Huntington’s disease

Motor symptoms

The motor symptoms of Huntington’s disease can be divided into two categories: added involuntary movements such as chorea and impaired voluntary movements, which cause limb incoordination and impaired hand function. These symptoms are worsened by loss of postural reflexes. The pattern of symptoms tends to change over time, with chorea declining and dystonia, rigidity, and bradykinesia becoming more marked.

Cognitive symptoms

Cognitive impairment includes slowing of thought processing and deterioration of executive functions (high level cognitive processes that control other aspects of cognitive function). Typically, patients report difficulty with multitasking, concentration, and short term memory. Thinking style becomes more concrete and less efficient, and the planning, initiation, and organisation of time, thoughts, and activities become harder. People with Huntington’s disease are often impulsive and develop psychomotor perseveration. Visuospatial perception can also deteriorate.4 9

Psychiatric symptoms

Depression is one of the most common psychiatric symptoms and occurs as part of the disease, rather than merely as a response to diagnosis. A recent survey of 2835 patients with the disease found that 40% had symptoms of depression, and 50% reported having sought treatment for depression in the past.10 Other reported psychiatric symptoms include obsessive-compulsive symptoms and psychosis.^w3-w5

It is important to recognise psychiatric symptoms in Huntington’s disease so that symptomatic treatment can be offered. This may be difficult later in the disease because diagnoses may be obscured by other features of the disease; depression, for example, may be difficult to detect in a patient who has altered facial expressions and tone of voice. Conversely, metabolic symptoms such as weight loss and sleep disturbance may be wrongly attributed to depression.

Suicide risk

Patients with Huntington’s disease are more likely than members of the general population to commit suicide according to a meta-analysis of studies that reported mortality associated with mental disorders (standardised mortality ratio of 290).^w6 A survey of 4171 carriers of the Huntington’s gene with premanifest and manifest disease found that 17.5% had suicidal thoughts at or around the time of assessment and 10% of those surveyed had made at least one suicide attempt in the past.11 Suicidal ideation was highest in gene carriers who were nearing the threshold of being diagnosed with manifest disease (those with soft motor signs of Huntington’s disease), and in those who were beginning to lose their functional ability and independence (those with stage 2 disease). Risk factors for suicide in Huntington’s disease include depression and impulsivity.4 Some people with the disease also have suicidal thoughts in the absence of depression^w7: for some, thoughts of suicide seem to be a rational response to their imminent loss of independence.

Metabolic symptoms

Huntington’s disease causes metabolic symptoms, which include catabolic weight loss, endocrine dysfunction, and sleep disturbance.12

Advanced disease

By the time patients have endstage disease they are profoundly disabled. Communication may be severely limited and muteness is common, which can result in agitation and frustration. Huntington’s disease does not cause global dementia, however, and the ability to recognise and interact with people is often preserved. Huntington’s disease is a catabolic condition, and this, combined with marked dysphagia, means that it can be difficult to provide sufficient nutrition to maintain a patient’s weight.

What is the genetic basis of the disease?

Huntington’s disease is a single gene disease with autosomal dominant inheritance. The genetic abnormality is an expanded CAG trinucleotide repeat within the Huntingtin (HTT) gene on chromosome 4, and it can be identified through genetic testing.13 The HTT gene encodes the protein huntingtin, which is essential for normal neural development, although its functions are incompletely understood.14 ^{w8 w9} In Huntington’s disease, the expanded HTT gene encodes a mutant form of huntingtin protein. The mutant protein causes or contributes to the development of Huntington’s disease through many pathogenic mechanisms.15

Offspring of an affected parent have a 50% chance of inheriting the genetic abnormality, and males and females are affected equally. Huntington’s disease does not skip generations.

What is the meaning of CAG repeat length in Huntington’s disease?

