Whatever the exact pathophysiological mechanisms in HD, the net result is neuronal dysfunct ion, shrinkage, and ultimately loss in a wide range of structures, which have traditionally been classifi ed using striatal atrophy and Vonsattel staging (61). Th is approach, whilst being a useful way to stage tissue for analysis, can be mis- leading as it relegates the a trophy and cell loss at other sites to being of secondary importance, when this might well not be the case given much of the recent imaging and clinical work in pre-manifest and esta blished disease (62, 63). Whatever the exact sequence of Oxford Textbook of Movement Disorders 216 pathological events and cell loss, the advanced HD brain is char- acterized by extensive ne uronal loss, atrophy, and the formation of intracellular inclusions with a marked astroglio sis (64). resting. With time, these movements become more prominent and involve all body parts symmet rically; it is very unusual to see any major asymmetry. Th e resultant picture is of patien ts with invol- untary facial grimaces and smiles, a tongue that they cannot keep protruded (see Video 20.3), and slightly slurred speech. Th eir gait becomes abnormal in a way that i s hard to characterize, as it has elements of chorea, dystonia, and some ataxia (see Video 20.4). As the patients advance, they oft en move into a phase of the illness where the chor ea becomes less prominent and is replaced by a more bradykinetic dystonic movement disorder (see Fig. 20.2), with signs of spasticity in the legs and, in some instances, a degree of hemibal- lismus which is very hard to treat (see below). In younger-onset cases, especially the juvenile Westphal variant of HD, the patient typically develops a parkinsonian syndrom e with relatively little if any chorea (66). Clinical features (see videos and Table 20.1) Th e clinical features of HD are well describ ed and classically con- sist of a triad of problems involving disorders of movement, cog- n ition, and mood (65). However, which of these is predominant varies from patient to patient , and indeed there are a host of other features that are now increasingly recognized as bei ng a part of HD, and which may even occur before the overt motor features of the illness. Th e earliest features of HD vary depending on the extent to which one searches for defi ci ts (63), but in clinic they are oft en the choreiform movements (see Videos 20.1 and 20.2) which typi- cally are brought out by walking or other motor actions, such as repetitive han d-tapping. Th ese movements oft en consist of slight fl icks of chorea around the head, sho ulder, or fi ngers, and are oft en not noticed by the patient themselves. Indeed it is wort h asking the patient \200\231s partner whether they have noticed abnormal fi dgety movement s at night in bed or in the evening when the patient is Whilst these are the typical movement disorders seen in HD, some patients, especially young er-onset cases, can develop myo- clonus, but tremor is very rare and any focal motor defi c its should Table 20.1 Clinical features of HD Motor Chorea; ballismus; dystonia; parkinsonism Cognitive Frontal executive dysfunction with problems of set-shifting and attention; dementia in adva nced cases Psychiatric Depression; mood swings; impulsiveness and irritability; suicidality; paranoia and psychoti c episodes; obsessive behavior; apathy Non classical features: \200 epilepsy \200 circadian rhythm abnormalities with insomnia and daytime somnolence \200 weight loss \200 vomiting \200 constipation z Video 20.2 Common choreiform movements of the extremities and trunk. z Video 20.1 Intermittent choreiform movements of the extremities and trunk. z Video 20.3 Impersistence of tongue protrusion. CHAPTER 20 Huntington \200\231s Disease 217 Cognitively, the earliest defi cits in HD are an inability to make decisions about issues t hat are oft en not that important, such as choosing outfi ts to wear or food items to buy. Some patients can articulate these types of defi cit, but more typically patients and their families complain that the patient has lost the ability to make deci- sions over complex i ssues or that they are fi ne as long as they fol- low routines. Th us a change in circumsta nce (job change etc.) can sometimes precipitate