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Huntington's disease was first discovered by an American doctor George Huntington in 1872. Dr. Huntington based his description on personal clinical observations and observations of his father and grandfather.
Huntington disease is a rare neurodegenerative disease caused by an autosomal dominant gene defect on chromosome 4 (Gusella et al., 1983). The protein expressed by this gene is called 'huntingtin' and normally contains a polyglutamine repeat sequence (PRS) of between 6 and 36 glutamine residues near its N-terminus (Protein Aggregation, 2003). Huntington disease is a serious neurodegenerative disorder resulting from an expanded CAG repeat in a specific gene on chromosome 4(HD Encyclopedia of HG, 2003). This disorder causes progressive lose of voluntary movement because of degeneration of the brain especially in the basal ganglia. The motor cortex sends information to the basal ganglia but because of the CAG repeats, the protein that is involved with this reaction is unable to function correctly. HD was the first autosomal dominant disorder in which the gene was mapped to a specific chromosome by the new DNA polymorphic markers (HD Encyclopedia of HG, 2003). Huntington is one of the most common Mendelian disorders, a genetic disease showing a Mendelian pattern of inheritance caused by a mutation in DNA. With an effected population density of 3-10 people per every 100,000 people of European origin, Huntington affects less people then other disorders of similar mutation.
Fragile X syndrome
1 in 3500
1 in 100 000
1 in 8000
2-4 in 100 000
SBMA (Kennedy disease)
1 in 40 000 men
3-7 in 100 000
All autosomal dominant cerebellar ataxias, including DRPLAa
1-2 in 100 000a
Movement disorders in HD consist of involuntary movements (chorea and dystonia) and impairment of voluntary movements (eg, gait, speech, swallowing, fine motor tasks). (MHD, 2011). Suffers do not die of the disorder itself; they often die of compilations such as losing the ability to breath or heart compilations.
The severity of the motor problems depends upon age of onset and sex of the transmitting parent. Age of onset is usually from 40- 50 years of age but rarely suffers may be younger but condition is worst. There currently is not a cure for Huntington. Most medication given to HD patients is given to try to control the involuntary movement. Most HD sufferers will have completed their families, and potentially transmitted the mutant gene to another generation of their family, before finding out that they are themselves affected (HD PGT, 2003). HD is transmitted genetically as an autosomal dominant trait meaning that offspring has a 50/50 chance of inheriting the disease, while those that do not inherit the HD gene will not pass it to their offspring.
Biological details of Huntington.
Huntington is a result of an expanded CAG repeat in the Huntingtin gene on chromosome 4. In 1993, the mutation responsible for HD was identified as a (CAG)n triplet repeat mutation in the huntingtin gene on chromosome 4, which is expanded in affected individuals (Huntington's disease Collaborative Research Group, 1993)(HD PGT, 2003). The trinucleotide repeat is known to cause severe neurodegenerative disorders in adults who experience onset. This mutation is responsible for many other neurological disorders, such as fragile X mental retardation and myotonic dystrophy.
MHD reports, "In the human genome, short tandem repeats occur on average every 2000 base pairs (bp) and localize in up to 8% in coding gene regions. The high mutation rate in short tandem repeats makes them most polymorphic and therefore suitable for genetic linkage or association studies because of their high degree of informativeness."
The number of repeats in a normal person is between 6 -32 while in a person with Huntington the repeats are from 38 -128. Childhood onset cases may show 70 or more repeats. These repeats are unstable and sometimes subject to further expansion when transmitted to offspring.
The expansion of unstable trinucleotide repeats is called a dynamic mutation. There are 14 known neurological disorders that are the results of dynamic mutations. The mutation is called dynamic because of instability and how prone the alleles are to expansion as they are passed from one generation to the next.
Polyglutamine expansions in coding sequences, which are inherited in a dominant manner, cause the resulting protein to gain some toxic function (TRE: Disease, 2003). Because of this dynamic mutation the huntingtin gene produces and protein that is toxic to the brain's neuron. http://journals.cambridge.org/fulltext_content/ERM/ERM5_20/S1462399403006549sup003.gif
The HD gene is expressed throughout the brain, and the protein localizes to the cytoplasm of neurons as well as to the dendrites and axons (TRE: Disease, 2003). Abnormal aggregation of mutant huntingtin has been found in postmortem brains from people with HD, especially in the dendrites and dendritic spines (TRE: Disease, 2003).
