Huntington’s disease, HD, is an incurable, hereditary brain disorder. Nerve cells become damaged, causing various parts of the brain to deteriorate. The disease affects movement, behavior and cognition – the affected individual’s abilities to walk, think, reason, and talk are gradually eroded to such a point that they eventually become entirely reliant on other people for care. HD has a major emotional, mental, social and economic impact on the lives of the patients as well as their friends and family.
It used to be called Huntington’s Chorea, because the involuntary movements made by patients with the disease can appear to be like jerky dancing – “Chorea” comes form the Greek word choreia meaning “dancing”. This disease affects both men and women equally. According to the Department of Health, UK, there are about 6,000 people in the UK with the disease. The Huntington’s Society of America says 1 in every 10,000 Americans have the disease- about 30,000 people. It is estimated that at least 150,000 other Americans have a 50% risk of developing HD.
Prevalence of the disease varies according to ethnic ancestry. People with Asian or African inheritance have a 1 in 1,000,000 risk of becoming affected, while the risk for Caucasian people is 70 to 100 times higher. Huntington’s disease, which afflicted the folksinger Woody Guthrie, is a fatal, inherited neurodegenerative disorder. The faulty gene that causes HD is found on chromosome number 4. Huntington’s disease results from a gene mutation that leads to a defective form of the huntingtin protein (htt).
The mutation is dominant, meaning that a child of an affected parent has a 50 percent chance of inheriting Huntington’s. “Studies have shown that Huntington’s disease occurs in part because the mutated huntingtin protein accumulates within cells and is toxic to them,” said Ana Maria Cuervo, M. D. , Ph. D. “In our investigation of how the accumulating huntingtin protein affects the functioning of cells, we found that it interferes with the cells’ ability to digest and recycle their contents.
” All cells rely on several different mechanisms to break down “old” proteins and other components and recycle them. Collectively known as autophagy (literally, “self-eating”), these processes keep cells clean and uncluttered and provide them with replacement parts that will function better. After studying two mouse models of Huntington’s disease as well as lymphoblasts (white cells) from people with the disease, she and her team found that the mutated huntingtin protein was sabotaging the cell’s garbage-collecting efforts.
Using state of the art technology, Dr Danny Hatters and his colleagues at the University of Melbourne’s Department of Biochemistry and Molecular Biology at the Bio 21 Institute observed how human mutant ‘huntingtin’ proteins form into large clumps, which kills brain cells and leads to progressed Huntington’s disease. While researchers previously thought that small clusters of the mutant protein kept accumulating over time until they overwhelmed and killed the brain cells, Dr Hatters’ team found that these clusters were static, which means they form in a more unpredictable manner than previously thought.
The discovery reveals the clusters place a steady stress on cells over time rather than steadily building up over time to some critical “toxic” level as previously thought. “Why it takes so long for the cells to die in human disease is not known – however it could be that cells eventually cannot compensate anymore from the process where toxicity is built up to form one cluster called oligomers,” he says. “Given the predominant neurological signs and striking neuronal death in HD, most studies on htt function have focused on adult neurons,” explains Dr.
Sandrine Humbert from the Institut Curie in Orsay, France. “However, although htt is not restricted to differentiated neurons and is found at high levels in dividing cells, no studies have investigated a possible role for htt during cell division. ” Cell division, known as mitosis, is the process where a single cell divides into two new but identical daughter cells. One key step of mitosis involves the assembly and orientation of a structure called the “mitotic spindle. ” During mitosis, the proteins dynein and dynactin must interact with the spindle.
Because htt is known to facilitate dynein/dynactin activity, Dr. Humbert’s group investigated whether htt played a functional role during mitosis. “Our findings demonstrate a previously unknown function for htt protein and open new lines of investigation for elucidating the pathogenic mechanisms in HD,” concludes Dr. Humbert. “Our work also identifies htt as a crucial part of spindle orientation and neurogenesis. ” Although symptoms of HD vary from person to person, even within the same family, the progression of the disease can be roughly divided into three stages.
