Huntington's disease (HD) was named after Dr. George Huntington an American physician who described it in 1872 as a movement disorder (Chorea) for long island families. HD is an inherited autosomal dominant expansion of a triplet (CAG) repeat mutation on the huntingtin gene encoding for poly glutamine tail (polyQ) near the N-terminal of the huntingtin protein leading to progressive degeneration of neurones in the specific areas of the brain which causes difficult movements as well as deterioration of cognitive and behavioural capacity (Huntington, 1872; Kirkwood et al., 2001). There has been tremendous progress in the molecular genetics study of HD starting in identification of the HD gene in 1993, followed by understanding the mutant gene (triplet repeat), development of HD cell, use of genetic animal models, and development of therapeutics to reduce symptoms as the effective teatment is not yet fully described (Mangiarini et al., 1996). Transgenic mice (N-171-82Q and R6/2 models), knock-in and knock-out mice models development has been the most valuable tool in characterisation of candidate disease gene as they show HD like behavioural, biochemical, transcription activity and neuropathological alterations observed in HD patients (Mangiarini et al., 1996; Schilling et al., 1999; Stack et al., 2005; Smith et al., 2006).
HD is an adult onset (30 to 50 years) neurodegenerative disorder affecting specific areas of the brain (the putamen and the caudate) resulting in chorea, loss of intellectual abilities and mood swings. There is also juvenile HD or early onset HD which affects children and teenagers below 20 years of age mainly characterised by rigidity and seizures in affected individuals. The distinction between the two forms of HD is based on age of onset and repeat lengths where the juvenile HD has more CAG (80-100) repeats as compared to adult onset HD. The pathology of HD is based on the interactions of the expanded polyQ tails with various mechanisms of the neurons in the putamen and caudate. HD has highest prevalence of approximately 5 in 100000 in Europe, India and United States of America; lowest frequency in Africa, China, Japan and Finland (Haper, 1986). The most common cause of death in HD patients are complications (such as infections e.g. pneumonia), injuries due to falling.
Milestones in HD research started in 1872 with the first description of HD by George Huntington, was followed by Alois Alzheimer in 1911describing the pathological characteristics of HD in the striatum and the cortex of the human brain. Use of anonymous markers in 1983 by Marcy MacDonald, James Gusella and colleagues mapped the HD gene to the chromosome 4 loci which opened the way for more research and in 1986 Joseph Martin, Susan Folstein and Jason Brandt developed and used linkage analysis for HD gene carriers (HDSA, 2008; HOPES, 2007). In 1993, the HD gene was discovered by the Huntington's Disease Collaborative Research Group. After the discovery of the gene individuals at risk could now undergo predictive testing and clinical diagnosis could now be confirmed. This caused a dramatic interest and increase in HD research. Since the inception of molecular HD research the functions of huntingtin protein are not well understood as it is ubiquitous in all cells and interacts with a wide range of proteins.
Understanding the functions of the huntingtin protein has been based mainly on animal models, an important tool, though not so accurate. Gillian Bates and colleagues have developed the first HD transgenic mice R6/2 and knock in mice which allowed preclinical testing of potential therapeutics (Sathasivam et al 2010). Elucidation of various functions of huntingtin protein ranging from spindle orientation, transcription activation, mitochondrial transport, Golgi apparatus transport along microtubules, neuroprotection, and essential in embryogenesis has been based on animal models (Duyao et al., 1995; Trushima et al., 2004; Zhang et al., 2006; Pérez-De La Cruz and Santamaría, 2007).
As HD is characterised by late onset and slow progression to reproduce the same phenotypes and the short lifespan of mouse represents a challenge hence use of R6/2 and N-171 mouse models in which acute neuronal toxicity by fragments of the Poly Q. (Mangiarini et al., 1996; Schilling et al., 1999). Warby et al., 2005 have shown that truncated mHTT have different localisation with intracellular cleaved mHTT which challenges the value of the mouse models as the pathogenicity is somehow different as intracellular it is pathogenic in its own. Full length mHTT mouse models YAC46 and YAC72 have been used as from 1999 and they showed close resemblance to the human phenotype with age dependent striatal and culminating in cortical degeneration (Hodgson et al., 1999; Slow et al., 2005; Show et al., 2003; Van Raamsdonk et al 2005).