and expose the cognitive problems which bec ome more apparent as the disease progresses, with all patients developing dementia in the a dvanced stages of the disease. Th ese cognitive abnormalities can be seen by using formal n europsycho- logical tests such as the STROOP or trail-making tasks and high- light that the early cognitive defi cits have a mainly frontostriatal basis (67, 68). It is very rare for patients with HD to present with major memory or language defi cits, and it is worth remem bering that a patient who has become almost mute could be depressed. Th is may also be impo rtant in some patients who, for some reason, seem to have suddenly become much more cogniti vely impaired. z Video 20.4 Choreiform and dystonic gait. Psychiatric features can be very varied (69, 70). Some patients remain well throughout thei r illness, with no fl orid psychiatric fea- tures. However, some patients can develop depre ssion, which may be exacerbated by some of the medications used to treat the motor features of HD (e.g. tetrabenazine). In other cases the depression seems to run independently of th e disease (i.e. precedes the devel- opment of overt motor features of the illness by years) . Th e most common problems in the early stages of HD are much more likely to be irritabili ty and impulsiveness as well as major mood swings, with patients getting very worked up ove r oft en trivial issues. Th is can lead to violent outbursts and problems with the law. Mor eover, one in four HD patients attempts suicide (71, 72). With time these problems resolve and are oft en replaced by a more abulic apathetic stage of disease which can be very frust rating for the carers and family, as it can be perceived as the patient being lazy. Independence score 100 LATE EARLY P R E M A N I F E S T Chorea Agitated/mood swings Distractable Dystonic/bradykinetic Abulic Demented 20 Years ? Levodopa ? Hypnotic ?PEG Respite care Advanced directives Psychotic problems can be seen in HD but are less common than perseverations. When present, these can cause profound problems, as can the more frontal presentation of HD when patient s have no insight into their problems so that they do not seek help or take the required me dication for their condition (73). Finally, in juve- nile HD, behavioral problems can be th e dominant problem with development of obsessive behaviors associated with violent out- bur sts when confronted about them. Atypical antipsychotics Antidepressants Antiepileptics Fig. 20.2 Schematic diagram of the progress of HD over time. Other features which can also be seen in HD include the following. Circadian rhythm disturbances may begin early in the course of the illness and become more obvious once an imposed sleep \200\223 wake regime is lost (e.g. end of employment) (74, 75 ). Th is can create major management problems as the partner of the patient may have to ado pt a similar sleep \200\223wake cycle whilst still trying to work normally. Weight loss is very common and can be due to problems of dys- phagia, mood, and motivation as well as depr ession. However, there may also be a more fundamental problem with metabolism in this condi tion which predisposes patients to lose weight (76). Epilepsy is rarely seen, and when pres ent tends to occur in young-onset cases. Vomiting and constipation are common in advanced p atients, but whether this refl ects a degree of autonomic or enteric nerv- ous system invol vement is unclear. \227\206 z Video 20.5 Impaired ocular pursuit and saccades. be investigated as they are not a feature of HD. Eye-movement abnormalities in terms of pro blems of saccadic movements are common \200\224initially slowed, leading on to problems of initiation with head movements to compensate (see Video 20.5). Th e same is also true of sm ooth pursuit eye movements: in the early stages they can be jerky and/or interrupted (see V ideo 20.5) before becoming more impaired and almost absent in advanced disease. Th ese eye- movement abnormalities are oft en more obvious in younger-onset cases and should always be specifi cally assessed in any patient with suspected HD. \227\206 \227\206 \227\206 Oxford Textbook of Movement Disorders 218 Diagnosis Th e diagnosis of HD is straightforward in the right clinical con- text, given th e ease