| |
Dementia in Huntington's disease
|
| |
F022
|
| |
|
|
or '''Huntington's chorea''' (HD) is a
Rare inherited disorder characterized by abnormal body movements called
Chorea , and a reduction of various mental abilities. It takes its name from the Ohio physician
George Huntington who described it precisely in
1872 .
Symptoms of the disorder include loss of cognitive ability (thinking, speaking), changes in personality, jerking movements of the face and body in general and unsteady walking. These symptoms develop into
Dementia and an advanced form of rapid jerking called
Chorea , the Greek word for dance.
The symptoms of Huntington’s disease occur gradually over time - there is no sudden loss of abilities and it is hard to determine when symptoms initially occur. One-half to three-fourths of the patients present abnormal movement or rigidity. The remainder of the patients present mental status changes, such as irritability, moodiness, or antisocial behavior. Most of the patients eventually exhibit chorea, which is jerky, random, uncontrollable, rapid movements. Typically, the abnormal movements begin at the extremities and then later progress.
To determine if a patient has the initial symptoms, a physical and/or psychological examination is required. The uncontrollable movements are often the symptoms which cause most alarm to patients and families and lead to diagnosis; however, the disease may begin with cognitive or emotional symptoms, which are not always recognized.
Every child of a person with Huntington's Disease is "at-risk", which means they have a fifty percent chance of inheriting the gene and the disease. testing is possible by means of a
Blood Test which counts the number of repetitions in the gene. A negative blood test means that the individual does not carry the gene, will never develop symptoms, and cannot pass it on to children. If the test is positive, then the individual will develop the disease at some point in the future, assuming he or she lives long enough to do so. A pre-symptomatic positive blood test is not considered a diagnosis, since it may be decades before onset.
Because of the ramifications on the life of an at-risk individual, with no cure for the disease and no proven way of slowing it, several counseling sessions are usually required before the blood test. Unless a child shows significant symptoms of the juvenile form, children under eighteen cannot be tested. The Huntington's Disease Society of America strongly encourages these restrictions in their testing protocol. A pre-symptomatic test is a life-changing event and a very personal decision. For those living in America, there is a list of testing centers available on the HDSA homepage: http://www.hdsa.org/site/PageServer?pagename=testing_centers
In-vitro and embryonic genetic screening are also possible, enabling gene-positive or at-risk individuals the option of making sure their children will be clear of the disease. Expense and the ethical considerations of abortion are potential drawbacks to these procedures.
The full pathological diagnosis is established by neurological examination findings and/or demonstration of cell loss, especially in the caudate nucleus, supported by a cranial
CT or
MRI scan findings.
Degeneration of the
Caudate and the
Putamen (striatum) can be found. There is also neuronal loss and astrogliosis, as well as loss of medium spiny neurons, a GABAergic result. Intranuclear inclusions that stain for ubiquitin and huntingtin can be seen, as well as huntingtin in cortical
Neurite s. Genetically, huntingtin is found on chromosome 4, as are CAG repeats. It is suspected that the cross-linking of huntingtin results in aggregates which are toxic, and can lead to dysfunction of the proteosome system. This mitochondrial dysfunction can lead to
Excitotoxicity and
Oxidative Stress .
Linkage between CAG repeats (huntingtin) and mitochondrial failure, however, is far from clear. There is some evidence that aggregates may trap critical enzymes that are involved in energy metabolism.
The causative
Gene for Huntington's disease, ''
HD '' is located on
Chromosome 4 . Huntington's disease is inherited in an autosomal
Dominant fashion. That is, a recipient of the gene only needs one allele, from one parent, to inherit the disease. More often, genetic diseases are autosomal recessive, meaning that they need two alleles, one from each parent, to inherit the disease. The dominant nature of Huntington's disease increases the chance of the disease occurring in offspring. A parent who has the disorder has a 50% chance of passing on the gene to each child.
When the gene has more than 35 repeats, the replication process becomes unstable and the number of repeats can change in successive generations.
If the gene is inherited from the mother the count is usually similar, but tends to increase if inherited from the father.
