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Huntington's disease is a fatal syndrome with neither remission nor cure named after Doctor George Huntington in 1872. At first, it was believed that the disease sufferers were haunted by spirits or victimized as witches, and were rejected by the community. In 1872, Dr. George Huntington described the disease in detail and expressed family linkage. Over 100 years later, in 1993, the US-Venezuela Huntington's Disease Collaborative Research Project found out the causal gene which is responsible for abnormally large CAG repeat.
Huntington's disease is a progressive neurodegenerative genetic disorder, inherited in an autosomal dominant pattern. So, one copy of the altered gene with an expanded tri-nucleotide repeats (mutant allele) is required to develop the disease. All human beings have the Huntington gene (Htt gene), which codes for the Huntingtin protein. The Huntington gene is present on the short arm of chromosome 4, at exon 1 of the interesting transcript 15 (IT15) gene on chromosome 4p 16.3. The Huntington gene contains a three Deoxyribonucleic acid (DNA) bases sequence: cytosine-adenine-guanine (CAG) repeats, known as a tri-nucleotide repeat, which varies in length between each individual and between each generation. In a normal person, this tri-nucleotide repeat consists of less than 35 CAG units. When the length of this repeat expansion reaches a certain threshold, beyond 35 triplets, it produces an abnormal protein, known as a mutant Huntingtin protein (mHtt), a cytoplasmic protein, whose presence causes slow but steady damage to specific areas of the brain. The CAG trinucleotide repeats are translated into more than 35 glutamines in the mutant Huntingtin protein of the Huntington's disease patients.
2. Different types of Huntington's disease
There are 3 different types of Huntington's disease depending on the age of onset: juvenile form, typical form and late form. These three different types are also different in the numbers of CAG repeats they possess.
3. Genetic inheritance pattern of Huntington's disease
Huntington's disease is due to the expanded CAG tri-nucleotide repeat determined in the DNA since conception. Since Huntington's disease is the autosomal dominant inherited disease, if one parent carries the mutant gene, 50 percent of the offspring will be affected. The genetic inheritance pattern of the Huntington's disease is described in figure 1.
However, the percentage of inheritance varies from study to study suggesting that genetic is not the only component in the Huntington's disease development.
One study conducted in Southern India found that the juvenile form of Huntington's patients was inherited from their fathers. Among them, the fathers of two patients showed clinical features of Huntington's disease whereas the other two were asymptomatic but they had expanded CAG repeats with the mean CAG repeats of 48.4. Moreover, only 88.5 percent of the 26 Huntington's disease patients were found to have family history in the above study. Furthermore, family history was not found in 8 percent of 171 DNA confirmed Huntington's disease patients in New South Wales. Lipe and Bird's study in 2009 also mentioned that among 34 cases of the Huntington's disease patients, 68 percent had no recognized family history of this disease. Since these studies were conducted on a small scale involving few numbers of patients, great caution should be exercised in interpretation and generalization of these findings. Kartsaki and co-workers, 2006, pointed out that the lack of obvious family history of Huntington's disease was due to small CAG repeat size in their family members because CAG repeats size of 35-39 shows reduced penetrance and may be asymptomatic for the whole life-span. So, the absent of family history in Huntington's disease patients may be due to the small sample size and/or due to the reduced penetrance.
The total number of CAG repeats was related to the age of onset of Huntington's disease in case of maternally inherited pattern. Large CAG repeat expansion pattern was unlikely to be occurred in maternally inherited patients while it was found to be vice versa in paternally inherited ones. However, Murgod and co-workers found no obvious difference in the age of onset between those who inherited the disease from the father when compared to those who inherited it from the mother; the mean age of disease onset was found to be 36.9 years in both cases.