The HD gene was first characterised in 1993 by the Huntington's disease collaborative research group as triplet repeat expansion mutation on chromosome loci 4p16.3 on the exon 1 of the Huntington (originally IT-15) gene with 67 exons which code for huntingtin protein with 3144 amino acids. The htt has CAG repeats near the N-terminal which encode for glutamine hence polyglutamine tract. These glutamine amino acids are followed by two stretches of proline. The mutation is a triple repeat expansion characterised by misfolding of the huntingtin protein resulting in a toxic gain of function and a wildtype loss of function (Borrell-Pages et al., 2006; Cattaneo et al., 2005). Wildtype huntingtin protein (HTT) is useful in anti apoptosis, organelle movements and embryonic development. The mutant huntingtin protein (htt) fragments accumulate and aggregate in the nucleus and cytoplasm of neurons through polar zippers and transglutaminases mediated events (Gervias et al., 2002) a result of the interference with the interactions of the N-teminus Htt with the nuclear exporter translocated promoter region (Tpr) (DiFiglia et al., 1997). The aggregated htt leads to pathogenicity by initiation of a cascade of events which leads to neurotoxicity, this cascade involves, oxidative injury, transcriptional dysregulation, glutamate excitotoxicity, apoptotic signals, mitochondrial dysfunction, inflammation and energy depletion (Beal and Ferrante, 2004; Jarabek et al., 2004; Li et al., 2003). The impairment of energy metabolism causes lactate accumulation in the Central nervous System (CNS) creating conducive environment for polar polyQ tails aggregation and accumulation forming inclusion bodies degeneration in the cingulated cortex and striatum observed in animal and cell models (Wemmie et al., 2003).
This cascade of events has been shown to be coupled to neurochemical changes not only limited to glutamine receptors but also involving dopamine and adenosine receptors in genetic animal models (Ferre et al., 1993; Pavesse et al., 2003; Teunissen et al., 2001). Alterations to neurotransmitter receptors, inhibition and down regulation of caspase1 activation contribute to pathology not only because they are involved with cell death, but cell dysfunction as well (Ona et al., 1999).
Glutamate is the major excitatory neurotransmitter in the CNS, glutamate accumulation causes prolonged excitatory signal transduction for influx of calcium ions (Ca+2) and water into the cell resulting in neuronal death. This Ca+2 influx overload activates phosphatases, proteases, phospholipases enzymes which degrade proteins, membranes and nucleic acid resulting in necrosis of the neurons (Berliocchi et al., 2005). The activation of nitric oxide synthatase leads to production of nitric oxide which causes apoptosis or alternatively through coupling to superoxide leading to production of peroxynitrite which may react with CuZn-SOD to form nitronium ion which nitrates tyrosine residues in proteins. Ca+2 elevation may lead to increased free radical generation in the mitochondrial which overwhelms the mitochondrial antioxidant and repair mechanism resulting in increasing oxidative damage which explains the slow neurodegenerative nature of HD (Wang et al., 2009). Weight loss in HD is caused by bio-energetic dysfunction due to defects in Adenosine triphosphate (ATP) production as a result of dysfunctional mitochondrial Tricarboxylic acid (TCA) cycle particularly the complex II, complex IV and aconitase due to increased Ca+2 influx through N-methyl-D-aspartate (NMDA) receptors (Lim et al., 2008; Mancuso et al., 2008). Basal ganglia γ-amino butyric acid (GABA) is an inhibitory neurotransmitter inhibiting spontaneous involuntary movements, GABAergic and enkephalin linked neurons are lost in HD through similar molecular mechanisms still to be elucidated, chorea and involuntary movements are due to imbalances on the excitatory and inhibitory neurotransmitters in the neurons (Mitchell et al., 1999; Calabresi et al., 1990; Hodges et al., 2006).
HTT is integral and regulates the microtubule dependent transport of organelles in post-mitotic neurons through interactions with dynein/dynactin complex and kinesin (Gauthier et al., 2004; McGuire et al., 2006). The dividing neurones get support from these HTT as it is involved in the regulation and orientation of the centromeres and microtubules for efficient cell division (Sathasivam et al., 2001). Animal model studies have shown that HTT is concentrated on the spindle poles during metaphase as it regulates spindle orientation during mitosis in neuronal cells (Godin et al., 2010).