A “normal” HTT gene has fewer than 36 repeats. The gene is abnormal, or expanded, if it has 36 or more repeats, and CAG repeats of 40 or more will always cause Huntington’s disease. Genes with CAG repeat lengths between 36 and 39 show reduced penetrance, which means that some people with these lengths will develop Huntington’s disease and some will not; those who do develop disease are likely to develop later onset disease.^w10 An intermediate repeat length between 29 and 35 does not cause the disease but may expand into the pathogenic range in future generations.

The instability of intermediate alleles is one cause of sporadic Huntington’s disease, in which the disease develops in someone with no apparent family history. Apparent sporadic Huntington’s disease occurs in 6-8% of new cases of Huntington’s disease,^{w11 w12} and it can also be caused by unexpected or unknown paternity, or a parent dying before they develop symptoms of the disease. Instability of the CAG repeats can also cause “genetic anticipation,” in which the CAG repeat length increases and causes onset of the disease at a younger age in affected offspring than in the parent. Genetic anticipation is more common when the expanded allele is inherited from a father than from a mother. About 90% of people with juvenile disease (with CAG repeats typically >60) inherit the mutation from their father.^{w13 w14}

CAG repeat length is related to age of onset of disease at a population level: the longer the CAG repeat length, the earlier the onset of symptoms tends to be. However, repeat length only accounts for 50-70% of this variance, and disease onset in an individual cannot be predicted reliably through genetic testing.^w15 The CAG repeat length is related less strongly to the rate of disease progression.^{w16 w17}

Confidentiality and consent

According to internationally agreed guidelines,18 19 20 strict confidentiality is observed before, during, and after predictive testing. No one other than the adult being tested is told about the process without their express permission. This includes partners and family members. Some people with positive predictive Huntington’s disease test results choose not to inform their general practitioner so that the information remains confidential. Written informed consent must be obtained from the patient before either predictive testing or diagnostic testing. If the patient lacks capacity to make the decision themselves for diagnostic testing, consent can be given by an authorised representative.

Having children

Deciding whether or not to have children is often difficult for people with or at risk of having an expanded HTT gene. A minority choose to have either prenatal testing or preimplantation genetic diagnosis, which ensures that their child has a less than 1% chance of carrying the mutant gene. Although couples in which one partner is at risk of or has Huntington’s disease are not usually eligible to adopt, some adoption agencies will consider it, and fostering may also be possible.

Exclusion (non-disclosing) prenatal testing and preimplantation genetic diagnosis

Exclusion (non-disclosing) prenatal testing or preimplantation genetic diagnosis can be carried out for couples in which one partner is at risk but does not wish to have a predictive test. With this test the potential parents do not find out their own Huntington’s disease gene status. The test requires blood samples from several family members, and linkage techniques are used rather than testing for the CAG expansion (see fig 2⇓ for more details). A “high risk” result means that the fetus is at 50% risk of developing Huntington’s disease—the same risk as the at risk parent. A couple undergoing this test may choose to terminate a pregnancy at 50% risk. Clearly this test requires detailed discussion with the couple beforehand. In practice, very few of these tests are performed, but it is a helpful option for some couples.

Fig 2 Use of linkage analysis for prenatal testing. Adapted, with permission, from material of the Guy’s and St Thomas’ NHS Foundation Trust reproductive medicine clinic and assisted conception unit

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Emotional implications

A patient who receives a diagnosis of manifest Huntington’s disease learns that he or she has a slowly progressive incurable disease. A person who receives a positive predictive test experiences the extra burden of being uncertain when the disease will begin to take effect. Most people who have genetic testing for Huntington’s disease will have watched a parent develop the disease, will be familiar with the change in personality and cognition that it causes, and will know what effect their illness will have on those around them.

Since direct genetic testing for Huntington’s disease became available in 1993, a steadily increasing cohort of premanifest gene carriers has been created. Many of this group may not wish to engage with health or social services until they develop manifest disease, whereas others value emotional and practical support to help them deal with the implications of a predictive test result.

In 1996, one study followed up 135 Canadians who had entered a predictive testing programme.^w21 Adverse events, including psychological distress, substance misuse, and relationship breakdowns, were recorded in seven of the 37 who received a positive result compared with eight of the 58 who received a negative result. (The remaining subjects received equivocal results or chose not to proceed with testing.) One subject in each group reported suicidal ideation.