Interestingly, sex of the patients also affects the type of familial inheritance and age of onset of the disease. In Venezuelan sibling pairs, 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%). In the study conducted by Roos and co-workers among 822 cases showed that the age of onset in female patients (mean age of onset = 39.9 years) were higher than that of male patients (mean age of onset = 37.5 years). Furthermore, the Roos study mentioned that the mean age of onset in both male and female is lowest in the grandmother-father lineage compared to the other grandmother-mother lineage, grandfather-mother lineage and grandfather-father lineage. These above findings suggest that females have less severe phenotype and generate less offspring with the disease.
Homozygous Huntington's disease patients inherit two expanded tri-nucleotide repeats copies, one from each parent. However, the age of onset of the Huntington's disease is not altered. So, the age of onset of the Huntington's disease is independent of inheritance of one copy or two copies of an expanded CAG repeats, but dependent on the length of the tri-nucleotide repeats.
In 1994, Andrew and his colleagues reported Huntington's disease cases with no CAG repeats expansion pointing that Huntington's disease has phenocopies. In their study, 1.17 percent of 1, 022 Huntington's disease patients have no CAG repeats expansion. Pedigree analysis of the Huntington's disease patients with phenocopies showed that chromosome 20p12 region encoding the prion proteins were responsible for the phenocopy effects. In 1999, doppel or prion protein 2 (dublet) (Prnd) genes which are prion protein like genes were discovered as the new members for Huntington's phenocopy genes. Huntington's disease phenocopy patients showed atypical presentation such as epileptic seizures.
4. CAG repeats and ethnicity in Huntington's disease
There is ethnic 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; Indian immigrants to Britain have prevalence of 1.75 per 100,000 people.
The CAG repeats expansions in Htt gene correlate to a specific predisposing haplo-group in Western Europeans. European Huntington's disease patients possess a specific set of twenty two tagged single nucleotide polymorphisms which make up a single haplo-group. This haplo-group is also seen in chromosome of general population indicating that there may be the predisposing cis-elements mutation in Htt gene in the Europeans causing the CAG repeats instability. However, this predisposing haplo-group for CAG expansion is not seen in the Chinese and Japanese people, meaning that the difference in the predisposing background distribution among populations explain the different prevalence of Huntington's disease in different populations.
Next to the 3′ end of CAG repeats in Htt gene is a CCG repeats site. In the Caucasian population, expanded CAG repeats are highly associated with (CCG) 7, whereas in the Japanese population and Chinese population, expanded CAG repeats are associated with (CCG)10 suggesting that the different CCG alleles 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 Japanese populace and Chinese populace as compare to the Western Europeans. The specific single nucleotide polymorphism alleles are strongly associated with the CAG repeats expansions. We need to find out the single polynucleotide polymorphisms that reveal to cis-elements responsible for the instability of the CAG repeats in Htt gene. By knowing this, we can develop the new therapy for the Huntington's disease patients using personalized allele-specific targets medicine.
5. Reasons for the expansion of CAG repeat in the Htt gene
There are different proposals for the underlying reasons of the expansion of CAG repeats in the Htt gene. Flap endonuclease 1 (FEN1), is a structure-specific endonuclease that is involved in the correction of DNA-damage. In mammals, the loss of FEN1gene expression is embryonically lethal. Normally, FEN1 protein cleaves a double flap substrate possessing the 5′ flap with one 3′ overhangs in vitro. In this case, flap equilibration is achieved by correct mechanisms of FEN1 protein, followed by ligation with DNA ligase and no CAG repeat expansion. FEN1 gene takes part in prevention of CAG tri-nucleotide repeat sequences instability because an increase in occurrence of CAG repeats expansion is found in FEN1 gene mutants in yeast cells with defective yeast homolog of FEN1, RAD27. Moreover, the FEN1 protein concentration is directly proportional to the length of CAG repeats, i.e., if the cells have longer CAG repeats, more FEN1 proteins are required in order to maintain the stability. If concentration of FEN1 protein is limited, the unprocessed flap substrate could equilibrate into different types of intermediate structures and some of the intermediate structures will be ligated by DNA ligase resulting in expansion of the sequence. This finding is supported by Henricksen and co-workers, 2002. Their study showed that FEN1 and DNA ligase competed at the flap, and when the amount of ligase is increased, there will be the ligation of unprocessed flaps causing sequence expansions. Spiro and McMurray, 2003 studied the relationship between CAG repeats expansion and FEN1 gene in FEN1 +/- mice with expanded CAG-120 repeats within the human Huntington's disease gene. They found that there was increase in CAG repeats expansion in the progeny of the FEN1+/- male mice. Therefore, FEN1 gene plays the role in prevention of CAG repeat expansion during the flap processing. The role of FEN1 in CAG repeats expansion is demonstrated in the figure 2.
