Huntingtons Disease Fatal Syndrome Neither Remission Nor Cure Biology Essay

Huntington ‘s disease is a fatal syndrome with neither remittal nor remedy named after Doctor George Huntington in 1872. At first, it was believed that the disease sick persons were haunted by liquors or victimized as enchantresss, and were rejected by the community. In 1872, Dr. George Huntington described the disease in item and expressed household linkage. Over 100 old ages subsequently, in 1993, the US-Venezuela Huntington ‘s Disease Collaborative Research Project found out the causal cistron which is responsible for abnormally big CAG repetition ( Huntington ‘s Disease Collaborative Research Group, 1993 ) .

Huntington ‘s disease is a progressive neurodegenerative familial upset, inherited in an autosomal dominant form. So, one transcript of the altered cistron with an expanded tri-nucleotide repetitions ( mutant allelomorph ) is required to develop the disease ( Walker, 2007 ) . All human existences have the Huntington cistron ( Htt cistron ) , which codes for the Huntingtin protein. The Huntington cistron is present on the short arm of chromosome 4, at exon 1 of the interesting transcript 15 ( IT15 ) cistron on chromosome 4p 16.3 ( Rubinsztein et al. , 1997 ) . The Huntington cistron contains a three Deoxyribonucleic acid ( DNA ) bases sequence: cytosine-adenine-guanine ( CAG ) repeats, known as a tri-nucleotide repetition, which varies in length between each person and between each coevals ( Walker, 2007 ) . In a normal individual, this tri-nucleotide repetition consists of less than 35 CAG units ( Huntington ‘s Disease Collaborative Research Group, 1993 ) . When the length of this repetition enlargement reaches a certain threshold, beyond 35 threes ( Huntington ‘s Disease Collaborative Research Group, 1993 ) , it produces an unnatural protein, known as a mutant Huntingtin protein ( mHtt ) , a cytoplasmatic protein, whose presence causes slow but steady harm to specific countries of the encephalon ( Walker, 2007 ) . The CAG trinucleotide repetitions are translated into more than 35 glutamines in the mutant Huntingtin protein of the Huntington ‘s disease patients ( Warby et al. , 2010 ) .

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Different types of Huntington ‘s disease

There are 3 different types of Huntington ‘s disease depending on the age of oncoming: juvenile signifier, typical signifier and late signifier ( Wexler et al. , 2004 ) . These three different types are besides different in the Numberss of CAG repetitions they possess ( Wexler et al. , 2004 ) .

Table 1: Relationship between different types of Huntington ‘s disease depending on the age of oncoming and figure of CAG repetitions ( Adapted from Wexler et al. , 2004 )

Types of Huntington ‘s disease

Age of oncoming

Average Numberss of CAG repetitions

Juvenile

From 2 old ages to 20 old ages

60.15

Typical

From 21 old ages to 50 old ages

45.72

Late

Older than 50 old ages

41.85

Familial heritage form of Huntington ‘s disease

Huntington ‘s disease is due to the expanded CAG tri-nucleotide repetition determined in the Deoxyribonucleic acid since construct. Since Huntington ‘s disease is the autosomal dominant familial disease, if one parent carries the mutant cistron, 50 per centum of the progeny will be affected ( Lipe and Bird, 2009 ) . The familial heritage form of the Huntington ‘s disease is described in figure 1.

Figure 1: Familial heritage form of the Huntington ‘s disease

If one parent possesses the mutant Huntington cistron, half of his or her progeny will be affected regardless of the sex of the progeny.

However, the per centum of heritage varies from survey to analyze proposing that familial is non the lone constituent in the Huntington ‘s disease development.

One survey conducted in Southern India found that the juvenile signifier of Huntington ‘s patients was inherited from their male parents ( Murgod et al. , 2001 ) . Among them, the male parents of two patients showed clinical characteristics of Huntington ‘s disease whereas the other two were symptomless but they had expanded CAG repetitions with the average CAG repetitions of 48.4 ( Murgod et al. , 2001 ) . Furthermore, merely 88.5 per centum of the 26 Huntington ‘s disease patients were found to hold household history in the above survey. Furthermore, household history was non found in 8 per centum of 171 DNA confirmed Huntington ‘s disease patients in New South Wales ( McCusker et al. , 2000 ) . Lipe and Bird ‘s survey in 2009 besides mentioned that among 34 instances of the Huntington ‘s disease patients, 68 per centum had no recognized household history of this disease. Since these surveies were conducted on a little graduated table affecting few Numberss of patients, great cautiousness should be exercised in reading and generalisation of these findings. Kartsaki and colleagues, 2006, pointed out that the deficiency of obvious household history of Huntington ‘s disease was due to little CAG repetition size in their household members ( Kartsaki et al. , 2006 ) because CAG repetitions size of 35-39 shows reduced penetrance and may be symptomless for the whole life-span ( Langbehn et al. , 2004 ) . So, the absent of household history in Huntington ‘s disease patients may be due to the little sample size and/or due to the reduced penetrance.

