Huntington's disease

Written by Dr Linda Appai-Kubi, King's College Hospital and Guy's King's ST. Thomas's School of Medicine, London and Dr K Ray Chaudhuri, King's College Hospital and Guy's King's ST. Thomas's School of Medicine, London

Psychiatric symptoms
Many factors contribute to the psychiatric problems faced by patients with HD; stress and concern about the nature of the condition, family relationships and social support as well as the disease process in the brain itself.

Depression is a major problem in HD, affecting up to half of all sufferers. This may appear before other symptoms and may also occur in non-HD members of the family as knowing the disease affects someone in the family is a significant strain for them. Common 'biological' symptoms of depression include difficulty sleeping, and loss of appetite and weight.

Personality change also occurs early in the illness, and can appear as a lack of will and interest in life or as increased anger and irritability. This may be closely followed by changes in behaviour such as impulsive actions or violence, placing additional strain on the patient and the family.

Disinhibition may cause the HD sufferer to respond unexpectedly to social situations. Antisocial personality disorder may also occur. Schizophrenia is also more common in HD than in the general population (5 to 10 per cent versus 1 per cent). Patients may complain of hearing or feeling things, or other hallucinations, and may develop unusual or paranoid beliefs.

HD may also be associated with alcoholism and sexual promiscuity. Suicide is also more common in HD. Another condition known as 'intermittent explosive disorder', which includes irritability, can occur.

Other symptoms
Patients experience a gradual loss of ability to care for themselves as mobility and their ability to control their movements decreases.

Diet suffers through difficulty in eating and decreased appetite, leading to weight loss. Patients may also experience bowel or bladder problems such as difficulty in passing urine, incontinence and constipation.

What happens to the brain in HD?
The disease mainly affects the brain and spinal cord and abnormal brain cells are mainly found in the areas deep down in the brain that control movement (caudate nuclei and striatum).

All cells in the body use energy to live and carry out their functions. As part of this natural process, cells produce chemicals (oxidants) that may damage the cell, but cells also have ways of making these poisons harmless.

Current theories suggest that huntingtin, the protein formed as a result of the abnormal HD gene (IT15), somehow prevents the brain cells from protecting themselves against the toxic chemicals.

It is also believed that the situation is worsened by falls in the amounts of signalling chemicals in the brain (neurotransmitters) such as gamma amino butyric acid (GABA) and substance P.

Much evidence exists to suggest that these cells are unable to use energy efficiently and may die as a result. This is the basis for new experimental treatments for HD that aim to slow the disease process by providing added protection against the toxic chemicals that are formed when cells use energy.

Remacemide and coenzyme Q are two drugs that may be protective, and are currently being studied in several hospitals worldwide, in the hope that they might slow the progression of HD.

How does the doctor make the diagnosis?
If the patient is known to have a family history of HD, and begins to show symptoms of the disease that cannot be explained by other illness, the diagnosis of HD is usually clear.

Unusual symptoms in HD may sometimes mimic other diseases affecting control of movement, such as Parkinson's disease and other similar disorders.

Without knowledge of the full family history, diagnosis is more difficult but there are tests available which may reveal some of the abnormalities in memory and thought processing.

Other investigations include computed tomography or magnetic resonance imaging scans of the brain, in which the characteristically affected areas (caudate, striatum) appear shrunken later in the course of the disease. The distance between the two caudate nuclei on MRI brain scans may identify shrinkage of these structures, which is a typical finding in HD.

Scans revealing brain function will show higher levels in these areas of lactic acid, a by-product of cell energy use, as the brain cells are working harder or using energy in an abnormal way.

Research scans may be performed using positron emission tomography (PET) in a few centres. These scans which use injected tracers such as flumazenil or raclopride show reduction of dopamine D1 and D2 receptors in the brain regions called 'basal ganglia'. However, these brain scans are mainly used to support the diagnosis, or for research to understand more about HD as these changes can occur in other brain diseases.

The diagnosis may be confirmed by genetic testing for the abnormal huntingtin gene. This test is a recent useful addition to diagnosis but unfortunately gives no reliable information on when symptoms will begin to occur or how quickly the disease will progress. This is a very difficult issue for HD families and requires a great deal of consideration as well as genetic counselling.

The value of testing younger family members is also questionable as there is no cure or method of halting the disease process. A positive result is likely to be very distressing and presents a substantial psychological strain to be borne for many years with possibly life-changing consequences.

A positive result in a child also has implications for parents who may not wish to know whether they have the disease. For these reasons genetic testing is not offered in the UK to people under 18 years of age. However, this situation may change in the future if ways to slow the disease process (such as nerve-protecting treatments) are discovered.