Another factor contributing to the formation of the CAG trinucleotide repeats is defect in double strand break repair system. Meiotic recombination-11 (Mre11) gene of Saccharomyces cerevisiae is involved in the double strand break repair pathway and in Mre11-deficient strains; there is an accumulation of CAG trinucleotide repeats expansions. Moreover, CAG repeats expansion is seen in the absence of small ubiqutin-related modifier-1(SUMO1) activating enzyme subunit-2 (sae2) genes which is also involved in double strand break repair pathway and in the absence of Rad52 gene which is involved not only in double strand break repair but also in homologous recombination. Both double strand break repair and homologous recombination are important mechanisms for preventing the trinucleotide repeats expansion.
Another possible mechanism for CAG repeat expansions is due to the mis-match repair (MMR) system. A function for MMR system in CAG expansion is poorly understood. During DNA replication, the tri-nucleotide repeats can misalign causing an extra-helical DNA loop. DNA loops are repaired by mutS homolog2/mutS homolog3 (MSH2/MSH3) by insertion leading to the tri-nucleotide expansion in vivo. In yeast and bacterial studies, deletions of tri-nucleotide repeats tracts are more likely to occur than insertions during cell proliferation by 10-1000 times in wild type cells compared to the MMR system defective cells. Furthermore, Manley and co-workers found that when there was no MSH2, the CAG repeats expansion were not developed in germ cell lines as well as in somatic cells during the development in animals.
MSH2/MSH3 protein is also involved in somatic age-dependent expansion in Huntington's disease. However, in the proliferating fibroblasts of the Huntington's disease patients, CAG tracts are also deleted with an intact MMR system. These findings oppose a mechanism in which MMR system is responsible for CAG repeats expansion during post-replicative repair suggesting that not only the MMR system but also the other repair systems like double strand break repair system and homologous recombination are involved in the development of the CAG repeats expansions. Mechanism of MMR system in polyglutamine repeats is described in figure 3.
However, it is difficult to conclude the extent of these MMR system involved in CAG repeats expansion. It is not possible to test the role of repair mechanisms in causing CAG repeats expansions because the MMR mechanism is important in preventing the development of the abnormal new DNA strand during the DNA replication. Different cell types might be affected by different mechanisms to develop the polyglutamine repeats.
A DNA glycosylase, 7, 8-dihydro-8-oxo-guanine-DNA glycosylase-1 (OGG1), is one of the contributing factors for Huntington's disease. In Huntington's disease mice, age-dependent expansion of CAG repeats takes place alongside with the oxidative DNA damage accumulation. Importantly, absence of OGG1 protein, a DNA glycosylase, suppresses expansion in Huntington's disease mice. OGG1 null animals inhibit the CAG repeats expansions in the presence of MSH2 proteins as well as MSH2 null animals inhibit CAG repeats expansion in the presence of OGG1 proteins. So, these two proteins are responsible in the development of CAG repeats expansions.
6. Functions of Normal Huntingtin protein
Huntington protein is 348 kDa (kilodalton), soluble protein and has a polyglutamine of not more than 35 residues of glutamine. Huntingtin protein contains HEAT-like repeats (Huntingtin, Elongation factor 3, protein phosphatsase 2A, TOR1) from its amino-terminus to the carboxyl-terminus. Having the HEAT-repeats structure, Huntingtin protein may possess a solenoid-like structure acting as a scaffold for interactions of multiple proteins. Huntington's protein is cytosolic and is present not only in the brain but also in other organs like lungs, heart, liver, kidneys, lymphoblasts, etc. Using the poly and mono clonal antibodies, Huntingtin proteins are detected in all over the brain and neurons. In the nervous system, Huntingtin protein augments the neurotrophic factors production thereby contributing to the neuro-protective function.
