The requirements for the diagnosis of Huntington's disease (HD) include medical history, family history, neurological examination, brain imaging testing (including magnetic resonance imaging or MRI and computerized tomography or CT), laboratory tests, and genetic testing (when necessary).
Genetic testing - direct mutation analysis:
HD is usually inherited as an autosomal dominant trait, meaning that each child of an affected parent has a 50% risk of inheriting the mutated gene for the disease. Those who do not inherit a copy of the disease gene (or have a spontaneous mutation in that gene) do not develop HD and cannot pass the disease trait on to future generations.
Scientists discovered the gene for HD in 1993, called the IT15 gene. This discovery helped in the development of specialized testing that may help to confirm the diagnosis of HD in patients with an affected parent with the disease. During such testing, blood samples are taken from patients and DNA is directly analyzed for HD mutations.
Implications of genetic testing: Although the discovery of the HD gene has facilitated predictive testing, the disease remains without a cure, and no treatment is currently available to slow or alter the disease's progression. Therefore, the availability of such testing continues to be associated with numerous emotional, practical, and ethical concerns. Even confirmed positive results do not currently provide accurate information concerning the approximate age at onset, clinical severity, or rate of disease progression. Individuals at risk for HD who are interested in the possibility of genetic testing are referred to specialized, designated testing centers that have staff with the necessary expertise and appropriate psychosocial counseling experience.
Genetic counseling is the process by which patients or relatives, at risk of an inherited disorder such as HD, are advised of the consequences and nature of the disorder, the probability of developing or transmitting it, and the options open to them in management and family planning in order to prevent or stop passing the gene on. A genetic counselor is a healthcare provider who helps in this process. At risk individuals include those with a parent or sibling who has HD or individuals known to carry an HD gene mutation. Individuals considering genetic testing require sufficient information and appropriate counseling concerning the limitations of genetic testing, their potential level of risk, and the possible implications of results including negative, positive, or inconclusive findings.
Genetic counseling concerning the implications of positive or questionable results should address a number of essential areas, including long-term emotional and lifestyle issues, confidentiality concerns (including the fact that patient confidentiality laws are governed by individual states), and possible effects in the areas of health insurance, life insurance, and employment. Counseling regarding the practical, emotional, and personal impact on spouses as well as relatives who themselves may be at risk including children, parents, or other relatives is important as well as family planning. Individuals who are considering such testing may wish to have a relative or close friend accompany them to their counseling sessions. A decision to receive genetic testing must be carefully considered and made solely by the individual.
Predictive testing in children: It is generally believed that pre-symptomatic testing should not be conducted in at-risk children who are under the age of 18 years. Once individuals are aged 18 or older, they have the choice to receive testing based on a personal, informed decision. An exception may be made for children with symptoms characteristic of HD. In such cases, genetic testing is provided in association with a thorough clinical evaluation.
Prenatal testing: Predictive genetic testing before birth (prenatal testing) is associated with unique concerns. For example, direct mutational analysis that provides a positive result indicates that a parent also carries the mutation. However, in some cases, parents may wish to determine the risk of disease development in the developing fetus, yet may not wish to know their own risk. Proper counseling in these individuals is necessary.
Physical and neurological assessment: Although predictive genetic tests may indicate whether individuals carry the disease gene, these tests are not able to confirm the onset of the disorder. Therefore, the diagnosis of HD is also based on a thorough clinical evaluation including a complete physical and neurological assessment and detection of characteristic symptoms and findings (such as involuntary movements, emotional and behavioral disturbances, and progressive dementia). A careful patient and family history will also be taken. Neurological assessment may include testing to evaluate cognitive (brain thinking and memory) status, reflexes, balance, and movement, including evaluation of certain voluntary eye movements necessary in focusing on moving targets.
Imaging techniques: Specialized brain imaging studies may also provide evidence that supports a diagnosis of HD. For example, in moderately advanced cases, computerized tomography (CT) scanning demonstrates characteristic changes in the brain. CT scanning may also detect characteristic enlargement of cavities of the brain (ventricles). In addition, positron emission tomography (PET) scanning may show decreased glucose and oxygen metabolism within the brain. Although such findings may also be associated with other neurodegenerative disorders, they may be helpful in supporting a suspected diagnosis of HD when associated with characteristic clinical findings and family history. In general, neuroimaging is performed only if a symptomatic individual does not have the HD gene and there is a suspicion of another neurodegenerative disorder.