The htt is unable to bind cellular proteins such as Hip1, chlatrin and AP2 to inhibit endocytosis and secretion of neurotransmitters but enhances apoptosis of the neurones (Gervias et al., 2002). Inflammation as a cellular response to aggregation and accumulation of htt in the neurones leads to neuronal death mediated by pathologically hyper active monocytes, macrophages and microglia activating cytokines Interleukin-6(IL-6) through the IκB kinase/ Nf-κB pathway which is up-regulated by the huntingtin protein. The use of YAC128 mouse models which mimic early events in HD patients have shown the increase in IL6 by monitoring levels and detected by multiplex ELISA of HD patients (Björkqvist et al., 2008). Expression of inflammatory transcripts of IL-6 and IL-8 were detected in post-mortem striatal tissue by use of reverse transcriptase-Polymerase Chain Reaction (RT-PCR) (Björkqvist et al., 2008).
The age and severity of HD is dependent on the type of mutation on the htt gene and modifying genes. Environmental factors also are responsible for different phenotypes. The expansion of the polyQ trait is due to transmission from parent to offspring due to DNA replication slippage, DNA damage repair during mitosis thus premeiotic cell divisions, and meiotic recombination (Yoon et al., 2003). HD inheritance is autosomal dominant where if either parent is affected hence all the offsprings have a 50% chance of inheriting HD.
The length of the polyglutamine is inversely proportional to age at onset of the disease (Myers, 2004). Modifier gene GRIK2 has been accountable for modifying the htt gene changing age of onset by 13% through TAA repeat polymorphism in the 3'UTR (Zeng et al., 2006). Anticipation often observed in early age of onset HD is due to expansion of repeat length during paternal transmission (Duyao et al., 1993; Snell., 1993; Shelbourne, 2000)
Homozygosity inheritance in HD alleles is rare but in cases where its found it double not confer early onset due to double negative but accelerates the disease progression in HD patients mainly due to lack of putative protective role of from the HTT (Gervias et al., 2002).
Table 1. Repeat length interpretation:
repeat length in triplets
Disease status
Interpretation
<28
Unaffected
Normal allele
28-35
Unaffectedlikely to expand in the paternal meiosis
intermediate
36-40
+/- affected
Variable penetrance
>40
affected
Fully penetrant
The huntingtin protein is useful on mitosis hence its inability and expansion renders it toxic to cells which are dividing and reduce their capacity to be multipotent cells (Jankowski and Nag, 2002).
The ubiquitin-proteasome system which is involved with maturation of cells has been shown to be rendered useless by htt, interestingly the efficiency of this system decreases with age which further explain the late onset of the HD ranging from 30-50 years (Bence et al., 2001). Matrix metalloproteinases which cleave htt to produce toxic htt fragments can be inhibited to reduce aggregation and toxicity to neurons (Johri and Beal, 2010).
Knock out mice experiments have shown that HTT is involved in the correct trafficking and translocation of the endoplasmic reticulum (ER)/Golgi apparatus through a membrane targeting domain to the nucleus in response to ER stress in HD after the inhibition of ER associated protein degradation leading to further accumulation of toxic htt. Rrs1 is useful for transcription repression of both ribosomal protein and rRNA genes which have failed to be secreted (Tsuno et al., 2000; Mizuta and Warner, 1994)
The mutant Htt polyQ is cleaved by proteases into fragments in the cytoplasm and nucleus which are toxic especially the N terminal 171 amino acid fragment (Slow et al., 2005; Gafni et al., 2004; Wellington et al., 2000). The proteases implicated are mainly intracellular including caspases 1, 3, 6, 7, and 8, calpain (CAPN5 and CAPN7) which cleave between amino acid 469 and 586 (Gafni et al., 2004; Graham et al., 2006). Also serine secreted kallikrein family (KLK10 and KLK11) and the members of the matrix metalloproteinase family (MMP-10, -14, -23B) are also implicated in the cleavage of the N-terminal leading to toxicity and neurodegeneration of HD, hence their inhibition will decrease the degree of penetrance of the Htt fragments as has been found in knock out mice and post-mortem human brain (Johri and Beal, 2010). The cleavage entails the htt fragments the ability to aggregate continuously in the pathogenesis and behavioural phenotype of HD (Gafni et al., 2004).
