Huntington's disease is a distressing fatal syndrome without remission named after Doctor George Huntington in 1872. At first, it was thought that the disease sufferers were haunted by spirits or victimized as witches, and were rejected or banished by society. In 1872, Dr. George Huntington described the disease in detail and expressed family linkage. Over 100 years later, in 1983, the US-Venezuela Huntington's Disease Collaborative Research Project discovered the estimated location of a gene that causing Huntington's disease and in 1993 the research group identified 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; one copy of the altered gene with an expanded tri-nucleotide repeats (mutant allele) is required to develop the disease. All humans have the Huntington gene (Htt gene) that code for the protein Huntington. The Htt gene is present on the short arm of chromosome 4, at exon 1 of the IT15 gene on chromosome 4p 16.3. The Htt gene contains a sequence of three DNA bases: cytosine-adenine-guanine (CAG) repeated multiple times, known as a tri-nucleotide repeat, which varies in length between each individual and between each generation. In the 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 form of the protein, known as mutant Huntington protein (mHtt), a cytoplasmic protein, whose presence causes slow but steady damage to specific areas of the brain.
Different types of Huntington's disease
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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 possessed.
Table 1: Different types of Huntington's disease depending on the age of onset
Types of Huntington's disease
Age of onset
Mean numbers of CAG repeats
From 2 years to 20 years
From 21 years to 50 years
Older than 50 years
Genetic inheritance pattern of Huntington's disease
Huntington's disease is due to the expanded CAG tri-nucleotide repeat determined in the Deoxyribonucleic acid (DNA) since conception. Since Huntington's disease is the autosomal dominant inherited disease, there are many affected persons in the family and both sexes are equally affected. If one parent carries the mutant gene, 50 percent of the offspring will be affected. However, the percentage of inheritance varies from study to study suggesting that genetic is not the only component of in the Huntington's disease development.
In one study conducted in Southern India found that all juvenile form of Huntington's patients inherited the disease from their fathers. Among them, the fathers of two patients showed clinical features of Huntington's disease whereas the other two were asymptomatic but had CAG repeats. However familial history cannot be elucidated in all cases. Family history was not found in 8 percent of the Huntington's patients in New South Wales. Lipe and Bird, 2009 study showed that 68 percent of the Huntington's patients had no known family history of Huntington's disease. The lack of obvious family history of Huntington's disease is due to small in CAG repeat size in their family members. In variance-components analysis with controlled effect of the length of the allele which is an accurate method in estimation of the familiarity showed 59 percent of familial history in Huntington's disease and pointing that either genetic or environmental factors shared among the family members. So, the Huntington's disease has phenocopy effect, an environmental effect that mimics a genetic disease.
The total number of CAG repeats on the normal allele was related to the age of onset of HD in case of maternally inherited pattern. The disease chromosome was unlikely to suffer large expansions when it was inherited from the mother and larger CAG repeat numbers were seen in case of paternally inherited patients. However, there was no significant 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.
Homozygous Huntington's disease patients are inherited two expanded tri-nucleotide repeats copies, one from each Huntington's disease parents. 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.
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Sex of the patients also affects the type of familial inheritance, even though it is not statistically significant. For sibling pairs, the sister inheritance is highest among the sister-brother inheritance and the brother inheritance. For parent-offspring pairs, the same-sex inheritance is greater than the different-sex inheritance. These interesting gender differences may be due to favored same-sex inheritance and it is strange for the Huntington's disease which is autosomal inheritance.
CAG repeats and ethnicity in Huntington's disease
There is ethnic variation in the prevalence of the Huntington's disease. The prevalence rate 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, while Japanese and Africans have lower prevalence.
The CAG expansions in Htt gene correlates to a specific predisposing haplo-group in Western Europeans. 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 3â€² end of CAG repeats in HTT gene is a CCG repeats site. In the Caucasian populace , expanded CAG repeats are highly associated with (CCG)7, whereas in Japanese populace, 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 responsible for the low prevalence of Huntington's disease in Japanese populace as compare to the Western Europeans.
Reasons of 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. Expansions of CAG repeats occur as a result of incorrect Okazaki fragment synthesis during the DNA replication processing. Flap endonuclease 1 (Fen1), is an endonuclease and it is involved in Okazaki fragment synthesis and in the correction of sensitivity of the cells to DNA-damaging agents, decreasing the high rates of mutation, and synthetic lethality due to mutation in double-strand-break repair gene. In mammals, the loss of FEN1gene expression is embryonically lethal. Normally, FEN1 protein cleaves a double flap substrate possessing the 5â€² flap with a one 3â€² overhangs in vitro. In this case, flap equilibration is achieved by correct processing of FEN1 protein, followed by DNA ligation and no CAG repeat expansion. FEN1 gene takes part in prevention of CAG/CTG tri-nucleotide repeat sequences instability because an increase in frequency of CAG/CTG repeats expansion is found in FEN1 gene mutants not only in vitro but also in yeast cells with defective yeast homolog, RAD27. Moreover, the FEN1 protein concentration is directly proportionate 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 sequence expansion. This finding is supported by Henricksen and co-workers, 2002 study which shows that FEN1 and DNA ligase are competed at the flap, and when the amount of ligase is increased, there will be the ligation of unprocessed flaps causing expansions. Spiro and McMurray, 2003 study 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. However another study conducted by Van den Broek and co-workers found that there was no increase in CAG repeats expansion in FEN1 +/âˆ’ mice. Therefore, FEN1 gene plays the role in prevention of CAG repeat expansion during the flap processing even though it is uncertain that whether only one copy of FEN1 gene can prevent the expansion or not.