If a symptomatic individual is gene negative, diagnostic studies may be conducted to eliminate other neurodegenerative disorders that have similar symptoms including Wilson's disease (excessive copper in the body), drug-induced tardive dyskinesia (involuntary movements of the tongue, lips, face, trunk, and extremities), Sydenham's chorea (infectious disease caused by bacteria that involves involuntary movements), systemic lupus erythematosus (SLE, an autoimmune disease), or senile chorea (a symptom complex primarily characterized by the development of chorea after age 60). Such studies may include blood tests, neurophysiologic tests, and neuro-imaging techniques.
signs and symptoms
Although there is no sudden loss of abilities or exhibition of symptoms, there is a progressive decline. Symptoms are classified as physical, cognitive (the process of knowing and thinking), and psychological (mental illnesses). Physical signs are usually the first noticed, but it is unknown how long before the cognitive and psychopathology are affected. Physical symptoms are almost always visible and cognitive symptoms are exhibited differently from person to person.
Psychopathological symptoms vary more than cognitive and physical symptoms, and may include anxiety, depression, a reduced display of emotions called blunting, egocentrism, aggressive behavior, hypersexuality (increased desire for sex), and compulsivity, which can cause addictions such as alcoholism, drug addiction, and gambling.
Many patients are unable to recognize expressions in others and also do not show reactions of disgust to foul odors or tastes. The inability to recognize disgust in others appears in carriers of the Huntington gene before symptoms are manifest.
The rate of disease progression and the age at onset vary from person to person. Symptoms of Huntington's disease (HD) usually become noticeable in the mid 30s to mid 40s. Adult-onset HD is characterized by disabling, uncontrolled movements (chorea).
Some individuals with adult-onset HD may not have chorea. They may appear rigid and move very little, or not at all, a condition called akinesia.
The earlier the onset, the faster the disease seems to progress. In general, the duration of the illness ranges from 10-30 years. The most common causes of death are infection (most often pneumonia), injuries related to a fall, and suicide.
Early signs and symptoms: Early signs of the disease vary greatly with each individual. Normally, the earlier the symptoms appear, the faster the disease progresses. Family members may first notice that the individual experiences mood swings or becomes irritable, apathetic (a lack of interest or concern), depressed, or angry. These symptoms may lessen as the disease progresses or, in some individuals, may continue and include hostile outbursts or deep bouts of depression. HD may affect the individual's judgment, memory, and other cognitive functions.
Some early signs include having trouble driving, learning new things, remembering a fact, answering a question, or making a decision. Some may even display changes in handwriting. As the disease progresses, concentration on intellectual tasks becomes increasingly difficult. In some individuals, the disease may begin with uncontrolled movements in the fingers, feet, face, or trunk. These movements, which are signs of chorea (involuntary movements), often intensify when the individual is anxious. HD can also begin with mild clumsiness or problems with balance.
Late signs and symptoms: Some individuals develop involuntary movements later, after the disease has progressed. They may stumble or appear uncoordinated. Chorea often creates serious problems with walking, increasing the likelihood of falls. The disease can reach the point where speech is slurred and vital functions, such as swallowing, eating, speaking, and especially walking, continue to decline. Some individuals cannot recognize other family members. Many, however, remain aware of their environment and are able to express emotions.
Juvenile HD has an age of onset anywhere between infancy and 20 years of age. The symptoms of juvenile HD are different from those of adult-onset HD in that they generally progress faster and are more likely to exhibit rigidity and bradykinesia (very slow movement) instead of chorea. A common sign of HD in a younger individual is a rapid decline in school performance. Symptoms can also include subtle changes in handwriting and slight problems with movement such as slowness, rigidity, tremor, and rapid muscular twitching called myoclonus. Several of these symptoms are similar to those seen in Parkinson's disease, and they differ from the chorea seen in individuals who develop the disease as adults. These young individuals are said to have akinetic-rigid HD or the Westphal variant of HD. People with juvenile HD may also have seizures and mental disabilities.
risk factors and causes
Huntington's disease (HD) is an inherited condition caused by a single abnormal gene. It is found in every country in the world. Each child of an HD parent has a 50% chance of inheriting the HD gene. Because signs and symptoms typically appear in middle age, some parents may not know they carry the gene until they've already had children and possibly passed on the trait. If a child does not inherit the HD gene, he or she will not develop the disease and cannot pass it to subsequent generations.