From the animal study using mice, it was found that the polyglutamine segment is not indispensable because, even though it is removed from Huntingtin protein, mice are surviving with minor symptoms. However, when the whole normal Huntingtin protein is removed, it is embryonically lethal in mice and adult cell degeneration is observed in the conditional knockout of the Htt gene in mice. So, Huntingtin protein is essential for life but the polyglutamine segment is not essential for life.
Moreover, Huntingtin protein has an anti-apoptotic action. Position 548 of the N-terminal of the normal Huntingtin protein is responsible for anti-apoptosis. Huntingtin protein inhibits the pro-caspase 9 and it also prevents the formation of the pro-apoptotic complex, Huntington Interacting Protein-1 Protein Interactor-Huntington Interacting Protein-1 (HIPPI-HIP-1) complex.
7. Impact of mutant Huntington protein
How mutant Htt protein containing more than 35 glutamine residues stimulates a cascade of cellular alterations, resulting in cell dysfunction and deterioration, have not yet been fully understood. And again, the exact mechanisms of mutant Htt proteins accumulation are still unknown. The cellular toxicity sites for the mutant Huntingtin protein are not only in the nucleus but also in the cytoplasm of the cells. Mutant Huntingtin proteins affect many proteins present in the nucleus and cytoplasm of the cells that are involved in the gene transcription, programmed cell death, mitochondrial function, suppression of tumor, release of neurotransmitter and axonal transport. Transcriptional dysfunction of polyglutamine expansions might take a role in the development of neurotoxicity in Huntington's disease because in transgenic Huntington's disease model mouse, improve survival was seen after treating with histone deacetylase inhibitor, sodium butyrate, that modulated transcription significantly. In the nucleus, there are abnormal interactions between the abnormal polyglutamine protein and p53 tumor suppressor protein, cyclic adenosine monophosphate (cAMP) response element binding (CREB) protein (co-activator), stable protein-1 transcription factor and TATA-associated factor-130. Both normal and mutant form of Huntingtin protein act on stable protein-1 transcription factor and TATA-associated factor-130 but mutant Huntingtin protein has the stronger interaction than normal one. Mutant Huntington proteins cause toxicity to the cells as well as impairment to the function of the wild type Huntington proteins.
In human, polyglutamine causes over activation of the N-methyl-D Aspartate (NMDA) receptors leading to cell death and loss of medium-sized spiny neurons (MSNs) of the striatum. Loss of MSNs of the striatum is one of the contributing factors for neurological and psychological defects. In MSNs from the Huntington's disease model mouse, there was an increase in apoptosis of MSNs through activation of the NMDA receptors by polyglutamine.
Neuronal intranuclear inclusions of expanded polyglutamine protein are one of the factors that contribute to the clinical manifestation of Huntington's disease. Neuronal intranuclear inclusions of expanded polyglutamine protein are the most distinct pathological characteristic of polyglutamine diseases. Neuronal intranuclear inclusions are correlated with toxic level of protein and disease severity. Neuronal intranuclear inclusions of mutant Huntingtin protein and progressive cerebral deterioration starting from caudate nucleus and putamen are involved in Huntington's disease pathophysiology.
In Huntington's disease, there is an impairment of the ubiquitin-proteasome system and this impairment is due to ubiquitin and ubiquitin-proteosome system's component localization in neuronal intranuclear inclusions. Expanded polyglutamine causes abnormal protein folding and the proteins themselves directly inhibit the proteasome resulting in accumulation of the poly-ubiquitinated proteins. Moreover, there is accumulation of mutant Htt protein due to the impairment in the autophagy-lysosomal pathway and inhibition of the autophagy resulting in the ubiquitinated proteisn accumulation.