Mutant htt fragments which are soluble are specific for neuronal targeting because they are in monomers or hetero-oligomers which interact with transcription factors. Use of microarrays have identified several pathways that mhtt uses in regulating transcription which can be through the cyclic adenosine monophosphate (cAMP) element and specific protein1 (Sp1) pathways where mhtt interacts with cAMP responsive element binding protein (CREB) through the glutamine rich and acetyltransferase domains seen in animal models (Landles and Bates,2004).
HD transgenic mice and human HD patients have shown that mHTT reduces transcription through histone acetlylation mediated by histone deacetylases (HDAC) through histone modification by hypermethylation of H3 at lysine 9 to silence genes (Bannister et al., 2002; Hake and Allis, 2006; Ferrante et al., 2004; Ryu et al., 2006). In murine and human HD experimental studies there is hypoacetylation of histone protein H4 resulting in gene silencing (Ferrante et al., 2003).
The use of animal models for HD have helped tremendously the molecular studies of the HD phenotype and it treatment options but the question of how good are these animals in representing the pathogenesis in HD as there are differences in the environment of the proteins in the human brain and the mice brain, the mouse has been very useful as it has anatomical, physiological and genomic similarities too the humans but the closest will be primates but the cost of using them for therapeutic trials is very expensive.
The disorder of sleep-wakefulness observed in HD is due to the neurodegeneration in the hypothalamus on the circadian pacemaker of the suprachiasmatic nuclei which is a regulator of sleep wake cycle and circardian timing (Kassubek et al., 2004; Morton et al., 2005). The neurogeneration causes repression of the transcription of core genes period and cryptochrome which controll by basic helix loop helix heterometic protein complexes CLOCK and BMAL activity to close the oscillatory loop (Reppert and Weaver, 2002; Kremer, 1992; Kassubek et al., 2004)
Diagnosis of HD is based on three parts first clinical (thorough review the personal or family medical history, physical examination including a neurological exam), genetic testing to confirm the clinical diagnosis and also for prenatal testing of in vitro fertilised embroyos, and thirdly differential diagnosis to rule out HD like neurodegenerative disorders. Clinically the onset of HD is characterised physically by clumsiness, tremors, balance problems and jerkiness which prompt patients to seek medical care (Margolis and Ross, 2003) these usually worsens into chorea and cognitive abnormalities. HD causes atrophy to the caudate, putamen and cerebral cortex in the brain resulting in 25-30% reduction of the brain weight which is confirmed by magnetic resonance imaging scan, computed tomography and volumetric analysis (Ferrante et al., 1985). Microscopically neurological examination indicates loss of medium spiny neurons in the caudate and putamen, large neurons in layers of III, IV, and V of the cortex can be distinguished. The presence of inclusion bodies is diagnostic with amyloid like fibril and containing mutant huntingtin, ubiquitin and synuclein equally useful from the microscope (DiFiglia et al., 1997; Becher et al., 1998). There are several non hereditary disorders that resemble HD in clinical presentations hence genetic testing is mandatory for confirmation.
In 1993 use of positional cloning, resulted in the discovery of the CAG triplicate repeat expansion mutation (The Huntington's Disease Collaborative Research Group, 1993). The use of mutant repeat length is crucial in differentiating HD from nine other neurodegenerative disorder caused by CAG repeat expansion (Margolis and Ross, 2001). The difference within these degenerative disorders is the chromosomal and gene locations but all have an expansion of polyglutamine tract (Huntington's Disease Collaborative Research Group, 1993).
The discovery of the mutant gene in 1993 led to the development of PCR based assays in determining the length of CAG repeat which is diagnostic, this was initially calculated from the PCR product that contain both neighbouring CCG and CCT triplets repeats (Goldberg et al., 1993), but now laboratories are required to test for CAG repeat lengths only to prevent overestimating due to variability of the CCG (7 -12) and CCT (2-3) (Andrew et al., 1994; American College of Medical Genetics/American Society of Human Genetics(ACMG/ASHG) statement, 1998).
The length of the PCR product is detected by Radiolabelled (CAG)n or (CTG)n oligonucleotide or fluorescently tagged primers which are read by automated genotyping systems (Ampion, 2010; Toth et al., 2001; Williams et al., 1999).
There is a new one step scalable throughput molecular screening for HD based on two separate amplification and detection steps (Teo et al., 2008) This scalable one step procedure is based on rapid microplate format which combines amplification and detection procedures in one plate thus automated melting curve analysis (MCA) of the HTT CAG repeat and PCR of the amplicon. As the combined PCR and MCA is rapid, simple therefore, can be scaled up but there is need for negative results need to be confirmed by the southern blotting and pedigree analysis as this will reveal. It reduces false positives from the PCR as the MCA will reveal the melting points of the amplicon working as a confirmatory test in one (Teo et al., 2008).