with which one can test for the mutant gene. Th ere are two main situations in which a genetic test is needed or requested: the fi rst is in the manifest patient when a diagno stic test is needed to confi rm the diagnosis; the second situation is when an individual a t risk of developing HD wishes to have a genetic test to ascertain if they carry the mutant gene (77). In both cases genetic counseling is needed, given the implications of a positiv e test to the patients and their family. of possible agents can be considered, but those used most com- monly are the antipsychotic drugs, olanzapine and tiapride, or the catecholamine-depleting agent, tetrabenazine (TBZ). Olanzapine can be given once a day starting at 2.5 mg and increasing to a maxi- mum dose of 20 mg. Tiapride is oft en given at 50 \200\223100 mg tds with a maximum daily dose of 1200 mg. TBZ is given two or three times a day, starting at around 12.5 mg bd/tds with a maximu m dose of 200 mg/day. In addition to the antichorea eff ects, olanzapine has a number of ot her desirable properties in that it helps patients sleep if it is given at night and it cal ms down the mood swings that are common in HD. Th e drug eff ectively suppresses chorea in most people, but it causes increased appetite and therefore weight gain, which may be of va lue given the problems of weight loss in many cases. Th e main side eff ects of olanzapine are unacceptable weight gain and daytime sedation. In contrast, TBZ is the only proven drug to treat the chorea of HD, but can cause daytime sedation and, in some cases, depression. Tiapride is also effi cacious in controlling the hyperkinesias and gait disturbance associa ted with HD. Other drugs that can be used to help treat the chorea are sulpiride, ami- sulp iride, risperidone, and other antipsychotics. Some patients do not respond to these drugs, and anecdotally other agents have been tried with some success including baclofen, amantadi ne, and nabilone in refractory cases. Th e role for pallidal deep brain stimu- lation is co ntentious, with the fi rst clinical studies underway to test its use in treating the chorea of HD. In the case of a manifest patient, the need to ascertain the family history is important \200\224check that when there is no apparent family history, the age at which the parents d ied is known as their early death may hide the family history. However, given that HD is th e most common cause of chorea (apart from levodopa-induced dys- kinesias in Parkinson \200 \231s disease), undertaking the genetic test is logi- cal and it is only worth looking for the other rarer causes of chorea if it is negative (see Chapters 21 and 22). Th ere are clear guidelines as to how predictive testing can best be done, given the implic ations of a positive test to future employment, life assurance, etc (78). If a patient test s positive for the abnormal gene, it is our practice to follow them up so that they can be assessed for early features and oft en reassured that many symptoms that they have are norm al with ageing. Th ere are currently two major studies looking at pre-manifest patients, TR ACK-HD (79) and PREDICT-HD (80), with the aim of identifying cognitive, motor, imaging, and biomarker tests. Such a result would not only help in informing patients as to whether the disease has actually begun, but would also open up a window for introducing disease-modify ing therapies earlier. Th e dystonic aspects of HD occasionally respond to TBZ. Although levodopa is oft en tried for parkinsonian features, espe- cially in juvenile HD, the eff ects are not convincing. Ot her agents are occasionally tried, including baclofen and benzodiazepines, but generally sp eaking they have a marginal subjective benefi t without much evidence of a major clinical e ff ect. Management Th e management of HD patients (70, 81, 82) is best done in a multidisciplinary clinic which should include a number of diff er- ent medical specialities (see Table 20.2). Th e involvement of such a team enables all aspects of patient care to be addressed, and n ot just from a pharmacological perspective. Having the team available outside the clinic ap pointment is also helpful, given that most fam- ily doctors understandably have limited kno wledge and lack confi - dence in