat length (longer repeats are broadly associated with earlier onset and, to some extent, faster progression). Juvenile-onset disease tends to progress more rapidly. Death commonly results from aspiration pneumonia or other complications of advanced immobility and dysphagia, rather than the neurodegeneration itself. As with MND, honest early discussion of prognosis, proactive symptom and psychiatric management, and genetic counselling for the family are as important to overall care as any specific drug treatment.

Carers require support in their own right. Because the disease runs in families, the person caring for an affected patient is frequently at 50% risk themselves, and may be caring for a parent while facing the same diagnosis - a burden that is quite unlike most other neurodegenerative conditions and one that services should recognise explicitly.

Although no treatment yet alters the underlying neurodegeneration, this is one of the most active areas in translational neurology, with several approaches aimed at lowering mutant huntingtin protein in clinical development. Patients and families frequently ask about these, and it is reasonable to acknowledge the research honestly while being clear that nothing currently available modifies the disease course, and to signpost patients to specialist centres and registries if they wish to consider participating in trials.