Moreover, ubiquitin+1 (UBB+1), an abnormal form of ubiquitin, is accumulated in Huntington's disease. This UBB+1 is unable to ubiquitinate substrate polyglutamine proteins. In addition, at high concentration, UBB+1 also inhibits proteasomal degradation of substrate polyglutamine proteins causing neuroblastoma cells death. UBB+1 does not induce neuropathlogy itself but together with the polyglutamine proteins, UBB+1 mediated proteasomal inhibition causes exacerbated neurological signs and symptoms. Differences in ubiquitin-proteasomal system effectiveness or the level at which abnormal proteins like UBB+1 deposited determine the inter-patients variation in onset of disease or extent of atrophy of corpus striatum in Huntington's disease patients.
Interestingly, the pre-symptomatic individuals show the abnormalities in non-neuronal tissues such as fibroblast, platelets, cultured lymphoblasts, blood-nucleated cells and skeletal muscle cells due to the presence of mutant Huntingtin protein in these tissues. The mutant Htt gene causes the pathological changes in any cells not only in the brain cells.
Therefore the neurological features of Huntington's disease patients are due to the polyglutamine themselves, impaired ubiquitin-proteasomal degradation system, and autophagy-lysosomal system and accumulation of the abnormal protein like UBB + 1. The impact of the mutant Huntingtin protein can be seen in neuronal as well as in non-neuronal tissues. Polyglutamine repeats become the therapeutic target in the treatment of Huntington's disease as they play the key role in the development of clinical manifestations of Huntington's disease.
8. Juvenile form and classical form of Huntington's disease
There are some differences between the Juvenile form and classical form of Huntington's disease. Firstly, the prevalence of Juvenile Huntington's disease is about 8-10% of cases and it rises to 70-80% if it is inherited from father. Majority of the juvenile Huntington's disease patients are inherited from their fathers.
Over 60 repeats of CAG expansion, there is strict linear relationship between the age of onset of the disease and expansion mutations, implying that the onset of juvenile Huntington's disease is more closely related to length of CAG repeats than adult form. Studying the candidate for gene modifiers and age at disease onset, Li and colleagues in 2003 found that juvenile Huntington's disease showed an effect specifically on gene polymorphisms. However, in the different study conducted by MacDonald and co-workers found that there was no such effect in adult onset Huntington's disease patients.
Only in juvenile Huntington's disease patients with large repeat expansion, biochemical and biophysical changes were observed in lymphoblasts such as augmented caspase 3 action, diminished potential of mitochondrial membrane and enhanced cytoplasmic autophagosomes activity.
In juvenile Huntington's disease, atypical motor symptoms are more common without chorea. The symptoms may include dystonia, bradykinesia, cerebral features or rigidity and are usually coupled with extensive brain atrophy. Rigidity, although common in Juvenile form, is also found in adult onset of Huntington's disease.
However, the juvenile form and classical Huntington's disease patients share some clinical features. Psychiatric problems and behavioral disorders are key elements of the clinical manifestation of Huntington's disease. This is of practical importance since these neuropsychiatric symptoms have a considerable impact on daily activities. The most common neuropsychiatric symptom is depressed mood occurring in 33-69% of patients.
Huntington's disease patients are easily recognized by their distinctive clinical features. They have low quality of life due to motor and psychiatric problems. Moreover, the younger the age of onset, the more severe the disease manifestation because juvenile Huntington's disease patients have larger numbers of CAG repeats.
9. Number of CAG repeats and Huntington's disease severity
There are many evidences of correlation between the numbers of CAG repeats and the severity of the disease. Relationship between numbers of CAG repeats and phenotypes are as follows.
