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Huntington's Disease
Huntington disease (HD) is a rare neurodegenerative disorder of the central nervous system characterized by unwanted choreatic movements, behavioral and psychiatric disturbances and dementia.''' Patients experience psychiatric symptoms and cognitive decline. HD is an autosomal dominant inherited disease caused by an elongated CAG repeat (36 repeats or more) on the short arm of chromosome 4p16.3 in the Huntingtine gene. The longer the CAG repeat, the earlier the onset of disease.

Signs And Symptoms
The nuclear symptoms and signs of Huntington's disease (HD) consist of motor, cognitive and psychiatric disturbances. Other less well-known, but prevalent and often debilitating features of HD include unintended weight loss, sleep- and circadian rhythm disturbances and autonomic nervous system dysfunction. The mean age at onset is between 30 and 50 years, with a range of 2 to 85 years. The mean duration of the disease is 17-20 years. The progression of the disease leads to more dependency in daily life and finally death. The most common cause of death is pneumonia, followed by suicide.

The motor symptoms and signs
The characteristic motor changes are involuntary, unwanted movements. Initially, the movements often occur in the distal extremities such as fingers and toes, but also in small facial muscles. For bystanders these muscle twitches are often invisible or can be explained as nervousness. In daily life, walking becomes unstable and the person can look as if he/she is slightly drunk. Gradually the unwanted movements spread to all other muscles from distal to more proximal and axial. Choreatic movements are present all the time the patient is awake. No single pattern exists, but facial choreatic movements can lead to a continuous movement of facial muscles where for instance an eyebrow is lifted, an eye closed, the head is bent or turned while the tongue is protruded with the lips pouting. The most prominent are the extension movements of the long back muscles. Talking and swallowing gradually become more problematic leading to choking at any time in some patients. In later stages the patient even becomes mute. Dysarthria and dysphagia become very prominent during the course of the disease.

Behaviour and psychiatric symptoms and signs
Psychiatric symptoms are very frequently present in the early stage of the disease, often prior to the onset of motor symptoms. The percentage of patients with psychiatric signs varies between 33% and 76% depending on the methodology of the study[4]. Because of their impact on daily life, these symptoms and signs usually have a highly negative impact on functioning and on the family [5]. The most frequently occurring sign is depression. The diagnosis is difficult because weight loss, apathy and inactivity also occur in HD. Usually there is low self-esteem, feelings of guilt and anxiety. Apathy is related to disease stage, whereas anxiety and depression are not. Suicide occurs more frequently in early symptomatic individuals and also in premanifest gene carriers. Around the time of the gene test and the stage when independence diminishes are the most risky periods for suicide. Anxiety also occurs frequently (34-61%), sometimes in relation to uncertainty about the start and or the course of the disease. Obsessions and compulsions can disturb the patient's life and also lead to irritability and aggression. Irritability is often the very first sign, in retrospect, but in fact occurs during all stages of the disease [4]. The way irritability is expressed varies enormously from serious disputes to physical aggression. A loss of interest and increasing passive behaviour are seen as part of the apathy syndrome. It can be difficult to discriminate apathy from depression. Pychosis may appear, mainly in the later stages of the disease. In most cases this goes together with cognitive decline. The complete clinical picture is comparable to schizophrenia with paranoid and acoustic hallucinations.

Dementia
Cognitive decline is the other main sign of HD and can be present long before the first motor symptoms appear, but can also be very mild in far advanced stages of the disease. The cognitive changes are particularly in relation to executive functions. In normal conditions, cognitive and motor behavior is goal-directed and planned. Normally individuals are able to distinguish what is relevant and what can be ignored, but patients with HD lose this capability. The patients are no longer able to organise their life or to plan things which in the past were simple. They lose flexibility of mind, and can no longer make mental adjustments. Misjudgments lead to complicated situations, with patients no longer reacting as they did in the past or in a way that the environment expects. Language is relatively spared. Memory certainly becomes impaired, although the semantic memory can be spared to a certain extent. All psycho motor processes become severely retarded.