The entire figure of CAG repetitions was related to the age of oncoming of Huntington ‘s disease in instance of motherly inherited form ( Snell et al. , 1993 ) . Large CAG repetition enlargement form was improbable to be occurred in motherly inherited patients while it was found to be frailty versa in paternally inherited 1s ( Rubinsztein et al. , 1997 ) . However, Murgod and colleagues found no obvious difference in the age of oncoming between those who inherited the disease from the male parent when compared to those who inherited it from the female parent ; the average age of disease oncoming was found to be 36.9 old ages in both instances ( Murgod et al. , 2001 ) .

Interestingly, sex of the patients besides affects the type of familial heritage and age of oncoming of the disease. In Venezuelan sibling braces, the prevalence of Huntington ‘s disease between the sisters is found to be 0.49 % and is higher than the prevalence of this disease between sister and brother ( 0.40 % ) and between the brothers ( 0.18 % ) ( Wexler et al. , 2004 ) . In the survey conducted by Roos and colleagues among 822 instances showed that the age of oncoming in female patients ( average age of oncoming = 39.9 old ages ) were higher than that of male patients ( average age of oncoming = 37.5 old ages ) ( Roos et al. , 1991 ) . Furthermore, the Roos survey mentioned that the average age of oncoming in both male and female is lowest in the grandmother-father line of descent compared to the other grandmother-mother line of descent, grandfather-mother line of descent and grandfather-father line of descent ( Roos et al. , 1991 ) . These above findings suggest that females have less terrible phenotype and generate less offspring with the disease.

Homozygous Huntington ‘s disease patients inherit two expanded tri-nucleotide repetitions transcripts, one from each parent. However, the age of oncoming of the Huntington ‘s disease is non altered ( Myers et al. , 1989 ) . So, the age of oncoming of the Huntington ‘s disease is independent of heritage of one transcript or two transcripts of an expanded CAG repetitions, but dependant on the length of the tri-nucleotide repetitions.

In 1994, Andrew and his co-workers reported Huntington ‘s disease instances with no CAG repeats enlargement indicating that Huntington ‘s disease has phenocopies ( Andrew et al. , 1994 ) . In their survey, 1.17 per centum of 1, 022 Huntington ‘s disease patients have no CAG repeats enlargement. Pedigree analysis of the Huntington ‘s disease patients with phenocopies showed that chromosome 20p12 part encoding the prion proteins were responsible for the phenocopy effects ( Xiang et al. , 1998 ) . In 1999, doppel or prion protein 2 ( dublet ) ( Prnd ) cistrons which are prion protein like cistrons were discovered as the new members for Huntington ‘s phenocopy cistrons ( Moore et al. , 1999 ) . Huntington ‘s disease phenocopy patients showed untypical presentation such as epileptic ictuss ( Andrew et al. , 1994 ) .

CAG repetitions and ethnicity in Huntington ‘s disease

There is cultural difference in the prevalence of the Huntington ‘s disease. The prevalence among people of Europe and North America ranges from 2.5 to 10 per 100,000 people ( Walker, 2007 ; Murgod et al. , 2001 ) ; Indian immigrants to Britain have prevalence of 1.75 per 100,000 people ( Murgod et al. , 2001 ) .

The CAG repetitions enlargements in Htt cistron correlative to a specific predisposing haplo-group in Western Europeans ( Warby et al. , 2009 ) . European Huntington ‘s disease patients possess a specific set of 20 two tagged individual base polymorphisms which make up a individual haplo-group ( Warby et al. , 2009 ) . This haplo-group is besides seen in chromosome of general population bespeaking that there may be the predisposing cis-elements mutant in Htt cistron in the Europeans doing the CAG repetitions instability ( Warby et al. , 2009 ) . However, this predisposing haplo-group for CAG enlargement is non seen in the Chinese and Nipponese people, intending that the difference in the predisposing background distribution among populations explain the different prevalence of Huntington ‘s disease in different populations ( Warby et al. , 2009 ) .