managing this condition. Th e psychiatric features of HD generally respond to standard therapies. Th us depressive f eatures can be treated with standard antidepressants, of which our preferred choice is cita lopram because of its anxiolytic properties. However, sertraline, paroxetine, venla- faxine , and mirtazapine can be used to good eff ect. When mood swings are an issue, olanzapine ca n oft en help; if not, then standard mood-stabilizing antiepileptic medications such as lam otrigine, sodium valproate, and carbamazepine can be used. Carbamazepine can cause problems of somnolence as well as skin rashes. Lithium is rarely used for mood stabilization becaus e of problems of compli- ance and anxieties about side eff ects if it is not taken properly . In the early stages of the disease, management is mainly support- ive and provision of reas surance; treating the movement disorder is not necessary unless the patient has a disabilit y secondary to it. When the chorea becomes severe enough to merit therapy, a number Treatment of the cognitive aspects of HD is much more prob- lematic, unless there is an aff ective element to the problem. Cholinesterase inhibitors have been tried without much in t he way of documented benefi ts. Other drugs which can be of use in HD include modafi nil for daytime somnolence, zopiclone or even sodium oxybate for insom- nia (which can be a major problem in HD), oxybutynin for bladder instability, and standard laxatives for constipation. Table 20.2 Members of the multidisciplinary HD clinic \227\206 Neurologist \227\206 Neuropsychologist \227\206 Neuropsychiatrist In addition, patients can oft en benefi t from speech and language therapists, mainly to ch eck on swallowing, dieticians to help advise on the best diet from a calorifi c perspective (as well as which sup- plements to use) and to avoid choking and aspiration, and occu- pat ional therapists to ensure that appropriate measures are put in place to deal with the home situation to maximize independence and safety. Physiotherapy can be helpful in assessing a nd help- ing gait problems, and social workers and regional Huntington \200\231s \227\206 Clinical geneticist/Genetics counselor \227\206 HDA worker \227\206 Physiotherapist \227\206 Speech and language therapist \227\206 Dietician \227\206 Occupational therapist CHAPTER 20 Huntington \200\231s Disease 219 Disease Association advisers are also invaluable in supporting the patient and their family in the community. Th e detailed study of pre-manifest HD individuals with the aim of trying to identify the e arliest problems that mark the onset of the disease process, with the hope that these marke rs of disease onset could be used to help monitor the effi cacy of disease-modifying drugs. \227\206 Finally, two other issues are always worth bringing up sooner rather than later: advanced d irectives and percutaneous endo- scopic gastrostomy (PEG) feeding. Th e former deals with t he issue of what the patient and their family would like to be done as the disease enters t he fi nal phases, and this also helps shape discussions about power of attorney, nursing ho me placement/respite, and PEG placement. Th is last issue is something that will arise in a ll patients as their illness progresses, and some will decide early on that they would not want a PEG when the situation merits this. However, in other cases, this is sought and our own advice is to go for PEG placement sooner rather than later, with the main indications b eing weight loss, recurrent chest infections, or mounting anxieties about the time needed t o maintain suffi cient feeding to ensure that the calorifi c input is adequate (83). Future developments Th e main developments that are likely to occur in HD over the next few years will be the emergence of disease-modifying thera- pies that will involve cocktails o f drugs designed to target diff er- ent aspects of the pathogenic cascade. Th is will inclu de standard drug therapies designed, for example, to upregulate autophagy (rapamycin) or in hibit excitotoxicity (memantine), as well as more innovative therapies such as gene-silenci ng approaches (87). Th e latter approach will involve delivering some form of interfering R NA against the mutant gene mRNA with the aim of silencing its eff