Diagnosis
The diagnosis is based on the clinical symptoms and signs in a person with a parent with proven HD. First, it is obligatory to take a precise history from the person with symptoms followed by a detailed family history. When all information has been obtained the diagnosis is not very difficult, although non-specific clinical pictures can be misleading. Also when the parent is not known or has died due to another cause at a young age, the clinical picture can be difficult to recognize. It is often necessary to request old information in the form of medical records and autopsy reports. The current gold standard is DNA determination, showing a CAG-repeat of at least 36 on the Huntington gene on chromosome 4. Before 1993, a family history with clinical and morphological verification in at least one of the parents or grandparents was obligatory.

The clinical criteria currently necessary are still motor changes with or without psychiatric or cognitive changes. However, in most cases a combination of the three main signs is present. The combination with the family history is sufficient for diagnosis. No imaging, general blood tests or other diagnostic tools are helpful. For all diagnostic tests, it is necessary to obtain informed consent from the patient. This is important because if that person is given a diagnosis of Huntington's disease, then probably many more individuals around the patient will be confronted with an increased risk of Huntington's disease. Extensive studies are underway to detect bio markers (clinical, blood, MRI) and hence the transition determining parameters

Prenatal Diagnosis
As the test can be performed on any cell with a nucleus containing DNA, antenatal diagnosis is also possible. Between the 10th and 12th weeks of pregnancy, chorionic villus sampling and between the 15th and 17th weeks amniocentesis can be performed and DNA-testing carried out. The procedure is only initiated if the parents already know their own genetic status to prevent unwanted disclosure for two individuals at the same time. The procedure is embarked on with the intention of ending the pregnancy if the HD gene is found in the embryo. The mother cannot be forced to agree with this conclusion.

Management including treatment
Despite the fact that the pathogenesis of HD has still not been resolved and a cure is not available, many therapeutic options are available for treating symptoms and signs with a view to improving quality of life. Although many signs and symptoms can be treated, it is not always necessary to do so. The patient's limitations in daily life determine whether or not drugs are required. Very little evidence is available about the drug or the dosage to prescribe for any signs and symptoms. Drug treatment is, therefore, individualized and based on expert opinion and daily practice.

Treatment consists of drug prescription and non-medication advice.Besides medication, many other care measures are available. It is important to find the right therapy for the right person at the right time. Non-medical interventions available are: physiotherapy, occupational therapy, speech therapy, dietician, psychologist, social worker, and nurse.

During the course of the disease, the patient requires more care, which can also help his/her partner, for example by having a nurse at home to help with showering. The burden for the caregiver can become too heavy and so help must be found in day-care institutions, usually connected to nursing home facilities. In the period that follows the patient moves into a transition phase and eventually a 24-hour care situation. Throughout the whole process of increasing dependency, psychological help is often needed for the caregiver, who has to deal with increasing responsibilities while losing contact with his or her former partner. Partner groups can be very useful. In general, lay organizations play an enormous role in educating caregivers, patients and families.

Medical and non-medical treatment must be individually tailored, as the symptoms and signs differ by person and over time tremendously. Ideally treatment of patients and their families should be organised by a multidisciplinary team. Treatment is intended to improve quality of life. To date, no cure is available unfortunately.

Juvenile Huntington's Disease
If the first symptoms and signs start before the age of 20 years, the disease is called Juvenile Huntington's disease (JHD). Behaviour disturbances and learning difficulties at school are often the first signs. Motor behaviour is often hypokinetic and bradykinetic with dystonic components. Chorea is seldom seen in the first decade and only appears in the second decade. Epileptic fits are frequently seen. The CAG repeat length is over 55 in most cases. In 75% of the juveniles the father is the affected parent.

Future Perspectives
The basic studies mainly focus on the pathophysiology and the search for biomarkers. A better understanding of the pathophysiology will surely lead to drug development to interfere in the pathological process. Drugs that can slow down, delay, or stop the onset of the disease are being sought. The second issue is the search for reliable, early to detect and clinically relevant markers for onset of the end course of the disease. In the search for biomarkers, a very well organised study is underway: TRACK-HD, a multinational study with 366 participants. This will end in 2011 [22]. The Registry study, the main project of the European Huntington Disease Network, also aims to prepare the field for larger studies when drugs become available for human testing.

In parallel with the rational pathway to find solutions to treat this disorder, attention is being paid to finding the best care for all patients and at-risk persons at this point in time. The developments are promising, but one thing is certain: the road to a solution is a long one.