A person who inherits the HD gene will eventually develop the disease. Whether one child inherits the gene has no bearing on whether other siblings will or will not inherit the gene. A genetic test, coupled with a complete medical history and neurological and laboratory tests, helps physicians diagnose HD. Testing before symptoms occur is available for individuals who are at risk for carrying the HD gene.
Although the precise cause of cell death in HD is not yet known, scientists are paying close attention to the process of genetically programmed cell death that occurs deep within the brains of individuals with HD. This process involves a complex series of interlinked events leading to cellular suicide. Causes of cellular death in HD patients may include excitotoxicity (overstimulation of cells by natural chemicals found in the brain), defective energy metabolism (a defect in the cell's mitochondria where energy is produced), oxidative stress (normal metabolic activity in the brain that produces toxic compounds called free radicals that cause oxidation and death of cells), and trophic factors (natural chemical substances found in the human body that may protect against cell death).
Clinical studies for HD are focusing on understanding losses of nerve cells and receptors in HD. Neurons (nerve cells) in the striatum (a section deep within the brain) are classified both by their size (large, medium, or small) and appearance (spiny or a-spiny). Each type of neuron contains various combinations of neurotransmitters (brain chemicals). Researchers have found that the destructive process of HD affects different subsets of neurons to varying degrees. The hallmark of HD is selective degeneration of medium-sized spiny neurons in the striatum. Studies also suggest that losses of certain types of neurons and receptors are responsible for different symptoms and stages of HD.
In spiny neurons, two types of changes have been observed, each affecting the nerve cells' dendrites. Dendrites, found on every nerve cell, extend out from the cell body and are responsible for receiving messages from other nerve cells. In the intermediate stages of HD, dendrites grow out of control. New, incomplete branches form and other branches become contorted. In advanced severe stages of HD, degenerative changes cause sections of dendrites to swell, break off, or disappear altogether. Investigators believe that these alterations may be an attempt by the cell to rebuild nerve cell contacts lost early in the disease. As the new dendrites establish connections, however, they may in fact contribute to nerve cell death.
Huntington's disease (HD) is not fatal in itself. People with HD have a shorter life expectancy and die of life-threatening complications related to the disease. Pneumonia (a bacterial infection in the lungs and respiratory system) and heart disease (including heart attack, congestive heart failure or CHF, and atherosclerosis or hardening of the arteries) are the two leading causes of death for people with HD. Additionally, HD patients have higher incidence of choking and respiratory complications, gastrointestinal diseases (such as cancer of the pancreas), and suicide than the non-HD population.
One of the chief symptoms of HD is the inability to produce coordinated movements. In the latter stages of the disease, lack of muscle coordination becomes more pronounced to the point that people have difficulty swallowing. Swallowing is actually a complex series of movements by muscles in the throat to ensure passage of food into the esophagus (gastrointestinal tract) rather than the trachea (respiratory tract). As a result of these movements, the epiglottis, a flap that acts as a valve in the throat, prevents food from entering the airway. People with HD often lack this coordination, and food will accidentally enter the respiratory tract, leading to choking. Moreover, when food particles manage to get into the trachea (the "wind pipe" leading to the lungs), instead of the esophagus (the "food pipe" leading to the stomach), the lungs can become infected and cause what is known as aspiration pneumonia.
Although pneumonia is relatively common among people in the general population, it is only fatal in about five percent of HD cases. Researchers have demonstrated that stress imposed on a person for prolonged periods of time can severely damage the body's ability to fight off diseases. Long-term release of the stress hormone cortisol, released from the adrenal glands, can eventually suppress the immune system and cause other problems including hypertension (high blood pressure), impaired glucose tolerance (lack of blood sugar control), and weight gain. The physical, cognitive (thinking and memory), and psychiatric symptoms of HD add a great deal of stress to everyday life for these patients.
In addition, although studies have shown that suicide is not a leading cause of death for HD patients, suicide rates are higher than among the rest of the population. This is probably due to a combination of factors, including neuropsychiatric changes induced by HD and the added stress of daily life. Neuropsychiatric changes include mood disturbances (such as depression and anxiety), bipolar disorder (manic depressive illness), psychosis, and addiction.