Huntington's disease is a hereditary neurodegenerative disorder caused by an expansion in the IT-15, or huntingtin, gene on chromosome 4, which encodes the protein huntingtin. Huntington's disease is inherited in autosomal dominant fashion, so that each child of an affected parent has a 50 percent chance of developing the disease. Most people with Huntington's disease develop the symptoms in their forties and fifties, although there may be subtle changes much earlier. About 10 percent of patients have onset of symptoms before age 20 (juvenile Huntington's disease) and 10 percent have onset after age 60.

Huntington's disease manifests as a triad of motor, cognitive, and psychiatric symptoms which begin insidiously and progress over many years, until the death of the individual. The average survival time after diagnosis is about 15 to 20 years, but some patients have lived 30 or 40 years with the disease.

Themovement disorder is characterized both by the emergence of involuntary movements, or chorea, and by impairment of voluntary movements. This latter impairment often contributes more to disability than the chorea itself, resulting in reduced manual dexterity, slurred speech, swallowing difficulties, problems with balance, and falls. Both chorea and impairment of voluntary movements progress in the middle stages of Huntington's disease, but later, chorea often declines as patients become rigid and unable to initiate voluntary movements. Patients in this advanced state are unable to care for themselves

Thecognitive disorder is characterized initially by a loss of speed and flexibility. This may be seen first in complex tasks, when the patient is unable to keep up with the pace and lacks the flexibility required to alternate between tasks. Cognitive losses accumulate and patients develop more global impairments in the later stages of the disease.

The most common specificpsychiatric disorder in Huntington's disease is depression. Patients may also suffer from mania or obsessive compulsive disorder. Other symptoms (which may not fit a specific psychiatric category) include irritability, anxiety, agitation, impulsivity, apathy, social withdrawal and obsessiveness. Huntington's disease can be roughly divided into three stages. Early in the disease, patients are largely functional nand may continue to work, drive, and live independently. Symptoms may include minor involuntary movements, subtle loss of coordination, difficulty thinking through complex problems, and perhaps a depressed or irritable mood. In the middle stage, patients will probably not be able to work or drive and may no longer be able to manage their own finances or perform their own household chores, but will be able to eat, dress, and attend to personal hygiene with assistance. Chorea may be prominent, and patients will have increasing difficulty with voluntary motor tasks. There may be problems with swallowing, balance, falls, and weight loss. Problem solving becomes more difficult because patients cannot sequence, organize, or prioritize information.

In the advanced stage of Huntington's disease, patients will require assistance in all activities of daily living. Although they are often nonverbal anj bedridden in the end stages, it is important to note that patients seem to retain fair comprehension. Chorea may be severe, but more often it has been replaced by rigidity, dystonia, and bradykinesia. Psychiatric symptoms may occur at any point in the course of the disease, but are harder to recognize and treat late in the disease.

Huntington's disease with onset in childhood has somewhat different features. Chorea is a much less prominent feature, and may be absent altogether. Initial symptoms usually include attentional deficits, behavioral disorders, school failure, dystonia, bradykinesia, and sometimes tremor. Seizures, rarely found in adults, may occur in this juvenile form. Juvenile-onset Huntington's disease tends to follow a more rapid course, with survival less than 15 years. The vast majority of patients with juvenile onset have inherited their Huntington's disease gene from an affected father. The reason for this tendency is now understood in genetic terms and will be explained in detail in chapter 2.

The Huntington's disease gene was identified in 1993. It contains a repeating sequence of three base-pairs, called a triplet repeat. An excess number of CAG repeats in the gene results in a protein containing an excess number of glutamine units. The normal function of huntingtin is not known, but the expansion of the huntingtin gene is likely to be a so-called "gain of function" mutation. In Huntington's disease, huntingtin protein encoded by the abnormal gene collects in the nucleus of the cell, giving rise to a structure called an inclusion body. Similar intranuclear inclusions have been seen in other neurodegenerative disorders caused by polyglutamine expansions. The mechanism by which the protein aggregation may cause a brain disorder is not fully understood. The neurons may first become dysfunctional then undergo progressive degeneration and die. Certain neurons appear to be more vulnerable in Huntington's disease. Atrophy is most marked in the corpus striatum of the basal ganglia, including the caudate and putamen. In later phases of the disease, other regions of the brain may be affected.