ects, whilst ensuring tha t the expression of normal huntingtin (which is vital for normal cellular function) remains unaff ected. Th e main problem with this approach will be (a) ensuring that the iRNA silen ces only the mutant form, (b) that it can do this in all the relevant cell types in the CNS , (c) that it can do this for the lifetime of the patient, and (d) that it causes no side e ff ects by interfering with other RNAs. Th is is a tall order, but is becom- ing more feasi ble with evolving and improving gene delivery technologies. Key advances Th e major advances in HD in the last 20 years have been substantial and are l isted below. Identifi cation of the genetic basis of HD in 1993. Th is seminal international collaborati ve piece of research identifi ed the mutant gene in HD as a CAG expansion in exon 1 of the huntingtin gene. Th is discovery has had a number of major implications: (a) patients can n ow be diagnosed with certainty; (b) patients at risk of the disease can now be tested to se e if they are gene carriers, which has implications for their own future as well as family plan- ning; (c) where relevant, in vitro fertilization can be performed with selection of n on-aff ected embryos; (d) transgenic models of HD have been developed which have revealed u nique pathologi- cal and pathogenic insights into the disease (see above) as well as provid ing a model by which to test for novel disease-modifying agents. Th is has shown that the r oute to cell death in HD follows many diff erent pathways and involves cells other than neu rons. \227\206 Other novel therapeutic approaches include the use of growth factors to help rescue dysfunc tional cells, of which the most obvious candidate is BDNF, as this has been shown to be dow n- regulated in HD (88). This is likely to be delivered using a gene delivery system, altho ugh interestingly this growth factor is upregulated in the brain after exercise/environment al enrich- ment. Thus another approach could be through using pro- grammes of intense physi otherapy/enrichment in patients with HD (89). Th e development of cell-based therapies for treating HD is less clear cut, given some of t he recent data showing that transplants of fetal striatal tissue survive poorly in the long term in the HD brain (90, 91). Nevertheless cells may have some role to play, pos- sibly t hrough improved disease modeling in vitro using neurons derived from induced pluripotent st em (iPS) cells from patients with HD. Th is is important as it will help to dissect the pat ho- genic process and pathways that take place in cells carrying the mutant gene, so that l ogical cocktails of agents can be used to tar- get these relevant pathways, akin to what ha s been achieved in HIV therapeutics. Th e establishment of specialist clinics and integrated networks of HD research (Huntington Study Group in North America (http://www.huntington-study-group.org) and EURO-HD in Europe (http://www.euro-hd.net). Th is has ensured that patients are properly supported and treat ed, and that research into this rare condition is more integrated at an international level in terms of both a better understanding of the natural history of the disease and the deve lopment of drug trials. \227\206 Th e adoption and successful completion of a number of drug therapies in large numbers of p atients, including ethyl- eicosapentaenoic acid (negative outcome) (84), pridopidine (possi bly some benefi ts) (85), and latrepirdine (negative out- come aft er initial positive smal l trial) (86). Th is work has laid the foundation for conducting more trials with possible disease-modifying therapies, which are emerging from a number of laboratories using transge nic models of HD. \227\206 Th e use of these new therapeutics will require the development of better biomarkers with w hich one can follow disease progres- sion at a pathogenic level. Th is may necessitate a co mbination of measures including imaging (MRI and PET), wet biomarkers (blood and possibly C SF samples subject to -omics analysis (like transcriptomics, proteomics, etc.), and more ob jective clinical measures (92). Th ese are likely to become more evident as longi- tudinal data emerge from ongoing studies. Th e recognition that HD has problems outside the classical area of