Following to the 3? terminal of CAG repetitions in Htt cistron is a CCG repeats site ( Pecheux et. , 1995 ) . In the Caucasic population, expanded CAG repetitions are extremely associated with ( CCG ) 7 ( Squitieri et al. , 1994 ) , whereas in the Nipponese population and Chinese population, expanded CAG repetitions are associated with ( CCG ) 10 ( Masuda et al. , 1995 ; ( Ma et al. , 2010 ) proposing that the different CCG allelomorphs that are present in the different ethnicity produce different prevalence of Huntington ‘s disease in different populations. ( CCG ) 10 is found to be accountable for the low prevalence of Huntington ‘s disease in Nipponese public and Chinese public as comparison to the Western Europeans. The specific individual nucleotide polymorphism allelomorphs are strongly associated with the CAG repetitions enlargements. We need to happen out the individual polynucleotide polymorphisms that reveal to cis-elements responsible for the instability of the CAG repetitions in Htt cistron ( Warby et al. , 2009 ) . By cognizing this, we can develop the new therapy for the Huntington ‘s disease patients utilizing individualized allele-specific marks medicine.

Reasons for the enlargement of CAG repetition in the Htt cistron

There are different proposals for the implicit in grounds of the enlargement of CAG repetitions in the Htt cistron. Flap endonuclease 1 ( FEN1 ) , is a structure-specific endonuclease that is involved in the rectification of DNA-damage. In mammals, the loss of FEN1gene look is embryonically deadly ( Yang and Freudenreich, 2007 ) . Normally, FEN1 protein cleaves a dual flap substrate possessing the 5? flap with a one 3? overhangs in vitro ( Rossi et al. , 2006 ) . In this instance, flap equilibration is achieved by right mechanisms of FEN1 protein, followed by ligation with DNA ligase and no CAG repetition enlargement ( Liu et al. , 2004 ) . FEN1 cistron takes portion in bar of CAG tri-nucleotide repetition sequences instability because an addition in happening of CAG repetitions enlargement is found in FEN1 cistron mutations in barm cells with faulty barm homolog of FEN1, RAD27 ( Yang and Freudenreich, 2007 ) . Furthermore, the FEN1 protein concentration is straight relative to the length of CAG repetitions, i.e. , if the cells have longer CAG repetitions, more FEN1 proteins are required in order to keep the stableness ( Yang and Freudenreich, 2007 ) . If concentration of FEN1 protein is limited, the unrefined flap substrate could equilibrate into different types of intermediate constructions and some of the intermediate constructions will be ligated by DNA ligase ensuing in enlargement of the sequence ( Yang and Freudenreich, 2007 ) . This determination is supported by Henricksen and colleagues, 2002. Their survey showed that FEN1 and DNA ligase competed at the flap, and when the sum of ligase is increased, there will be the ligation of unrefined flaps doing sequence enlargements ( Henricksen et al. , 2002 ) . Spiro and McMurray, 2003 studied the relationship between CAG repeats enlargement and FEN1 cistron in FEN1 +/- mice with expanded CAG-120 repetitions within the human Huntington ‘s disease cistron ( Spiro and McMurray, 2003 ) . They found that there was addition in CAG repetitions enlargement in the offspring of the FEN1+/- male mice. Therefore, FEN1 cistron plays the function in bar of CAG repetition enlargement during the flap processing. The mechanism of FEN1 in CAG repetitions enlargement is demonstrated in the figure 2.

Figure 2: Function of FEN1 in CAG repetitions enlargement

Another factor lending to the formation of the CAG trinucleotide repetition is defect in dual strand interruption fix system. Meiotic recombination-11 ( Mre11 ) cistron of Saccharomyces cerevisiae is involved in the dual strand interruption fix tract and in Mre11-deficient strains ; there is an accretion of CAG trinucleotide repetitions enlargements ( Sundararajan et al. , 2010 ) . Furthermore, CAG repeats enlargement is seen in the absence of little ubiqutin-related modifier-1 ( SUMO1 ) triping enzyme subunit-2 ( sae2 ) cistrons which is besides involved in dual strand interruption fix tract and in the absence of Rad52 cistron which is involved non merely in dual strand interruption fix but besides in homologous recombination ( Sundararajan et al. , 2010 ) . Both dual strand interruption fix and homologous recombination are of import mechanisms for forestalling the trinucleotide repeats enlargement.