{Link without Title}
This is known as
Anticipation . Because age of onset and severity is correlated to repeat number, these also show aniticipation.
The product of this gene is a 348
KDa Cytoplasmic Protein called
Huntingtin . The continuous aggregation of huntingtin
Molecule s in
Neuron al cells gives rise to
Cell Death , especially in the
Frontal Lobe s and the
Basal Ganglia (mainly in the
Caudate Nucleus ) by some unknown mechanism. Some think that the form of
Apoptosis is the splitting of the
Lysosome so that the hydrolytic enzymes within are released. This will cause the cell membrane to be split and the cell to die. Huntingtin has a characteristic sequence of fewer than 40
Glutamine Amino Acid residues (encoded by CAG
Trinucleotide Repeats ) in the normal form; the mutated huntingtin causing the disease has more than 40 residues. The severity of the disease is proportional to the number of extra residues.
While theories as to how the mutation brings about disease remain diverse and speculative, researchers have identified many specific subcellular abnormalities associated with the mutant protein, as well as unusual properties of the protein in vitro. Just as one example, in 2002,
Max Perutz , ''et al'' discovered that the glutamine residues form a
Nanotube 1 in vitro, and the mutated forms are long enough in principle to pierce
Cell Membrane s.
There is no treatment to fully stop the progression of the disease. There are already treatments available to help reduce some disease symptoms, though some treatments aggravate other symptoms like
Bradykinesia and dystonia (very slow movement and stiffness). Beyond treatments that are available to control abnormal movements, other agents may help with emotional symptoms like
Antidepressant s, sedatives, and tranquilizers.
Nutrition is an important part of treatment, most HD sufferers need an unusually high number of
Calories (3000-6000 calories a day) to maintain body weight,so a
Nutritionist 's advice is needed.
Speech Therapist s can help by improving speech and swallowing methods, this advice should be sought early as the ability to learn new things is reduced as the disease progresses.
To aid swallowing thickener can be added to drinks. When swallowing becomes hazardous the option of using a
Stomach PEG for intake of nutrients is often chosen, this reduces the chances of pnuemonia due to aspiration of food.
The most hopeful prospective treatment currently studied is based on
Gene Silencing . Since HD is caused by expression of a single gene, silencing of the gene could theoretically halt the progression of the disease. One study with a mouse model of HD treated with
SiRNA therapy achieved 60%
Knockdown in expression of the defective gene. Progression of the disease halted.[http://www.sirna.com/wt/page/neurology] More recent research shows full recovery of motor function due to siRNA therapy in late stage HD-model mice.[http://www.jneurosci.org/cgi/content/abstract/25/42/9773]
It has been shown that a
Calorie Restrictive (CR) diet delays the onset of symptoms in HD mice
{Link without Title} .
Candidate treatments to slow the progression of the disease are under study, yet have been slow to reach HD sufferers.
EPA , an Omega-III fatty acid, has been shown to slow and possibly reverse the progression of the disease. It is currently in FDA clinical trial, as Miraxiom© (LAX-101), for prescription use. Clinical trials utilize 2 grams per day of EPA. In the United States, it is available over the counter in lower concentrations in Omega-III and fish oil supplements.
According to initial research, other agents and measures might also slow the progress of Huntingon's. They include
Dopamine receptor blockers,
Creatine ,
CoQ10 , the antibiotic
Minocycline ,
Trehalose , exercise, antioxidant-containing foods and nutrients, antidepressants (notably, but not exclusively, selective serotonin reuptake inhibitors
SSRI s, such as sertraline, fluoxetine, and paroxetine) and select
Dopamine antagonists, such as
Tetrabenazine . Research is underway on all these and other approaches that have shown some promise in various experimental models. This research is reviewed on various websites for Huntington's patients and their families, including the Huntington's Disease Lighthouse, Hereditary Disease Foundation, and Stanford HOPES websites. Primary research can be found by searching the National Library of Medicine's PubMed.
In 2004 it was found that a simple
Sugar called
Trehalose can alleviate symptoms in genetically modified mice.