Degeneration of the neurons in Huntington's disease is characterized by presence of DNA fragmentation and there is a correlation between number of CAG repeats and degree of DNA fragmentation. In the same study, they found that in post-mortem striatal section of the brain of the Huntington's disease patients, number of trinucleotide (CAG) repeats was positively correlated to the extent of DNA fragmentation with the Pearson correlation value less than 0.0002. Moreover, loss of MSNs in the striatum was dependent on the length of the polyglutamine repeats. Shehadeh and co-workers found that NMDA receptor mediated toxicity of the cultured MSNs was 3.5-fold increase in 72 polyglutamine repeats and 8-fold increase in 128 polyglutamine repeats respectively in comparison with 18 polyglutamine repeats in transgenic Huntington's disease mouse. The longer the CAG repeats size, the greater the NMDA receptor mediated toxicity of the MSNs in the striatum. Furthermore, the numbers of CAG repeats also increase the progress of atrophy in the brain area of frontal lobes and basal ganglia. Ruocco and co-workers also found that more deficits in motor and cognitive function were found in the patients with larger CAG repeats.
Brandth and co-workers found that the longer CAG repeats length was seen in younger age of onset of Huntington's disease patients with the probability value less than 0.001 among 46 samples. CAG repeats more than 80-100 results in Huntington's disease before 10 years of age. Similar findings are documented by Lipe and Bird study in which thirty four cases of late Huntington's disease patients were retrospectively studied indicating that the longer the CAG repeats, the younger the onset of disease. Progressively more severe brain damage was observed among patients who manifest the disease at an early age.
Reduced penetrance, the percentage of the individuals showing the physical appearance of the genotype that they possess, is associated with late onset of disease and the late onset is associated with the small numbers of CAG repeats expansion. Therefore, CAG repeat length has an effect on the progression of the neurological signs and symptoms and the earlier the age of onset of the disease, the more severe the disease.
10. Do CAG repeats always cause Huntington's disease?
Huntington disease patients with classic history have more than 35 repeats of CAG and patients with triplet lengths less than 35 has not yet been reported so far. In 1994, Andrew and his colleagues stated that the patients with less than 36 CAG repeats showed symptoms like Huntington's disease but these symptoms were not due to Huntington's disease but are due to Huntington's disease phenocopies, wrong diagnosis or error in biological sample. The clinical signs and symptoms of Huntington's disease may be present in the person with CAG repeats less than 35 but the repeats tracts are not stable (toward increasing size) especially when it is inherited from the father. The number of CAG repeats associated with the signs and symptoms of the Huntington's disease is varied.
CAG repeats contribute to many neurological manifestations not only the Huntington's disease. Expanded tri-nucleotide repeats are responsible for at least nineteen inherited disorders such as Machado-Joseph Disease (MJD), Huntington's disease, myotonic dystrophy type 1 and several spinocerebellar ataxias (SCAs), etc. MJD is due to CAG tri-nucleotide repeats within the ataxin-3 (ATXN3) gene. In SCAs, there are forty CAG repeat expansion in the ataxin-1 gene. CAG repeats expansion is present in different genes and produces various kinds of diseases.
11. Treatment of Huntington's disease
The clinical manifestation of the Huntington's disease is due to the toxic effect of the mutant Huntingtin protein fragment and there is no curable for Huntington's disease so far. The current therapy is only symptomatic. Choreic movement can be treated with haloperidol and olanzapine both of which are neuroleptic agents. Psychiatric symptoms like depression are response to the psychotropic agents.
As for the curable treatment, possible regime for Huntington's disease is silencing the mutant Htt gene expression by using the RNA interference (RNAi) so that there will be less formation of mutant Huntingtin protein. In their study with Huntington's disease model mouse, they found that RNAi decreased the mutant Htt gene expression and mutant Huntingtin protein formation thereby decreasing the clinical manifestation of the Huntington's disease.
Sanchez and co-workers also found that azo-dye Congo red inhibited the formation of the polyglutamine aggregates and increased the removal of expanded polyglutamine repeats not only in vitro but also in vivo. In the same study they also found that in transgenic Huntington's disease model mouse showed improvement in survival and clinical symptoms of Huntington's disease after infusion of Congo red dye to them.