Another possible mechanism for CAG repetition enlargements is due to the mis-match fix ( MMR ) system. A map for MMR system in CAG enlargement is ill understood. During DNA reproduction, the tri-nucleotide repetitions can misalign doing an extra-helical Deoxyribonucleic acid cringle. Deoxyribonucleic acid cringles are repaired by mutS homolog2/mutS homolog3 ( MSH2/MSH3 ) by interpolation taking to the tri-nucleotide enlargement in vivo ( Kovtun et al. , 2004 ) . In barm and bacterial surveies, omissions of tri-nucleotide repetitions piece of lands are more likely to happen than interpolations during cell proliferation by 10-1000 times in wild type cells compared to the MMR system faulty cells ( Schweitzer and Livingston, 1999 ) . Furthermore, Manley and colleagues found that when there was no MSH2, the CAG repetitions enlargement were non developed in source cell lines every bit good as in bodily cells during the development in animate beings ( Manley et al, 1999 ) .

MSH2/MSH3 protein is besides involved in bodily age-dependent enlargement in Huntington ‘s disease ( Cleary et al. , 2002 ) . However, in the proliferating fibroblasts of the Huntington ‘s disease patients, CAG piece of lands are besides deleted with an integral MMR system ( Spiegel et al, 1996 ) . These findings oppose a mechanism in which MMR system is responsible for CAG repetitions enlargement during post-replicative fix proposing that non merely the MMR system but besides the other fix systems like dual strand interruption fix system and homologous recombination are involved in the development of the CAG repetitions enlargements. Role of MMR system in polyglutamine repetitions is described in figure 3.

Figure 3: Function of MSH2/MSH3 in CAG repetitions enlargement

However, it is hard to reason the extent of these MMR system involved in CAG repetitions enlargement. It is non possible to prove the function of fix mechanisms in doing CAG repetitions enlargements because the MMR mechanism is of import in forestalling the development of the unnatural new DNA strand during the DNA reproduction. Different cell types might be affected by different mechanisms to develop the polyglutamine repetition.

A Deoxyribonucleic acid glycosylase, 7, 8-dihydro-8-oxo-guanine-DNA glycosylase-1 ( OGG1 ) , is one of the conducive factors for Huntington ‘s disease. In Huntington ‘s disease mice, age-dependent enlargement of CAG repetitions takes topographic point aboard with the oxidative DNA harm accretion ( Kovtun et al. , 2007 ) . Importantly, absence of OGG1 protein, a Deoxyribonucleic acid glycosylase, suppresses enlargement in Huntington ‘s disease mice ( Kovtun et al. , 2007 ) . OGG1 void animate beings inhibit the CAG repetitions enlargements in the presence of MSH2 proteins every bit good as MSH2 nothing animate beings inhibit CAG repetitions enlargement in the presence of OGG1 proteins ( Kovtun and McMurray, 2001 ) . So, these two proteins are responsible in the development of CAG repetitions enlargements.

Functions of Normal Huntingtin protein

Huntington protein is 348 kDa ( kilodalton ) , soluble ( Cattaneo et al. , 2001 ) protein and has a polyglutamine of non more than 35 residues of glutamine. Huntingtin protein contains HEAT-like repetitions ( Huntingtin, Elongation factor 3, protein phosphatsase 2A, TOR1 ) from its amino-terminus to the carboxyl-terminus. Having the HEAT-repeats construction, Huntingtin protein may possess a solenoid-like construction moving as a scaffold for interactions of multiple proteins ( Takano and Gusella, 2002 ) . Huntington ‘s protein is cytosolic and is present non merely in the encephalon but besides in other variety meats like lungs, bosom, liver, kidneys, lymphoblasts, etc ( Sharp et al. , 1995 ) . Using the poly and single-channel clonal antibodies, Huntingtin proteins are detected in all over the encephalon and nerve cells ( Sharp et al. , 1995 ) . In the nervous system, Huntingtin protein augments the neurotrophic factors production thereby lending to the neuro-protective map ( Cattaneo et al. , 2001 ) .

From the animate being survey utilizing mice, it was found that the polyglutamine section is non indispensable because, even though it is removed from Huntingtin protein, mice are lasting with minor symptoms ( Clabough and Zeitlin, 2006 ) . However, when the whole normal Huntingtin protein is removed, it is embryonically deadly in mice and grownup cell devolution is observed in the conditional smasher of the Htt cistron in mice ( Duyao et al. , 1995 ; Nasir et al. , 1995 ) . So, Huntingtin protein is indispensable for life but the polyglutamine section is non indispensable for life.

Furthermore, Huntingtin protein has an anti-apoptotic action. Position 548 of the N-terminal of the normal Huntingtin protein is responsible for anti-apoptosis ( Rigamonti et al. , 2000 ) . Huntingtin protein inhibits the pro-caspase 9 ( Rigamonti et al. , 2000 ) and it besides prevents the formation of the pro-apoptotic composite, Huntington Interacting Protein-1 Protein Interactor-Huntington Interacting Protein-1 ( HIPPI-HIP-1 ) composite ( Gervais et al. , 2002 ) .