Treatments and care of sufferers
Treatment and care of sufferers of HD involves symptoms targeted diet, genetic, stem cell and restorative techniques. HD is incurable but there is tremendous research in the pipeline in trying to find the cure at the same time trying to define the exact function of the huntingtin protein in the human body. To add to this wide area or ongoing research is the clarification of specificity observed in htt to target caudate and medium spiny neurones in degeneration as it is ubiquitously distributed in cells.
Nutritional supplements such as Creatine and CoQ10 which are antioxidants to avert the impaired energy metabolism have been put through clinical trials but the usefulness has not been very helpful as compared to the success in the animal Ethyl eicosapentaenoic acid an omega 3 fatty acid has been under clinical trials but its success was limited hence there is need to further study the assimilation of therapeutic success in animal models to those in human HD sufferers (Huntington Disease Society of America, 2008).
Clinical trials for dopamine stabilisers and blockers to control the neurotransimitter availability that have an impact on movement control (chorea) been started in Europe and Canada which are now undergoing the III phase. Since normal levels of dopamine are toxic in HD the use of dopamine depleter tetrabenazine has been approved by the United States of America Food and Drug Administering (FDA) to treat chore (Huntington Disease Society of America, 2008). Excitatory neurotransmitter glutamate can be regulated by Dimebon which also inhibits acetylcholinesterase which is involved in the excitatory signal transduction from glutamate specifically in Ca+2 homeostasis through the mitochondrial permeability transition pores (Huntington Disease Society of America, 2008).
Anti-apoptosis drugs are also useful for reducing the neuronal death due to aggregate formation, they target various molecules involved in apoptosis (programmed cell death), for example monocycline has been shown to inhibit apoptosis is transgenic mice hence it has been put on clinical trials unfortunately it did not have the same benefits for HD patients as for HD mice (Huntington Disease Society of America, 2008). Methazolamide an antiapoptotic drug inhibits cytochrome c which is involved in apoptosis. CEP-1347 is an antiapoptotic which increase the survival of neurons and regeneration by increasing the levels of Brain derived Neutrotropic Factor (BDNF) as was observed in R6/2 transgenic mice (HDSA, 2008).
Western blot and immunocytochemistry techniques applied to the tissues of the transgenic mice have shown increased H3 and H4 acetylation activity in the brain (Ferrante et al., 2003). As polyglutamane decreases histone acetylation in the progression of pathogenesis its inhibition is of therapeutic value as has been shown by cell models and animal models in counteracting of the transcription down-regulation in HD through polyglutamine toxicity (Hughes et al., 2001; Steffan et al., 2001; McCampbell et al., 2001; Gardian et al., 2001; Dragatsis et al., 2000).
Mutant huntingtin fragments bind and inhibits Histone deacetylase inhibitors reducing the histone acetylation and repressing gene transcription hence development of drugs which can prevent deacetylation will result in gene transcription activation such drugs are known as HDAC inhibitors. HDAC inhibitors include sodium butyrate, phenylbutyarate, trichostatin A and suberoylanilide hydroxide (SAHA) act by relaxing the DNA conformation which promotes transcription selectively for 2-5 % of the genes inhibited in HD (Ferrante et al., 2003). Studies in Drosophila model and transgenic mice in HD have shown that SAHA and sodium butyrate ameliorates the lethality of neurodegenerative phenotype of HD (Steffan et al., 2001; Hockly et al., 2003). The treatments meant at the realignment of histone homeostasis by DNA binding drugs Chromomycin and Mithramycin displaces transcription activators and repressors which bind the guanine-cytosine rich region of promoters thereby modulating transcription (Mir et al., 2003; Sastry et al., 1995).
The development of Riluzole or lamotrigine is based on reducing the excitotoxicity observed in HD transgenic mice as they act on neurotransimitter receptor activity in trying to reduce opening of calcium channels under N-methyl-D-aspartate receptors unfortunately it did not show anticipated benefit in clinical trails carried out in Europe and Canada. Beneficial therapeutic trials in animal models do not necessary have high predictive value in humans as evidenced by creatine, minocycline and cylooxygenase which were very promising in mouse models are not effective in human trials (Groeneveld et al., 2003; Shefner et al., 2004).