Moreover, sodium butyrate chemotherapy improved the clinical manifestations in transgenic Huntington's disease model mouse by improving oxidative phosphorylation and transcriptional regulation as sodium butyrate augmented histone and Specificity protein-1 acetylation. A pilot study conducted by Ondo and co-workers found that Memantine (1-amino-3,5-dimethyl-adamantane), a partial non-competitive inhibitor of NMDA receptors, relieved motor symptoms including chorea in Huntington's disease patients by mitigating the NMDA receptors mediated toxicity and associated apoptosis of MSNs in striatum.
Furthermore, Trehalose, one of the disaccharides sugars, can bind to the expanded polyglutamines and prevent the formation of the polyglutamine aggregates in the brain and liver thereby ameliorating the motor function and survival rate in transgenic Huntington's disease model mouse. Moreover, Trehalose produces a dose and time dependent rise in the amount of autophagy in human derived neuroblastoma cell, NB69, thereby enhancing the elimination of abnormal proteins like mutant Huntingtin protein with polyglutamine and preventing the necrosis of NB69 by enhancing the autophagy activities i.e., increase degradation of mutant Htt protein. The advantages of Trehalose are less toxic, highly soluble and easy administration by orally.
In the study conducted by Sarkar and co-workers on African green monkey kidney cells, they found that lithium and rapamycin combination up-regulates the autophagy that degrades the mutant Huntingtin proteins. Rapamycin alone does not affectively decrease the mutant Huntingtin protein aggregates level if one third of the cell has aggregates but it decreases the aggregates if only ten percent of the cell contains aggregates in fly and mouse models of Huntington disease. Both lithium and rapamycin are lipophilic so that they can pass the blood brain barrier and therefore it is possible to use them in long-term treatment for Huntington's disease patients.
Since polyglutamine and polyglutamine aggregates take a central role in the development of neuropathology in the Huntington's disease, the treatments are targeting to them to get complete cure. However, these treatments are under the animal trials so far and more studies are needed in this area. Outline of pathology of Huntington's disease and possible therapeutic agents are summarized in the figure 4.
Huntington's disease is the autosomal dominant inherited disorder due to the CAG trinucleotide repeats expansion greater than normal limit of 35. The age of onset that disease developed is correlated to the length of the polyglutamine expansion. The longer the length of CAG repeats the younger the age of the onset of the Huntington's disease patients. The age of onset is independent of homozygous or heterozygous of the mutant gene in Huntington's disease patients but rate of disease progression is more rapid in homozygous disorder. The greater the number of CAG repeats length, the more severe the disease manifestation. Although it is the autosomal inherited disease, no family history is found in some cases. However, this may be due to the small CAG repeats size (reduced penetrance) or small study sample size. More longitudinal study with larger sample size is needed.
There is the ethnicity difference in the prevalence of Huntington's disease. Japanese and Chinese populations are less common than Europe and North-American population and this ethnic variation depends on the presence of specific predisposing haplotype.
FEN-1, MMR system, double strand break repair system, homologous recombination and OGG-1 play the role in the development of the CAG repeat expansion. Mutant Huntingtin protein containing the CAG repeats more than 35 produce the neurological signs and symptoms through their cytoplasmic and nucleus cytotoxicity. Clinical manifestations are more or less similar in Juvenile and adult form of Huntington's disease but atypical motor symptoms without chorea is more common in Juvenile form.
Currently, there is no curable regime for Huntington's disease, only symptomatic treatments can be given. Since the behavioral and psychiatric disorders disrupt the normal daily routine activities, curable therapy needs to be developed. Now we have some curative trials on transgenic Huntington's disease model mouse and pilot tests in Huntington's disease patients, we still need to prove on human beings that these therapies are effective and tolerated in human. Genetic counseling and DNA testing before marriage will prevent the transmission of disease from generation to the next generation after considering the ethical issues since there is the no cure for Huntington's disease.