The clinical diagnosis of Huntington's disease is made on the basis of the family history and the presence of an otherwise unexplained characteristic movement disorder, and is usually confirmed by a gene test. The gene test can be particularly useful when there is an unknown, or negative family history (as occurs in cases of early parental death, adoption, misdiagnosis, or non-paternity) or when the family history is positive, but the symptoms are atypical. The discovery of the huntingtin gene has greatly simplified the diagnostic evaluation of an individual suspected to have Huntington's disease. The implications of the diagnosis of Huntington's disease for the patient and family are profound, and provision should be made for genetic counseling of individuals affected by the results. Genetic counseling and genetic testing are discussed more fully in chapter 2. It is important to remember that the gene test only determines whether or not the Huntington's disease-causing genetic expansion is present, and not whether an individual's current symptoms are caused by the Huntington's disease gene.

Huntington's disease remains a clinical diagnosis. The motor disorder can be delineated and followed longitudinally using a quantitative examination designed for Huntington's disease, such as the Quantified Neurological Examination, or the Unified Huntington's disease Rating Scale, which also includes a useful scale for functional capacity. The Mini-Mental State Examination is useful in following the cognitive disorder longitudinally, but it lacks sensitivity in certain areas which are affected in Huntington's disease and may be supplemented by a more sophisticated cognitive battery such as the Mattis Dementia Rating Scale.

Principles of Treatment

Caring for patients with Huntington's disease is both challenging and rewarding. At times, the lack of definitive treatments can be frustrating, but careful attention to the changing symptoms and good communication between professionals, family members, and affected individuals all contribute to the successful management of the disease.

Huntington's disease is a progressive disease. The symptoms evolve over time such that treatments which were effective in the early stages may be unnecessary, or problematic later on, and vice versa. For example, medications such as neuroleptics may be started in the early to middle stages to control chorea. However, this category of medications may exacerbate the rigidity and bradykinesia of the later stages, and result in delirium or oversedation as the cognitive disorder progresses. The medication list and the rationale for each medication needs to be reevaluated at regular intervals. Sometimes the most helpful intervention a physician can perform is to discontinue an unnecessary drug.

Symptoms vary over time as a patient passes through different stages of the disease. Symptoms also vary from individual to individual, even within a family. For example, one patient may develop a severe mood disorder, requiring multiple hospitalizations, but have little motor disability. The patient's brother may have debilitating motor symptoms, but no mood disturbance at all. Thus interventions need to be tailored to individual symptoms, and fearful patients should be reassured that their symptoms may not necessarily resemble those of their relatives.

Huntington's disease patients, like others with injuries to the brain, are highly vulnerable to side effects, particularly cognitive side effects, of medications. The physician should begin with low doses and advance medicines slowly. Polypharmacy should be avoided where possible. Many of the drugs used in treating symptoms of Huntington's disease, such as neuroleptics and antidepressants, will not have immediate efficacy and patients need to be told that they may feel worse before they feel better, because they will experience the side effects, before the beneficial effects have appeared.

"Huntington's disease patients...are highly vulnerable to side effects, particularly cognitive side effects, of medications."

Pharmacologic interventions should not be launched in isolation, but in a setting of education, social support, and environmental management. Symptomatic treatment of Huntington's disease needs to be approached like any other medical problem. The clinician should elicit the details of the symptom, its character, onset and duration, and its context including precipitating, exacerbating and ameliorating factors. A differential diagnosis should be generated, non-pharmacologic interventions should be considered, and the clinician should have a way ot determining whether the goals or treatment are being met and should formulate a contingency plan if treatment is not working. Sharing some of this reasoning process with patients and famlies can be reassuring.

Patients with Huntington's disease will often be accompanied by a caregiver on visits to the doctor. This caregiver can be a crucial informant, particularly in the later stages of the disease, when speech and cognitive difficulties may prevent patients from supplying a history. However, both patient and caregiver may not feel comfortable discussing certain important issues in each other's presence, such as irritability, driving, relationship, or sexual problems. Therefore an effort should be made to speak to both individuals alone during the visit.

A few words should be said on the issue of "alternative treatments" for Huntington's disease -unproven remedies such as herbs, megadose vitamins, homeopathic preparations, or magnetic devices, which are to be distinguished from experimental treatments taking place as part of a scientific study. Patients should be encouraged to discuss their ideas about these therapies and not to be afraid to tell their physicians that they are trying them. This will allow the doctor to help the patient think through the pros and cons of such a decision, to avoid notoriously dangerous or ineffective nostrums, and to monitor for side effects. Patients should understand that there is no substance, no matter how "natural," which has pharmacologic activity without side effects, and that all treatments carry an element of risk.

We have found it useful to share certain caveats with patients to minimize the risk for those who have chosen to pursue these alternative therapies: 1) Don't spend too much money 2) Don't do something that common sense suggests is dangerous and 3) Don't neglect or discontinue effective medical treatments in favor of an unproven therapy. By following these principles patients are likely to avoid harm.