Impact of mutant Huntington protein

How mutant Htt protein incorporating more than 35 glutamine residues, stimulates a cascade of cellular changes, ensuing in cell disfunction and impairment, have non yet been to the full understood ( van Duijn et al. , 2007 ) . And once more, the exact mechanisms of mutant Htt proteins accretion are still unknown ( Casarejos et al. , 2011 ) . The cellular toxicity sites for the mutant Huntingtin protein are non merely in the karyon ( Saudou et al. , 1998 ) but besides in the cytol ( Panov et al. , 2003 ) . Mutant Huntingtin proteins affect many proteins present in the karyon and cytol of the cells that are involved in the cistron written text ( Cha, 2000 ) , programmed cell decease ( Hickey and Chesselet, 2003 ) , mitochondrial map ( Panov et al. , 2003 ) , suppression of tumour ( Bae et al. , 2005 ) , release of neurotransmitter and axonal conveyance ( Freeman and Mortan, 2004 ; Charrin et al. , 2005 ) . Transcriptional disfunction of polyglutamine enlargements might take a function in the development of neurotoxicity in Huntington ‘s disease because in transgenic Huntington ‘s disease theoretical account mouse, better endurance was seen after handling with histone deacetylase inhibitor, Na butyrate, that modulated written text significantly ( Ferrante et al. , 2003 ) . In the karyon, there are unnatural interactions between the unnatural polyglutamine protein and p53 tumour suppresser protein, cyclic adenosine monophosphate ( camp ) response component binding ( CREB ) protein ( co-activator ) , stable protein-1 written text factor and TATA-associated factor-130 ( Mc Campbell et al. , 2000 ; Nucifora et al. , 2001 ; Dunah et al. , 2002 ) . Both normal and mutant signifier of Huntingtin protein act on stable protein-1 written text factor and TATA-associated factor-130 but mutant Huntingtin protein has the stronger interaction than normal one ( Dunah et al. , 2002 ) . Mutant Huntington proteins do toxicity to the cells every bit good as damage to the map of the wild type Huntington proteins.

Neural intranuclear inclusions of expanded polyglutamine protein are one of the factors that contribute to the clinical manifestation of Huntington ‘s disease. Neural intranuclear inclusions of expanded polyglutamine protein are the most distinguishable pathological feature of polyglutamine diseases ( DiFiglia et al. , 1997 ) . Neural intranuclear inclusions are correlated with toxic degree of protein and disease badness ( Arrasate et al. , 2004 ) . Neural intranuclear inclusions of mutant Huntingtin protein and progressive intellectual impairment get downing from caudate karyons and putamen are involved in Huntington ‘s disease pathophysiology ( Arrasate et al. , 2004 ) .

In Huntington ‘s disease, there is an damage of the ubiquitin-proteasome system ( DiFiglia et al. , 1997 ) and this damage is due to ubiquitin and ubiquitin-proteosome system ‘s component localisation in neural intranuclear inclusions ( Schmidt et al. , 2002 ) . Expanded polyglutamine causes unnatural protein folding ( DePril et al. , 2004 ) and the proteins themselves straight inhibit the proteasome ensuing in accretion of the poly-ubiquitinated proteins ( Bence et al. , 2001 ) . Furthermore, there is accretion of mutant Htt protein due to the damage in the autophagy-lysosomal tract and suppression of the autophagy ensuing in the ubiquitinated proteisn accretion ( Korolchuk et al. , 2009 ) .

Furthermore, ubiquitin+1 ( UBB+1 ) , an unnatural signifier of ubiquitin, is accumulated in Huntington ‘s disease ( DePril et al. , 2004 ) . This UBB+1 is unable to ubiquitinate substrate polyglutamine proteins ( Fischer et al. , 2003 ) . In add-on, at high concentration, UBB+1 besides inhibits proteasomal debasement of substrate polyglutamine proteins doing neuroblastoma cells decease ( van Tijn et al. , 2007 ) . UBB+1 does non bring on neuropathlogy itself but together with the polyglutamine proteins, UBB+1 mediated proteasomal suppression causes exacerbated neurological marks and symptoms ( DePril et al. , 2004 ) . Differences in ubiquitin-proteasomal system effectivity or the degree at which unnatural proteins like UBB+1 deposited find the inter-patients fluctuation in oncoming of disease or extent of wasting of principal striate body in Huntington ‘s disease patients ( Wexler et al. , 2004 ; McNeil et al. , 1997 ) .