Another possible mechanism for CAG repeats expansion is due to the mis-match repair (MMR) system. A role for MMR system in CAG expansion, however, is poorly understood. MMR system corrects the post-replicative base pair mismatches and loops. In CAG repeats expansion, hairpins structure are present at the single strand breaks site, at Ori site of replication, during DNA recombination, or by polymerase slippage during proliferation of cells. Polymerase slippage during cell proliferation is one of the earliest models for CAG repeats expansion. During DNA replication, the tri-nucleotide repeats can misalign causing an extra-helical DNA loop. The length of the tri-nucleotide repeats increases in the daughter strand whereas it decreases in the template strand. DNA loops are repaired by mutS homolog2/mutS homolog3 (MSH2/MSH3), and are the intermediate products for expansion. Thus, MSH2/MSH3 processing during post-replicative repair mechanisms leads to the tri-nucleotide expansion in vivo. In yeast and bacterial studies, deletions of tri-nucleotide repeats tracts are more favored than insertions during cell proliferation by 10-1000 times in wild type cells compared to the MMR system defective cells. The deletion of tri-nucleotide repeat tracts does not depend on the MMR mechanisms. Absence of MSH2 stops expansion in both germ cells lines and somatic cells during animal development.
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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. In Huntington's disease animals, CAG repeats expansion occurs in post-mitotic neurons. These findings oppose a mechanism in which MMR system is responsible for CAG repeats expansion during post-replicative repair. Open break-dependent repair mechanisms for CAG repeats expansions might be predicted to include recombination, replication restart, or single strand break repair.
However, it is difficult to conclude the extent of these MMR system involved in CAG repeats expansion because fibroblasts from the Huntington's disease patients do not lack of MSH2/MSH3 proteins. Moreover, 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. Furthermore, tests of CAG repeats expansion among different cell types of Huntington's disease patients are needed to explore. Different cell types might be affected by different mechanisms to develop the polyglutamine repeats.
Slipped structures also contribute to the causation of the CAG repeats expansions. Loop size formation due to replication slippage requires larger energy than for duplex formation. The CAG repeats expansion arises from multiple slips on the CAG repeat template and it does not depend on the size of the any one slip. In vitro, primer extension assays indicate that triplet repeats expansions inhibit DNA polymerase progression and break in proceedings along the tract. Moreover, CAG repeat expansion inhibits the polymerase progression in vivo and this obstruction takes place only on the leading strand of the DNA because single-stranded DNA binding protein removes the obstruction on both sequences. Thus, the rate of DNA synthesis becomes slower than the unwinding rate by helicase when 5'-CAG is present in the leading template and intimidates functional coupling. To avoid uncoupling, the DNA polymerase pushes away and omits a small tract of 5'-CAG in the leading strand DNA template, reducing synthesis time, and the un-replicated 5'-CAG hairpin on the leading strand DNA template is trapped following polymerase passage. This trapping of loops explains why deletion is preferred than insertions during DNA replication. DNA polymerase stops on the CAG repeats expansion in vivo and this leads to the increase in expansion rate.
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.
Impact of polyglutamine expansion on normal function of the body
Huntington, having HEAT-repeat structure, seems to perform as a scaffold for transport and function of dynamic complexes. Huntington's proteins are cytosolic protein 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, Huntington proteins are detected in all over the brain and neurons and there is no difference in staining pattern between the Huntington's disease patients' brain and normal brain. From the animal study it was found that the polyglutamine segment is not indispensable because, even though it is removed from Huntington protein, mice are surviving with minor symptoms. The disease process initiated in Huntington's disease differs from those of other polyglutamine disorders suggesting that some aspects play parts in the development of the disease such as structural features, binding partners, sub-cellular localization.
How mutant Htt protein stimulates a cascade of cellular alterations, resulting in cell dysfunction and deterioration, have not yet been fully understood. Neuronal intranuclear inclusions of expanded polyglutamine protein is one of the factors that contributing to the clinical manifestation of Huntington's disease. Neuronal intranuclear inclusions of expanded polyglutamine protein are the most prominent pathological hallmark of polyglutamine diseases. Neuronal intranuclear inclusions are correlated with toxic level of protein and disease severity. Neuronal intranuclear inclusions of mutant Htt gene 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 they proteins themselves directly inhibit the proteasome resulting in the poly-ubiquitinated proteins up-regulation for degradation.