Huntingtin aggregates are recognized only with antibodies specific for the N-terminus of the protein, suggesting that proteolytic cleavage and release of a toxic expanded polyglutamine protein may be an important step in pathogenesis (TRE: Disease, 2003).
There is not a cure are any know treatments that can reverse the damage of Huntington Disease. Since the main case of Huntington has been known, there have been many clinical treatments that have begun to emerge. These treatments focus main on the symptoms and they try to reduce or stop the degeneration. Because there is no treatment available death usually occurring within 10-20 years of onset. The goals of managing HD are to reduce the impact of the disease on individuals' abilities, primarily improving motor function, in order to obtain a favorable impact on their quality of life. (MHD, 2011).
MHS reports "some medications that are effective on chorea may worsen voluntary movement, compromising gait or swallowing, and may induce depression, sedation, and tardive dyskinesia." (MHD, 2011).
Tetrabenazine (TBZ; Ro 1-9569) has been used since 1958 for the treatment of neuroses and psychoses/schizophrenia in Finland, the Netherlands, Switzerland, and the UK since it was first synthesized in 1956. In May 2008, it was approved by the US Food and Drug Administration for the treatment of chorea in HD. (MHD, 2011).
TBZ exerts its antichoreic effects by reducing the amount of dopamine in the brain in two ways.
The first and more widely recognized way is by preventing dopamine release from vesicles, inhibiting the uptake of monoamines. Special proteins called vesicular monoamine transporters (VMATs) are responsible for neurotransmitter transport into the vesicles. TBZ binds to the VMATs, preventing them from performing this function. As such, neurotransmitters like dopamine are not stored in vesicles and cannot be released into the synapse. (MHD, 2011).
Secondly by blocking dopamine receptors, TBZ reduces dopamine by blocking dopamine receptors, as has been shown in vitro studies.TBZ binds to receptors on the surface of the receiving nerve cell, blocking dopamine from passing on its message. The mechanism of inhibiting dopamine receptors, however, is thought to be less significant at the TBZ dosages used in HD patients, although it may possibly be responsible for acute dystonic reactions, which are rarely reported with TBZ. (MHD, 2011).
A study was done by the University of Bari Aldo Moro to test the effects of TBZ upon HD patients will seeing the effects of long term use.
Among 44 patients, 32 had been assigned to TBZ and 12 to clotiapine treatment. Four patients in the TBZ group and two in the clotiapine group were lost to the 2-year follow-up (two patients were hospitalized, two changed address, and two further patients discontinued TBZ after 2 months' therapy because of the sedation side effect).
The study showed that the effects of TBZ slowed the progression of chorea.
The motor performances worsend in a nonsignificant way in both groups, without significant differences between the two treatments. In particular, in the TBZ group, the progression of chorea seemed slightly reduced compared with the clotiapine group. (MHD, 2011).
Recently, long-term feeding with TBZ (combined with levodopa) alleviated the motor deficits and reduced the striatal neuronal loss in the mouse model of HD. However, MHD reports "retrospective observation does not exclude a lack of effect of both treatments on illness progression, for the absence of a placebo group, and may contribute to confirming the hypothesis suggested by Fasano et al TBZ losses its efficacy after long-term use". (MHD, 2011).
Overall, the longer-term prospect for effective therapy in HD seems more promising now than at any time before (HD Encyclopedia of HG, 2003).
Predictive Genetic TestingFigure 1
Predictive testing allows an at risk person to know how high of a probability they have of inheriting Huntington's. Since Huntington is spread from generation to generation with a 50% chance of offspring receiving the disorder, predictive testing is the only way of knowing if a person has it before symptoms of onset appear.
For linkage analysis testing, blood samples of family members must be taken and compared for the genetic marks of Huntington. But predictive testing has a few important limitations with linkage analysis in 1983.
It's only possible to offer testing for at-risk individuals if DNA samples are available for the relatives with Huntington.
If Samples was available the genetic markers commonly available at the time could also be a problem.
The last major problem was the possibility of recombination of the HD gene and the markers.
Newer test have since became possible. They no longer require DNA samples from family members. But the biggest problem is that the person who is taking the test is could receive unfavorable results. Unfavorable results would raise their cost to obtain life insurance or medical insurance coverage. Also the fact that they know their fate, since Huntington's has no cure the person will know his/her life will end in 10-20 years of onset. That is why people who undergo this testing are required to have counseling before and after the test.