Interestingly, the pre-symptomatic persons show the abnormalcies in non-neuronal tissues such as fibroblast, thrombocytes, civilized lymphoblasts, blood-nucleated cells and skeletal musculus cells due to the presence of mutant Huntingtin protein in these tissues ( Borovecki et al, 2005 ; Panov et Al, 2005 ) . The mutant Htt cistron causes the pathological alterations in any cells non merely in the encephalon cells.

Therefore the neurological characteristics of Huntington ‘s disease patients are due to the polyglutamine themselves, impaired ubiquitin-proteasomal debasement system, and autophagy-lysosomal system and accretion of the unnatural protein like UBB + 1. The impact of the mutant Huntingtin protein can be seen in neural every bit good as in non-neuronal tissues. Polyglutamine repeats become the curative mark in the intervention of Huntington ‘s disease as they play the cardinal function in the development of clinical manifestations of Huntington ‘s disease.

Juvenile signifier and classical signifier of Huntington ‘s disease

There are some differences between the Juvenile signifier and classical signifier of Huntington ‘s disease. First, the prevalence of Juvenile Huntington ‘s disease is about 8-10 % of instances and it rises to 70-80 % if it is inherited from male parent ( Squitieri et al. , 2006 ) . Majority of the juvenile Huntington ‘s disease patients are inherited from their male parents ( Murgod et al, 2001 ) .

Over 60 repetitions of CAG enlargement, there is rigorous additive relationship between the age of oncoming of the disease and enlargement mutants, connoting that the oncoming of juvenile Huntington ‘s disease is more closely related to length of CAG repetitions than big signifier ( Telenius et al. , 1993 ) . Analyzing the campaigner for cistron qualifiers and age at disease oncoming, Li and co-workers in 2003 found that juvenile Huntington ‘s disease showed an consequence specifically on cistron polymorphisms ( Li et al. , 2003 ) . However, in the different survey conducted by MacDonald and colleagues found that there was no such consequence in grownup onset Huntington ‘s disease patients ( MacDonald et al. , 1999 ) .

Merely in juvenile Huntington ‘s disease patients with big repetition enlargement, biochemical and biophysical alterations were observed in lymphoblasts such as augmented caspase 3 action ( Sawa et al. , 1999 ) , diminished potency of mitochondrial membrane ( Panov et al. , 2002 ) and enhanced cytoplasmatic autophagosomes activity ( Nagata et al. , 2004 ) .

In juvenile Huntington ‘s disease, untypical motor symptoms are more common without chorea. The symptoms may include dystonia, bradykinesia, intellectual characteristics or rigidness and are normally coupled with extended encephalon wasting ( Squitieri et al. , 2000a ) . Rigidity, although common in Juvenile signifier, is besides found in big oncoming of Huntington ‘s disease ( Squitieri et al. , 2000a ) .

However, the juvenile signifier and classical Huntington ‘s disease patients portion some clinical characteristics. Psychiatric jobs and behavioural upsets are cardinal elements of the clinical manifestation of Huntington ‘s disease ( van Duijn et al. , 2007 ) . This is of practical importance since these neuropsychiatric symptoms have a considerable impact on day-to-day activities ( Hamilton et al. , 2003 ) . The most common neuropsychiatric symptom is depressed temper happening in 33-69 % of patients ( van Duijn et al. , 2007 ) .

Huntington ‘s disease patients are easy recognized by their typical clinical characteristics. They have low quality of life due to motor and psychiatric jobs. Furthermore, the younger the age of oncoming, the more terrible the disease manifestation because juvenile Huntington ‘s disease patients have larger Numberss of CAG repetitions.

Number of CAG repetitions and Huntington ‘s disease badness

There are many groundss of correlativity between the Numberss of CAG repetitions and the badness of the disease. Relationship between Numberss of CAG repetitions and phenotypes are as follows.

Table 2: Relationship between Numberss of CAG repetitions and phenotype of the Huntington ‘s disease patients

Numbers of CAG repetitions

Phenotype

Mentions

Less than 26

Normal phenotype

Warby et al. , 2010

27-35

Not develop into clinical characteristics of Huntington ‘s disease, but have high potency for enlargement mutant in miosis and therefore can hold Huntington ‘s disease progeny

Semaka et al. , 2010

36-39

Incomplete penetrance. May be associated with Huntington ‘s disease phenotype or may be symptomless for the whole life.