The onset of the signs and symptoms can occur at any age but most commonly do so between the ages of 35 and 55 years. Early Stage HD usually includes subtle changes in coordination, perhaps some involuntary movements, difficulty thinking through problems and often, a depressed or irritable mood. Initial symptoms may initially be either ignored or attributed to something else for some time by most patients and their family and friends. The effects of the disease may make the person less able to work at their customary level and less functional in their regular activities at home.
In the Middle Stage, the movement disorder may become more of a problem. Medication for chorea may be considered to provide relief from involuntary movement. Occupational and physical therapists may be needed to help maintain control of voluntary movements and to deal with changes in thinking and reasoning abilities. Diminished speech and difficulty swallowing may require help from a speech language pathologist. Ordinary activities will become harder to do. In the Late Stage, the person with HD is totally dependent on others for their care. Choking becomes a major concern. Chorea may be severe or it may cease.
At this stage, the person with HD can no longer walk and will be unable to speak. However, he or she is generally still able to comprehend language and retains an awareness of family and friends. When a person with HD dies, it is typically from complications of the disease, such as choking or infection and not from the disease itself; this usually occurs 10 to 20 years after the first onset of the symptoms Mosaic winner Ahmad Aziz discovered that the abnormal protein associated with HD also aggregates in the hypothalamus, the part of the brain that regulates the autonomic nervous system and the endocrine system.
Aziz established that certain nerve cells are lost in a part of the hypothalamus. In this part as well as in other parts of the hypothalamus abnormal protein aggregates were found. These hypothalamic nerve cells play an important role in the maintenance of body weight and a normal sleeping pattern. A change in sleep patterns and weight loss can be more symptoms that can be associated with HD and could be an indication that something is wrong. Steps toward prevention are the key to keeping yourself healthy throughout your life.
Although there are no proven drugs or supplements that will for sure prevent HD in humans, there have been studies done that have shown great success in preventing many neurological diseases. Researchers at the Salk Institute for Biological Studies have found a naturally occurring compound that they believe will slow the onset of motor problems in Huntington’s disease. Fisetin, found in strawberries and other fruits and vegetables, is thought to help prevent HD. Pamela Maher, Ph.
D., a senior staff scientist in the Salk Cellular Neurobiology Laboratory, had found that fisetin exerted its neuroprotective and memory-enhancing effects through the activation of the Ras/ERK signaling pathway. “Because Ras/ERK is known to be less active in HD, we thought fisetin might prove useful in the condition,” Maher says. The Ras/ERK pathway is one of the intracellular signaling cascades affected by mutant huntingtin. Maher and her team began their study by looking at a nerve cell like that could be made to express a mutant form of the huntingtin protein.
Without treatment, about 50 percent of these cells died within a few days. Adding fisetin, however, prevented cell death and appeared to achieve it by activating the Ras/ERK cascade. They then moved on to study the effects of fisetin in fruit flies. The flies that had the mutant huntingtin in neurons in the brain did not live as long as normal and also had defective eye development. When they fed the flies with HD some fisetin, they maintained their life span and had fewer eye defects. Finally, Maher and her team tested the fisetin’s effects in a mouse model of HD.
The mice with HD develop motor defects early on and have a much shorter life span. When Maher and her team fed them fisetin and the onset of the motor defects was delayed, and their life span was extended by about 30 percent. “Fisetin was not able to reverse or stop the progress of the disease,” Maher notes, “but the treated nice retained butter motor function for longer, and they live longer. ” With compounds like fisetin, people are more likely to be tested for the mutation. “Cells are damaged and dying before there are overt symptoms,” Maher says.
“If patients know they have the mutation, then they could potentially start treatment before they start showing symptoms, which might be more effective than waiting for the symptoms to appear, as many do now. ” Stephen Ferguson of Robarts Research Institute at The University of Western Ontario identified a protective pathway in the brain that my explain why HD symptoms take so long to appear. Ferguson describes that metabotropic glutamate receptors (mGluRs), which are responsible for communication between brain cells, play an important role in protective effects.