The detailed molecular sequence analysis of mouse mHTT and human mHTT such that the results can be compared and integrated in interpretation of result analysis as for humans has 3144 amino acids compared to 3120 amino acids in mouse normal Htt protein (Ehrnhoefer et al ., 2009). Another interesting difference is the calpain cleavage site where in humans is between residues 468-470 with sequence Leu-Thr-Ala and contributes to toxicity when cleave whilst in mouse its Phen-Ala-Ala, the human sequence is more prone to cleavage than the mouse sequence hence use of such molecular information is useful for the interpretation (Gafni et al., 2004; Tompa et al., 2004; Gafni and Ellerby, 2002). HD study has benefited in the molecular genetics application on the animal models for therapeutic trials.
Potential for other treatments-gene therapy, use of stem cells
There is great potential in foetal neural transplant to stop the identified neuronal death pathways in HD using the Ribonucleic acid interference (RNAi) to stop sequence specific transcription of mutant gene (Harper, 2009). There is also pragmatic which bases on development of treatments which target the replacement of the lost striatal neurons and boosting neuronal defence mechanisms (Peschanski et al., 2004).
Gene therapy currently being researched and giving hope is the RNAi technique where treatment of HD is through silencing of htt silencing the HTT which results in undesirable outcomes, this has prompted research in the discovery of RNAi which targets the htt through targeting heterozygous single-nucleotide polymorphism (SNP) as opposed to targeting CAG repeat (Harper, 2009; Pfister and Zamore, 2009). There is need for long term HD suppression non viral siRNA delivery are short lived dose dependent but invasive, on the other hand the current viral delivery vehicle is good but there is uncertainty as to the consequences for off target as once activated RNAi can not be turned off (HDDW, 2010). There are prospects as current research based on the methods of delivery of RNAi in to the brain is being explored.
Foetal neural transplantation is based on the neuroplasticity of neurons being able to change structures and connections depending on the physiological environment in bolstering stabilisation and recovery of lost neuronal functions (Peschanski et al., 2004). The foetal neural grafting has shown promising benefits in mice and nonhuman primates experimental studies by reversing motor and cognitive symptoms elicited by neurodegeneration in striatal neurons (Fricker-Gates et al., 2001). These foetal neural stem cells are somatic stem sells harvested from brains of aborted foetuses (HDSA, 2008).
Stem cell research is promising as these cells have the ability to differentiate into any cell type (caution on developing in tumour cells) there are three types of stem cell one can get first the stem cells from the brain which have been activated to differentiate following a specific lineage, secondly the stem cells from embryos which are also in ethical controversy as to the donors and thirdly the stem cells from cord blood (Dunnet and Rosser, 2004). There are somatic stem cells which are tissue specific and
Ethical and social aspects related to diagnosis and treatments
Clinical trial on stem cells need to show efficacy and safety of the stem cell therapy as the delivery vehicles being used are viral particles which are immunogenic and raises the issue of safety. Testing for HD is voluntary as there are no cures yet its only management and helping those with the disease to live with the disease longer. Since its hereditary many of the sufferers are aware of the condition from their affected relatives.
The diagnosis of HD has a lot of ethical issues as it's a dominant autosomal incurable disease which affects the members of a pedigree when one undergoes the testing hence now that information has to be confidential. Insurance companies can use that information for discrimination as in the UK it's the only approved genetic testing when one apply for life cover more than £500000 (Association of British Insurers, 2008).
The safety of the foetal neuronal transplation as in the Tampa study where three subjects suffered subdural haemorrhage is still being improved depending on the stem cell donor adopted as current focus is on allograft (Hauser et al., 2002).
Animal cloning producing transgenic mice for HD has been the foundation of the knowledge that is known about HD. RNAi therapy is the promising treatment for neurodegenerative diseases through its study it is explaining some of the pathophyisiology of HD. Stem cell transplant are also being developed to cure and counteract the damage caused by htt. The molecular genetics applications in HD study have given hope to suffers as from being able to explain the pathology, inheritance, treatment options to alleviate movement disorders.
Figure 1. Factors for translation of transgenic mice therapies to clinical trials (Adapted from Hersch and Ferrante 2004). http://www.ncbi.nlm.nih.gov/pmc/articles/PMC534928/figure/f1/