Langbehn et al. , 2004

40 and above

Full penetrance

Warby et al. , 2010

Degeneration of the nerve cells in Huntington ‘s disease is characterized by presence of DNA atomization and there is a correlativity between figure of CAG repetitions and grade of DNA atomization ( Butterworth et al. , 1998 ) . In the same survey, they found that in post-mortem striatal subdivision of the encephalon of the Huntington ‘s disease patients, figure of trinucleotide ( CAG ) repetition was positively correlated to the extent of DNA atomization with the Pearson correlativity value less than 0.0002 ( Butterworth et al. , 1998 ) . The Numberss of CAG repetitions besides increase the advancement of wasting in the encephalon country of frontal lobes and basal ganglia ( Ruocco et al. , 2008 ) . Ruocco and colleagues besides found that more shortages in motor and cognitive map were found in the patients with larger CAG repetitions ( Ruocco et al. , 2008 ) .

Brandth and colleagues found that the longer CAG repetitions length was seen in younger age of oncoming of Huntington ‘s disease patients with the chance value less than 0.001 among 46 samples ( Brandth et al. , 1996 ) . CAG repeats more than 80-100 consequences in Huntington ‘s disease before 10 old ages of age ( Squitieri et al. , 2002 ) . Similar findings are documented by Lipe and Bird survey in which thirty four instances of late Huntington ‘s disease patients were retrospectively studied ( Lipe and Bird, 2009 ) bespeaking that the longer the CAG repetitions, the younger the oncoming of disease. Increasingly more terrible encephalon harm was observed among patients who manifest the disease at an early age ( Illarioshkin et al. , 1994 ) .

Reduced penetrance, the per centum of the persons demoing the physical visual aspect of the genotype that they possess, is associated with late oncoming of disease ( McNeil et al. , 1997 ) and the late oncoming is associated with the little Numberss of CAG repetitions enlargement. Therefore, CAG repetition length has an consequence on the patterned advance of the neurological marks and symptoms and the earlier the age of oncoming of the disease, the more terrible the disease.

Make CAG reiterate ever cause Huntington ‘s disease?

Huntington disease patients with authoritative history have more than 35 repetitions of CAG and patients with triplet lengths less than 35 has non yet been reported so far. In 1994, Andrew and his co-workers stated that the patients with less than 36 CAG repetitions showed symptoms like Huntington ‘s disease but these symptoms were non due to Huntington ‘s disease but are due to Huntington ‘s disease phenocopies, incorrect diagnosing or mistake in biological sample ( Andrew et al. , 1994 ) . The clinical marks and symptoms of Huntington ‘s disease may be present in the individual with CAG repetitions less than 35 but the repetitions piece of lands are non stable ( toward increasing size ) particularly when it is inherited from the male parent ( Herishanu et al, 2009 ) . The figure of CAG repetitions associated with the marks and symptoms of the Huntington ‘s disease is varied.

CAG repeats contribute to many neurological manifestations non merely the Huntington ‘s disease. Expanded tri-nucleotide repetitions are responsible for at least 19 inherited upsets ( Hu et al, 2009 ) such as Machado-Joseph Disease ( MJD ) , Huntington ‘s disease, myotonic dystrophy type 1 and several spinocerebellar ataxies ( SCAs ) ( Pearson et al, 2005 ) , etc. MJD is due to CAG tri-nucleotide repetitions within the ataxin-3 ( ATXN3 ) cistron ( Hu et al, 2009 ) . In SCAs, there are 40 CAG repetition enlargement in the ataxin-1 cistron ( Emamian et al. , 2003 ) . CAG repeats enlargement is present in different cistrons and produces assorted sorts of diseases.

Treatment of Huntington ‘s disease

The clinical manifestation of the Huntington ‘s disease is due to the toxic consequence of the mutant Huntingtin protein fragment and there is no curable for Huntington ‘s disease so far ( Sarkar et al. , 2008 ) . The current therapy is merely diagnostic. Choreic motion can be treated with Haldol and olanzapine both of which are neuroleptic agents ( de Tommaso et al. , 2005 ) . Psychiatric symptoms like depression are response to the psychotropic agents ( Warby et al. , 2010 ) .

As for the curable intervention, possible government for Huntington ‘s disease is hushing the mutant Htt cistron look by utilizing the RNA intervention ( RNAi ) ( Harper et al. , 2005 ) so that there will be less formation of mutant Huntingtin protein. In their survey with Huntington ‘s disease theoretical account mouse, they found that RNAi decreased the mutant Htt cistron look and mutant Huntingtin protein formation thereby diminishing the clinical manifestation of the Huntington ‘s disease ( Harper et al. , 2005 ) .