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 and acts as a reporter for error in proteasomal functions. 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 efficiency 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. Therefore the neurological features of Huntington's disease patients are due to the polyglutamine themselves, impaired ubiquitin-proteasomal degradation system and accumulation of the abnormal protein like UBB+1.
Juvenile form and classical form of Huntington's disease
There are some differences between 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 inherited from their fathers.
Over 60 repeats of CAG expansion, there is strict linear correlation between the age at 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 adult there was no such effect. These findings strengthen the suppositions that many factors play parts in induction of the Huntington's disease phenotype, genetic and non-genetic factors and environmental factors.
In juvenile Huntington's disease patients with large repeat expansion which were absent in cell lines from patients with low or moderate expanded CAG repeats, biochemical and biophysical changes are also observed in lymphoblasts such as augmented caspase 3 action, diminished mitochondrial membrane potential and enhanced cytoplasmic autophagosomes. A significant modification of energy metabolism was noted in muscle biopsies from a subject.
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.
The classical Huntington's disease is chorea is more common. Majority (88.5%) of the patient present with chorea and other symptoms include dysarthria, bradykinesia, rigidity, abnormal gait, ocular pursuit, and dystonia. Regarding the neurological symptoms, both juvenile form and adult onset are not very different in clinical presentation.
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. Many studies noted that depressive symptoms herald the beginning of the motor symptoms.
Depression is possibly due to the direct consequence of cerebral degeneration. There is limited study with regard to anxiety in patients with Huntington's disease. As a feature of generalized anxiety disorder, "worrying" is found in some patients and it is more of worries about the disease. Irritability is observed among patients even without history of bad temper and develops before the motor symptoms, particularly in gene carriers. Irritability occurs more commonly in late stage of the disease, initially manifests as restrained manner and later progress to aggressive behavior. This socially inappropriate behavior may be the result of progressive degeneration of the striatum and the orbitofrontal-subcortical circuit. Impairment of the anterior circulate-subcortical circuit leads to motivational disorders comprises of apathy of the brain. Apathy is closely related to the progress of the disease and as it becomes worsening; it disrupts more the everyday functioning.
Compulsive and obsessive symptoms are shown by Huntington's disease patients, preceded by personality and mental intransigence, due to damage of basal ganglia and frontostriatal circuits. Dementia was noted in about half of the patients and usually develops many years after the onset of chorea.
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 mutant Htt gene in these tissues. The mutant Htt gene causes the changes in any cells not only in the brain cells.
Huntington's disease patients are easily recognized by their distinctive clinical features. They have low quality of life due to motor and psychiatric problems. Therefore, prevention and prompt treatment is essential.
Number of CAG repeats and Huntington's disease severity
Although there is no evidence of correlation between the numbers of CAG repeats and the severity of the symptoms, progressively more severe brain damage was observed among patients who manifest the disease at an early age. The age at onset of the disease is the most commonly correlated factor of disease severity. The age of onset of the disease is inversely correlated with the expansion of CAG repeats. There is a negative correlation between the length of CAG repeats and age of onset. CAG repeats more than 80-100 results in Huntington's disease before 10 years of 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. Therefore, CAG repeat length had minimal effect on the progression of the neurological signs and symptoms and the earlier the age of onset of the disease, more severe the disease.
Does CAG repeat always cause Huntington's disease or all the Huntington's disease has CAG repeats?
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 stretch are not stable. 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 (Hu et al, 2009) such as Machado-Joseph Disease (MJD), Huntington's disease, myotonic dystrophy type 1(DM1) and several spinocerebellar ataxias (SCAs), etc. MJD is due to CAG tri-nucleotide repeats within the ataxin-3(ATXN3) gene.
However, the biological function of Huntington protein and how mutant Huntington proteins result in disease remains unclear, they are the focus of much study. Although animal studies improve the understanding of the disease, because of the difference in genetic background from humans, the findings cannot be directly applied to humans and limits the practical application for therapeutic research. The observations from human cells and transgenic animal models can offer new clues on the potential mechanisms which only influence on the Huntington's disease pathogenesis.
In the absence of treatment to cure the disease or even to deter the progression of the disease, researchers are needed to explore for a therapy that checks the primary initiating event or its direct biochemical outcomes. Genetic determinants of the Huntington's disease are fairly understood yet they could not explain all the pathogenic mechanisms and as such other factors like environmental factors are worth exploring to shed light on the complete picture of the variations of the disease. The genetic mutation in Huntington's disease offers an opportunity to recognize and impede the early disease process. Treatment targeting the trigger in the early disease process could inhibit development of subsequent phenotypes. Encouraging genetic counseling and DNA testing before marriage will prevent the transmission of disease from generation to the next. Since the behavioral and psychiatric disorders disrupt the daily activities, research on the role of other factors - biological and environmental factors, to the behavioral phenotype of Huntington's disease will improve the quality of life of the patients.