Pig cell implants in Huntington's Disease trial: Living Cell Technologies in New Zealand has attempted trials with positive results in primates
World health Article , but is yet to conduct a human trial.
There is a vast amount of research and clinical trials of various treatment. For example the US registar of trials has 79 ongoing trials and about 300 past trials (see
HD clinical trials ).
Onset of Huntington's disease seems to be correlated to the number of CAG repeats a person has in the their HD gene. Generally, the higher the number of repeats the sooner onset is.
{Link without Title}
The number of repeats may change slightly with each successive generation, so that the age of onset may vary as well.
Symptoms of Huntington’s disease usually become noticeable in patients in their mid 30s to their mid 40s.
About 10 percent of Huntington's disease cases occur in people under the age of 20 years and is called juvenile Huntington’s disease. It has an age of onset anywhere between infancy and 20 years of age. The symptoms of juvenile HD are very different from those of adult-onset HD and is generally more rapidly progressive. Individuals with juvenile HD often become stiff or rigid in their movements (instead of having chorea). Any case of HD with an onset before the age of 20 is considered to be the juvenile form.
Mortality is due to complications resulting from Huntington's Disease rather than the disease itself and is usually 10 to 25 years after the onset of obvious symptoms.
The incidence is 5 to 8 per 100,000.
Huntington's disease presents individuals and families with several dilemmas:
- Testing for the presence of the disease
- Whether to have children
- Informing children with an HD positive parent that they are at risk
- Coping with the discovery of the disease in a family member.
- Testing of grandchildren of a sufferer has serious ethical implications if their parent declines testing, a positive result in a grandchild's test automatically diagnoses the parent.
- Coping with the social and personal impacts of significant impairment of memory.
Genetic Counseling may provide perspective for those at risk of the disease. Some choose not to undergo HD testing due to numerous concerns (for example, insurability).
For those at risk, or known to have the disease, consideration is necessary prior to having children due to the genetically dominant nature of the disease. In vitro and embryonic genetic screening now make it possible (with 99% certainty) to have an HD-free child; however, the cost of this process can easily reach tens of thousands of dollars.
Parents and grandparents recently discovered to possess the disease are left with the question of when and how to tell their children and grandchildren. It is not unusual for entire segments of a family to become alienated as a result of such information or the withholding of it.
There is evidence that doctors as far back as the
Middle Ages knew of this disease. It was known, amongst other conditions with abnormal movements, as St Vitus dance.
St Vitus is the Christian patron saint of epileptics who was martyred in
303 .
One of the early medical descriptions of Huntington's disease was made in
1860 by a Norwegian district physician,
Johan Christian Lund . He noted that in
Setesdalen , a remote and rather secluded area, there was a high prevalence of dementia associated with a pattern of jerking movement disorders that tended to run in families. This is the reason for the disease being commonly referred to as ''Setesdalsrykkja'' (Setesdalen=the location, rykkja=jerking movements) in
Norwegian .
George Huntington was one of three generations of medical practitioners in
Long Island . With their combined experience of several generations of a family with the same symptoms, he realised their conditions where linked and set about describing it. His
Definiton of the disease in
1872 is still largely accurate.
In
2003 the first World Congress on Huntington's Disease was held in Toronto. This is a biennial meeting for associations and researchers to share ideas and research, which is held on odd-number years.
- 1979 The U.S-Venezuela Huntington's Disease Collaborative Research Project began an extensive study which gave the basis for the gene to be discovered. This was conducted in the small and isolated Venezuelan fishing village of Barranquitas. Families there have a high presence of the disease, which has proved invaluable in the research of the disease.
- 1983 The general location of the gene is found using DNA marking methods for the first time - an important first step toward the Human Genome Project .
- 1993 The Huntington's Disease Collaborative Research Group isolates the actual gene.
- 1996 A Transgenic mouse was created that could be made to exhibit HD greatly advancing how much experimentation can be achieved.
The full record of research is extensive. {Link without Title} {Link without Title}