Sanchez and colleagues besides found that azo-dye Congo red inhibited the formation of the polyglutamine sums and increased the remotion of expanded polyglutamine repeats non merely in vitro but besides in vivo ( Sanchez et al. , 2003 ) . In the same survey they besides found that in transgenic Huntington ‘s disease theoretical account mouse showed betterment in endurance and clinical symptoms of Huntington ‘s disease after extract of Congo ruddy dye to them ( Sanchez et al. , 2003 ) .

Furthermore, Na butyrate chemotherapy improved the clinical manifestations in transgenic Huntington ‘s disease theoretical account mouse by bettering oxidative phosphorylation and transcriptional ordinance as Na butyrate augmented histone and Specificity protein-1 acetylation ( Ferrante et al. , 2003 ) . Furthermore, Trehalose, one of the disaccharides sugars, can adhere to the expanded polyglutamines and prevent the formation of the polyglutamine aggregates in the encephalon and liver thereby bettering the motor map and survival rate in transgenic Huntington ‘s disease theoretical account mouse ( Tanaka et al. , 2004 ) . Furthermore, Trehalose produces a dosage and clip dependent rise in the sum of autophagy in NB69 human neuroblastoma cells thereby heightening the riddance of unnatural proteins like mutant Huntingtin protein with polyglutamine and forestalling the mortification of NB69 by heightening the autophagy activities i.e. , increase debasement of mutant Htt protein ( Casarejos et al. , 2011 ) . The advantages of Trehalose are less toxic, extremely soluble and easy disposal by orally ( Tanaka et al. , 2004 ) .

In the survey conducted by Sarkar and colleagues on African green monkey kidney cells, they found that Li and rapamycin combination up-regulates the autophagy that degrades the mutant Huntingtin proteins ( Sarkar et al. , 2008 ) . Rapamycin entirely does non affectively diminish the mutant Huntingtin protein aggregates flat if one tierce of the cell has sums but it decreases the sums if merely 10 per centum of the cell contains sums in fly and mouse theoretical accounts of Huntington disease ( Ravikumar et al. , 2004 ) . Both Li and rapamycin are lipotropic so that they can go through the blood encephalon barrier ( Sarkar et al. , 2008 ) and therefore it is possible to utilize them in long-run intervention for Huntington ‘s disease patients.

Since polyglutamine and polyglutamine sums take a cardinal function in the development of neuropathology in the Huntington ‘s disease, the interventions are aiming to them to acquire complete remedy. However, these interventions are under the carnal tests so far and more surveies are needed in this country. Outline of pathology of Huntington ‘s disease and possible curative agents are demonstrated in the figure 4.

Figure 4: Mechanisms of Huntington ‘s disease pathology and possible sites moving by different curative agents

Decision

Huntington ‘s disease is the autosomal dominant inherited upset due to the CAG trinucleotide repeats enlargement greater than normal bound of 35. The age of oncoming that disease developed is correlated to the length of the polyglutamine enlargement. The longer the length of CAG repeats the younger the age of the oncoming of the Huntington ‘s disease patients. The age of oncoming is independent of homozygous or heterozygous of the mutant cistron in Huntington ‘s disease patients but rate of disease patterned advance is more rapid in homozygous upset. The greater the figure of CAG repetitions length, the more terrible the disease manifestation. Although it is the autosomal familial disease, no household history is found in some instances. However, this may be due to the little CAG repetitions size ( reduced penetrance ) or little survey sample size. More longitudinal survey with larger sample size is needed.

There is the ethnicity difference in the prevalence of Huntington ‘s disease. Nipponese and Chinese populations are less common than Europe and North-American population and this cultural fluctuation depends on the presence of specific predisposing haplotype.

FEN-1, MMR system, dual strand interruption fix system, homologous recombination and OGG-1 play the function in the development of the CAG repetition enlargement. Mutant Huntingtin protein incorporating the CAG repeats more than 35 produce the neurological marks and symptoms through their cytoplasmatic and nucleus cytotoxicity. Clinical manifestations are more or less similar in Juvenile and big signifier of Huntington ‘s disease but untypical motor symptoms without chorea is more common in Juvenile signifier.

Presently, there is no curable government for Huntington ‘s disease, merely diagnostic interventions can be given. Since the behavioural and psychiatric upsets disrupt the normal day-to-day modus operandi activities, curable therapy demands to be developed. Now we have some healing tests on transgenic Huntington ‘s disease theoretical account mouse, we still necessitate to turn out on human existences that these therapies are effectual and tolerated in human. Familial guidance and DNA proving before matrimony will forestall the transmittal of disease from coevals to the following coevals after sing the ethical issues since there is the no remedy for Huntington ‘s disease.