A positive predictive test can come as a relief, however, because some people find a positive test result easier to cope with than the uncertainty of being at risk. As discussed above, only a minority of people at risk choose to have predictive testing; these people are a self selecting group, and the aim of genetic counselling is to ensure that they are equipped to deal with their predictive test result. Diagnostic testing can also be helpful in removing uncertainty—for example, a diagnosis of Huntington’s disease could alleviate the distress caused by an unexplained change in personality.

Practical implications: insurance and employment

In 2001, the Association of British Insurers (ABI; the trade association for the UK insurance industry; www.abi.org.uk/) and the UK government agreed a moratorium on access to any predictive genetic test results by insurance companies who are ABI members. In general, insurers will weight applicants who have a family history of Huntington’s disease but cannot require them to take a predictive genetic test. People at risk of Huntington’s disease can apply for up to £500 000 of life insurance, £300 000 of critical illness insurance, and income protection that pays benefits of up to £30 000 a year without disclosing the results of any predictive genetic test. Huntington’s disease is, however, the one disease that is exempt from a total ban on disclosure; applicants must disclose Huntington’s disease predictive test results if they apply for life insurance over £500 000. A negative predictive test result will bring insurance premiums back in line with those of people without a family history of Huntington’s disease. This insurance moratorium is due to be reviewed in 2011.

A positive predictive test does not need to be declared when applying for travel insurance in the UK, but manifest disease does. Specialist companies with experience of insuring people with pre-existing medical conditions are helpful, and the HDA can provide details of appropriate contacts.

Under the 1995 Disability Discrimination Act in the UK, it is illegal for employers to discriminate against someone who is disabled by dismissing them or by treating them negatively because of their disability. We strongly recommend that patients with Huntington’s disease who feel that their ability to work is deteriorating inform their employers about their diagnosis to ensure that their job is legally protected. Once diagnosis is revealed, regular assessment should take place according to occupational risk. The legal situation for people at risk of Huntington’s disease because of their family history is less clear cut, and there is currently no law in the UK to prevent discrimination against those with a genetic diagnosis (in employment, or elsewhere). A working group of the Human Genetics Commission in the UK is currently examining this area and is due to report in 2011. In the United States, the 2008 Genetic Information Nondiscrimination Act prohibits discrimination on the basis of genetic information in employment and health insurance provision.

In the UK, asymptomatic gene carriers are not obliged to disclose a positive predictive test result to their employer unless a health questionnaire has a specific question on this. In reality, however, some employers may place restrictions, based on family history, on the work of people who are at risk or are asymptomatic gene carriers. The police, for example, have separate rules for each authority but may ask employees at risk to have regular neurological reviews. The UK armed forces are a special case: until recently, applicants to the armed forces who were at risk of Huntington’s disease because of their family history were accepted only if they had received a negative predictive test result. This policy is now being reconsidered, with alternatives such as a shorter term of service being offered. As with patients with manifest Huntington’s disease, we recommend regular review of premanifest gene carriers as appropriate for their occupational level of risk.

Research on genetic discrimination in Huntington’s disease is limited, but a recent survey of 233 tested and untested people at risk of Huntington’s disease in Canada found that 6.4% reported genetic discrimination related to employment.^w22 Anecdotal evidence also suggests that some premanifest gene carriers have been discriminated against in the UK.

Managing the movement disorder

The first step is to decide whether symptoms need treating. Patients are often not bothered by early chorea, for example, and may not even be aware of it. As chorea develops, however, it can interfere with voluntary activities like writing or eating, and it often causes falls, making intervention necessary. Chorea can be distressing in itself, and patients often find themselves accused of drunkenness by people unaware of their diagnosis.