disorders of movement, cognition, and aff ect. It is now clear that HD patients have problems with sleep and metab olism. Attention to these features of the illness may be important, as many of these proble ms signifi cantly aff ect quality of life for the patients and their carers/families. \227\206 Finally, the identifi cation of genetic and environmental modifi ers of disease will be imp ortant in establishing how we can better alter the disease course as well as informing us a bout how individual patients are likely to progress over time. Oxford Textbook of Movement Disorders 220 Conclusion Since the gene for HD was identifi ed in 1993, great progress has been made in b etter modeling this disorder and understanding its pathogenic basis. Th is has generated a large number of candidate therapies that are now starting to enter the clinic. Moreover, th e necessary international infrastructure is now being developed to allow clinical trials to be performed more easily. However, these trials are hampered by problems of disease hetero geneity and the absence of robust and easy to use biomarkers that accurately mirror disease pathogenesis and progression. 5. Masuda N, Goto J, Murayama N, Watanabe M, Kondo I, Kanazawa I. Analysis of triplet repea ts in the huntingtin gene in Japanese families affected with Huntington \200\231s disease. J Med Genet 1995; 32 : 701 \200\2235 . 6. Wexler NS, Lorimer J, Porter J, et al. Venezuelan kindreds reveal that genetic and envir onmental factors modulate Huntington \200\231s disease age of onset. Proc Natl Acad Sci USA 2004; 101 : 3498 \200\223503 . 7. Spinney L. Uncovering the true prevalence of Huntington \200\231s disease. Lancet Neurol 2010; 9 : 760 \200\2231 . 8. Morrison PJ. Accurate prevalence and uptake of testing for Huntington \200\231s disease. Lancet Neurol 2010; 9 : 1147 . 9. Magazi DS, Krause A, Bonev V, et al. Huntington \200\231s disease: genetic heterogeneity in black African patients. S Afr Med J 2008; 98 : 200 \200\2233 . Nevertheless the management of HD has been transformed over the last 10 years by the widesp read adoption of specialist clinics that are now being linked up into large international n etworks. Th is ensures that all patients are assessed equally using similar tools, which en ables good natural history data to be collected whilst also facilitating drug trials. Th e latter include those designed to address best symptomatic therapies as well as those more c oncerned with disease modifi cation. 10. Margolis RL, Holmes SE, Rosenblatt A, et al. Huntington \200\231s Disease-like 2 (HDL2) in North America and Japan. Ann Neurol 2004; 56 : 670 \200\2234 . 11. Huntington \200\231s Disease Collaborative Research Group. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington \200\231s disease chromosomes. Cell 1993; 72 : 971 \200\22383 . 12. Rubinsztein DC, Leggo J, Coles R, et al. Phenotypic characterization of individuals wit h 30 \200\22340 CAG repeats in the Huntington disease (HD) gene reveals HD cases with 36 re peats and apparently normal elderly individuals with 36 \200\22339 repeats. Am J Hum Genet 59 : 16 \200\22322 . All of this sets the stage for the next phase of HD therapeutics which, it is hoped, will s tart to make inroads into disease modifi - cation by slowing down the progression of this d isorder. Indeed, simply slowing the disease down by 50% would make a huge dif- ference, giv en the average age at which it presents and that it typi- cally progresses over a 20-year p eriod. Th is knowledge may also encourage more at-risk patients to come to clinic, because the landscape of HD is changing every year. What we will be doing in 10 years \200\231 time may be very diff erent from what we do now, with most patients in trials of combinations o f drugs designed to slow the disease down. 13. Brinkman RR, Mezei MM, Th eilmann J, Almqvist E, Hayden MR. Th e likelihood of being af f ected with Huntington disease by a particular age, for a specifi c CAG size. Am J Hum Gen et 1997; 60 : 1202 \200\22310 . 14. Read AP. Huntington \200\231s disease: testing the test. Nat Genet 1993; 4 : 329 \200 \22330 . 15. Wexler NS, Young AB, Tanzi RE, et al. Homozygotes for Huntington \200\231s disease. Nature 1987; 326 : 194 \200\2237 . 