Huntington disease

Huntington disease is a progressive neurodegenerative condition characterised by motor, cognitive and psychiatric decline. It is inherited in an autosomal dominant pattern, which means that first-degree relatives (parents, children, siblings) of an affected individual have a 1 in 2 (50%) chance of being affected themselves.

The prevalence of Huntington disease in the UK is around 1 in 10,000, with the peak onset of motor symptoms occurring between the ages of 40 and 45.

Cognitive and psychiatric problems are often present at diagnosis, although affected individuals most commonly present with a movement condition. Involuntary movements (chorea) may be prominent, with bradykinesia, dystonia, mental disturbances and cognitive decline becoming more notable as the condition advances.

Clinical signs of Huntington disease

• Early: chorea, clumsiness, agitation, irritability, anxiety, delusions, disinhibition, apathy, hallucinations, depression, mild cognitive impairment, executive dysfunction.
• Middle: dystonia, chorea, weight loss, speech and swallowing difficulties, ataxia, slow voluntary movements, progressive cognitive decline.
• Late: dementia, rigidity, bradykinesia, inability to walk, inability to speak, swallowing problems, inability to care for oneself.

The median survival time after onset is 15 to 18 years, with the average age of death around 55 years.

Juvenile Huntington disease

Juvenile Huntington disease occurs when disease onset is before the age of 20. Individuals may still have motor, cognitive and psychiatric disturbances as mentioned above but in many cases the nature of the presentation may differ from adults.

Differences seen in juvenile Huntington disease can include:

• Cognitive: developmental delay may occur. Declining cognitive function may present early.
• Psychiatric: obsessive-compulsive behaviours are more common.
• Motor: postural instability, dystonia, bradykinesia and rigidity may occur early while chorea may be a later feature. Swallowing problems, drooling and speech difficulties may also occur early.
• Other: seizures occur in 30%–35%.

Decline may also occur more rapidly in some young people.

Huntington disease is caused by a heterozygous expanded CAG trinucleotide repeat expansion in the HTT gene.

There is a DNA segment in the HTT gene known as the CAG repeat, in which the three nucleotides, C, A and G, appear multiple times in a row. The number of repeats varies between individuals, and an expanded number of repeats results in Huntington disease (see figure 1). There is a broad association between the number of CAG repeats and the onset of clinical manifestations of Huntington disease.

Figure 1: CAG expansions in the HTT gene and risk of development of Huntington disease symptoms

Huntington disease is inherited in an autosomal dominant pattern. Individuals affected by an autosomal dominant condition have one working copy of the gene, and one with a pathogenic variant. Affected individuals have a 1 in 2 (50%) chance of passing the condition on to their children. Incomplete penetrance can occur when not everyone who has the variant develops the disease.

The CAG repeat size does not correlate well with age of onset, clinical phenotype or progression, all of which may vary considerably, even between individuals in the same family. Individuals with expansions of 55 CAG repeats or more are at risk of early onset symptoms (juvenile or paediatric-onset Huntington disease), although it is very rare in those under 10 years old.

Asymptomatic individuals at risk of developing Huntington disease can be offered predictive (presymptomatic) testing. Due to the implications of the diagnosis for an individual’s relationships and financial and psychological status, predictive testing is offered through clinical genetics services only. A series of appointments is recommended, including a mental health assessment, to support the individual in their decision.

The mainstay of management for Huntington disease is supportive treatment and symptom control. It is common for patients to have had treatment for mental health conditions such as anxiety and depression before a formal diagnosis.

Multidisciplinary management is vital, with input from neurologists, neuropsychiatrists, community mental health teams, geneticists, physiotherapists, speech and language therapists, dieticians and occupational therapists.

A wide range of potential therapies are under investigation in both human and animal models.

For clinicians

• GeneReviews: Huntington disease
• National Institute of Neurological Disorders and Stroke: Huntington’s disease
• NHS England: National Genomic Test Directory

References:

• Baig S, Strong M, Rosser E and others. ‘22 years of predictive testing for Huntington’s disease: The experience of the UK Huntington’s Prediction Consortium’. European Journal of Human Genetics 2016: volume 24, pages 1,396–1,402. DOI: 10.1038/ejhg.2016.36
• Craufurd D, MacLeod R, Frontali M and others. ‘Diagnostic genetic testing for Huntington’s disease‘. Practical Neurology 2015: volume 15, issue 1, pages 80–84. DOI: 10.1136/practneurol-2013-000790
• MacLeod R, Tibben A, Frontali M and others. ‘Recommendations for the predictive genetic test in Huntington’s disease‘. Clinical Genetics 2013: volume 83, issue 3, pages 221–231. DOI: 10.1111/j.1399-0004.2012.01900.x
• Stoker B, Mason SL, Greenland JC and others. ‘Huntington’s disease: diagnosis and management‘. Practical Neurology 2022: volume 22, issue 1, pages 32–41. DOI 10.1136/practneurol-2021-003074

For patients

• HD Buzz
• Huntington’s Disease Association
• NHS England: Huntington’s disease