Non-drug interventions should be considered first. Chorea often varies with posture or positioning, and devices such as padded chairs or wrist and ankle weights to reduce the amplitude of chorea may be helpful. Shoes with non-slip soles and grab rails around the home can improve safety, and assessment of the home by an occupational therapist is often extremely useful. Physiotherapy can also help optimise mobility, and can be especially beneficial early in the disease to preserve mobility and independence for as long as possible. Like most involuntary movements, chorea is worsened by stress, anxiety, and depression, so treating these and providing a calm predictable environment are beneficial.

If these measures are not sufficient to control symptoms, drugs can be tried. These are unlikely to prevent chorea completely, but they can dampen down symptoms considerably, and tetrabenazine is generally the first choice. It can exacerbate or trigger psychiatric symptoms, so it should be avoided in patients with a history of depression or other psychiatric disorders, and in these patients, or in those in whom symptoms are not controlled with tetrabenazine, the atypical neuroleptics are helpful. Of these, olanzapine is our first choice because it is an effective anti-chorea drug that also promotes weight gain, suppresses irritability, and improves sleep—all of which are useful side effects in Huntington’s disease.

Movement suppressing drugs used in the earlier stages may however exacerbate the impaired movements that develop later on. They will often need to be reduced and eventually stopped, so regular reassessment is vital.

Managing cognitive and psychiatric manifestations

Recognising and acknowledging that these symptoms are probably caused by Huntington’s disease is important so that strategies can be developed to deal with them. It is important to ask depressed patients about suicidal thoughts, and to take a proactive approach to the treatment of psychiatric symptoms. Treatment of depression in Huntington’s disease is with standard antidepressants. Although there is not an established evidence base for the treatment of depression in Huntington’s disease, our experience is that antidepressants are often very effective. Psychological treatments, such as cognitive behavioural therapy, can also be helpful in selected patients. This can also be a useful way for people with premanifest disease to learn cognitive strategies that will stand them in good stead once they develop cognitive and psychiatric symptoms. We know of no controlled trials of this treatment in Huntington’s disease, although one case study reported benefit for a patient with premanifest disease.^w24 Support from local community mental health teams is often invaluable.

No drug treatments are available for cognitive symptoms, but coping strategies can often be adopted to overcome problems or compensate for them. Difficulty with multitasking is an example of a common early symptom; concentrating in a busy office can be difficult and tension may develop in relationships with colleagues. This, in turn, will increase stress and exacerbate the underlying problem with concentration. Once these problems have been identified, appropriate compensatory strategies can be devised, such as moving into a quiet office and reducing workload. Employers have a statutory duty to optimise the working environment for people with a disability where possible, although this needs to be approached sensitively.

Apathy is also a challenging symptom to manage and can be difficult to differentiate from depression; it may be worth considering a trial of antidepressants if this is the case. It is important to gently impose structure on the day, because patients often find that having an appointment to aim for, such as coffee with a friend, helps them to initiate activities and organise their behaviour. It can be difficult for people with Huntington’s disease to initiate activities, but once started they are often able to participate fully with encouragement and support from carers.

End of life care

Planning for end of life care raises several ethical problems that often relate to how far medical interventions should be taken in patients who no longer have the capacity to make their wishes known. We find that advanced decisions to refuse treatment (previously known as advanced directives) can be extremely helpful. They give patients the security of knowing that their wishes will be carried out, even if they are no longer able to make decisions or communicate, and they relieve relatives of the responsibility of making choices. Advanced decisions to refuse treatment and end of life care should be raised as early as possible so that they can be discussed by the patient and their loved ones. The Independent Mental Capacity Advocate service (www.dh.gov.uk/en/SocialCare/Deliveringadultsocialcare/MentalCapacity/IMCA/index.htm) provided via the Department of Health can be helpful if a patient does not have capacity and his or her next of kin is unable or unwilling to make decisions on the patient’s behalf.

As Huntington’s disease progresses, it often becomes increasingly difficult to provide care at home, and a nursing home may be the best option. Insertion of a gastrostomy tube may be appropriate in patients who are unable to maintain adequate nutrition and body weight. Box 3 contains sources of information for palliative management in Huntington’s disease.