Can HD be prevented?
Although much is known about the gene that causes HD, little is known about how the presence of the gene causes the disease. It is not possible to prevent the disease or slow its progression once the abnormal gene is present. However several options are available to people in HD families particularly when planning a family of their own.

Prenatal diagnosis It is now possible to calculate the risk of developing HD early in pregnancy.

The tests currently offered are predictive, this means they do not actually look for the abnormal gene. Instead these tests look for other genes that are likely to be inherited along with the HD gene (linked genes), using genetic information from parents and grandparents.

For example, a woman whose father has HD wishes to know if the child she is carrying has HD. If the foetus is shown to have inherited a linked gene from the maternal grandmother then it is also likely that they have inherited a normal gene instead of the HD gene, as the grandmother is not affected by the disease. However if the foetus is shown to have inherited a linked gene from the maternal grandfather then there is still no more than a 50 per cent chance that the HD gene from the grandfather has also been inherited.

Without the predictive testing there is a one in four chance that the child will have the illness, providing the mother has not shown any symptoms. With the predictive testing the child still has no more risk than their mother - 50 per cent.

This test is useful, as it predicts a low risk of HD in some cases, however it cannot predict an increased risk. For this reason couples need much support, and genetic counselling about what the results of the test will mean for their family and their future.

Following counselling, testing is generally only offered to couples if the test results would influence their decision as to whether to continue with the pregnancy. It is thought that the distress caused by a positive result, for parents who would not change their plans in any case, is unnecessary, as there are no interventions that may prevent or change the course of the disease.

How is HD treated?
As there is no cure for HD, treatment is generally supportive, and involves many forms of medical and social care in an attempt to lessen the impact of symptoms on the patient and their carers. The disease is also progressive, and as there are no available methods of slowing its progression, symptoms are treated as and when they arise. A list of medicines found to be useful in managing some symptoms is shown in Table 1.

Table 1: Medicines used to treat the symptoms
Symptoms	Treatment	Notes
Depression	Tricyclic antidepressants, eg. amitriptyline, imipramine, desipramine, nortriptyline.	Treatment of depression also improves symptoms such as social withdrawal, lack of interest and sleep disturbance. This may in turn improve memory and ability to concentrate on tasks.
	Selective serotonin reuptake inhibitors (SSRIs), eg paroxetine, fluoxetine, sertraline.
Movement disorders	Tetrabenazine, haloperidol, fluphenazine. Drugs for treatment of parkinsonism and dystonia.	For treatment of disabling abnormal movements.
Antisocial behaviour, irritability, psychosis	Chlorpromazine, sulpiride, quetiapine, clozapine, risperidone, leuprorelin acetate.	Drugs treating behavioural problem and abnormal movements may have overlapping effects

These medicines have a wide range of actions, which may cause unpleasant side effects, and treatment will depend on striking a balance between side effects and benefits.

Attention must also be focussed on the general health of the HD sufferer, in particular diet and nutrition, as some patients may develop difficulty with swallowing and may be at risk of choking.

Social and psychiatric support becomes increasingly important as patients are at greater risk of harming themselves, both through accidents such as falls or accidental fires, and also through depression, which is common in HD, and prompts many to consider suicide.

Nerve protection (neuroprotection) Trials of neuroprotecting drugs in HD have not yet been successful. The first drug used for such a trial was baclofen. Subsequently drugs such as remacemide, d-alpha-tocopherol and coenzyme Q10 have been attempted without any major benefit

Neurotransplantation
Dopamine is one of the many neurotransmitter chemicals, which are important for brain function. Transplantation of dopamine-containing cells from an area in the foetal brain has been attempted to treat HD at a few centres around the world. The results are unclear and further research needs to be undertaken before this form of treatment can be recommended. There are practical and ethical issues which are yet to be fully resolved. For instance, it is still not possible to prevent uncontrolled growth of the transplanted cells.

Outlook for people with HD. What can the patient do?
HD is a devastating disorder and the impact of this diagnosis on patients and caregivers is enormous.

It is therefore critical that the patient is absolutely sure that he or she wants to know the diagnosis, as a positive diagnosis of HD usually means the certain appearance of symptoms and mental illness in the future. Furthermore, there is a great impact on the family. Affected persons should ask their physician for information on this condition and should also consider contacting their local HD support group or the HD Association.

Summary
HD is a genetically inherited progressive disorder that leads to the appearance of movement disorders and mental illness. The disease can be diagnosed by a blood test to detect the abnormal gene known as 'huntingtin'.

There is currently no cure available for this disorder although much research is being carried out worldwide to discover treatment strategies that may slow the progress of the condition.

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