By interacting with the mutant Htt protein, mGluRs change the way the brain signals in the early stages of HD in an attempt to offset the disease, and save the brain from cell death. As a result, mGluRs could offer a drug target for HD treatment. If people think that they are at risk for having HD, the doctor will examine the patient; ask about family history, personal medical history, and recent emotional and intellectual changes. The doctor may also recommend a psychiatric evaluation. Sometimes doctors order imaging tests to identify any changes in the patient’s brain structure, as well as to rule out other disorders.
This may include either a CT (computer tomography) scan or an MRI (magnetic resonance imaging) scan. If it is known that there is a family history of Huntington’s disease to doctor will recommend genetic testing to confirm the diagnosis. If there is no family history the doctor may recommend genetic testing if other possible diseases or conditions have been ruled out. Many countries have a minimum age for genetic testing for HD – in the USA and the UK it is 18 years. If someone is found to have the faulty gene but does not yet have symptoms, it is impossible to predict when they will appear.
A genetic test can be done on the 11th week of pregnancy. The test will determine whether the embryo has the faulty gene. Genetic counseling is an integral part of the process. The US Food and Drug Administration (FDA) announced on Friday, August 15, 2008 that it has approved Prestwick Pharmaceuticals Inc’s new drug Xenazine (generic name tetrabenazine) for the treatment of chorea in people with Huntington’s disease, heralding the first treatment to receive US approval for any of the disease’s symptoms.
Director of FDA’s Office of Orphan Products Development, Dr Timothy Cote, said in a press statement that for the first time Huntington’s patients will be able to gain some quality of life through treatment. He said, “Xenazine represents hope for patients and families dealing with this difficult disease. ” Xenazine reduces the amount of dopamine around certain synapses, the junctions through which brain cells communicate with each other using dopamine as a chemical messenger.
People with Huntington’s have too much dopamine around certain types of brain cells, which leads to chorea, the jerkiness of movement. Serious adverse reactions reported from trial use included depression and suicidal thoughts and behavior, so the FDA advises that doctors should not use Xenazine with patients who have untreated depression or who are actively suicidal. Other common side effects reported by patients in the trial include insomnia, depression, drowsiness, restlessness and nausea.
Also, although the trials showed the drug lessens chorea in the short term, it also caused worsening of mood, cognition, rigidity and functional capacity, so the FDA advises doctors and families of patients on the drug to pay attention to all the aspects of the disease. Dr Nancy Wexler, Higgins Professor of Neuropsychology in the departments of neurology and psychiatry at Columbia University and president of the Hereditary Disease Foundation, said, “We are ecstatic that, through the approval of Xenazine, patients and families will have the option to take the only drug developed specifically for treating the movements of Huntington’s disease.
Chorea is a major cause of disability and death in patients with Huntington’s disease. ” Wexler added that, “chorea is not just a mere inconvenience, it can prevent Huntington’s disease patients from walking, talking, working, watching television and almost every aspect of one’s life. ” Wexler called the approval of Xenazine a breakthrough for the Huntington’s disease community, and that everyone was still hopeful that one day there will be a cure. One of the first labs to use the newly approved drug was Cambridge Laboratories Group Limited (“Cambridge”).
Cambridge is a fast growing, dynamic and entrepreneurial pharmaceutical company with extensive product development and commercialization expertise focused on innovative products in diseases of the central nervous system.
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Cambridge has worldwide rights to tetrabenazine and markets the product through its own direct salesforce in the UK and Eire, and through marketing partners in Europe and other global markets. The product is available in most European markets, South Africa and New Zealand under the name XENAZINE(R), as TETRABENAZINE(R) in Australia, and as NITOMAN(R) in Canada and other key European territories including Germany.