16. Squitieri F, Gellera C, Cannella M, et al. Homozygosity for CAG muta- tion in Huntingto n disease is associated with a more severe clinical course. Brain 2003; 126 : 946 \200\2235 5 . 17. Aziz NA, Jurgens CK, Landwehrmeyer GB, et al. Normal and mutant HTT interact to aff ect clinical severity and progression in Huntington disease. Neurology 2009; 73 : 1280 \200 \2235 . Top clinical tips 18. Ranen NG, Stine OC, Abbott MH, et al. Anticipation and instability of IT-15 (CAG)N repe ats in parent \200\223off spring pairs with Huntington dis- ease. Am J Hum Genet 1995; 57 : 593 \200\223602 . HD is best managed in specialist clinics. \227\206 Diagnosing HD is straightforward but requires clinical genetics input early in the diagnost ic process. \227\206 19. Trottier Y, Biancalana V, Mandel J-L. Instability of CAG repeats in Huntington \200\231 s disease: relation to parental transmission and age of onset. J Med Genet 1994; 31 : 377 \200\22382 . Th e early features of HD are hard to defi ne but the partner report- ing abnormal movement s at night is helpful. \227\206 20. Warby SC, Montpetit A, Hayden AR, et al. CAG expansion in the Huntington disease gene i s associated with a specifi c and targetable pre- disposing haplogroup. Am J Hum Genet 2009 ; 84 : 351 \200\22366 . Th e best way to pick up early chorea is to watch the fi ngers when the patient is walking, or to listen whilst the patient does repeti- tive hand tapping and to watch the legs/feet for chorea when they are performing this test. \227\206 21. Semaka A, Collins JA, Hayden MR. Unstable familial transmissions of Huntington disease alleles with 27 \200\22335 CAG repeats (intermediate alle- les). Am J Med Genet 2010; 153B : 314 \200\22320 . 22. Rosenblatt A, Brinkman RR, Liang KY, et al. Familial infl uence on age of onset among s iblings with Huntington disease. Am J Med Genet 2001; 105 : 399 \200\223403 . Th e best fi rst-line therapy for HD is oft en olanzapine, tiapride, or tetrabenazine. \227\206 23. Norremolle A, Hasholt L, Petersen CB, et al. Mosaicism of the CAG repeat sequence in th e Huntington disease gene in a pair of monozygotic twins. Am J Med Genet 2004; 130A : 154 \200\2239 . Planning for the future is useful, and it should be ensured that all patients have equal ac cess to research/clinical trials. \227\206 24. Panas M, Karadima G, Markianos M, Kalfakis N, Vassilopoulos D. Phenotypic discordance i n a pair of monozygotic twins with Huntington \200\231s disease. Clin Genet 2008; 74 : 291 \200\2232 . References 1. Ramos-Arroyo MA, Moreno S, Valiente A. Incidence and mutation rates of Huntin gton \200\231s disease in Spain: experience of 9 years of direct genetic testing. J Neurol Neurosurg Psychiatry 2005; 76 : 337 \200\22342 . 25. Andresen JM, Gayan J, Cherny SS, et al. Replication of twelve association studies for H untington \200\231s disease residual age of onset in large Venezuelan kindreds. J Med Genet 2007; 44 : 44 \200\22350 . 2. Kokmen E, Ozekmek i FS, Beard CM, O \200\231Brien PC, Kurland LT. Incidence and preva lence of Huntington \200\231s disease in Olmsted County, Minnesota (1950 through 1989). Arc h Neurol 1994; 51 : 696 \200\2238 . 26. Metzger S, et al. Huntingtin-associated protein-1 is a modifi er of the age-at-onset of Huntington \200\231s disease. Hum Mol Genet 2008; 17 : 1137 \200\22346 . 3. Morrison PJ, Johnston WP, Nevin NC. Th e epidemiology of Huntington \200\231s disease in Northern Ireland. J Med Genet 1995; 32 : 524 \200\22330 . 27. Tartari M, Gissi C, Lo Sardo V, et al. Phylogenetic comparison of hunt- ingtin homologu es reveals the appearance of a primitive polyQ in sea urchin. Mol Biol Evol 2008; 25 : 330 \200\2238 . 4. Palo J, Somer H, Ikonen E, Karila L, Peltonen L. Low prevalence of Huntington \200\231s disease in Finland. Lancet 1987; 330 : 805 \200\2236 . CHAPTER 20 Huntington \200\231s Disease 221 50. Cowan CM, Fan MM, Fan J, et al. Polyglutamine-modulated striatal calpain activity in YA C transgenic huntington disease mouse model: impact on NMDA receptor function and toxicity. J Neurosci 2008; 28 : 12 725 \200\22335 . 28. Duyao MP, Auerbach AB, Ryan A, et al. Inactivation of the mouse Huntington \200\231s di sease gene homolog HdH. Science 1995; 269 : 407 \200\22310 . 29. Auerbach W, Hurlbert MS, H ilditch-Maguire P, et al. Th e HD mutation causes progressive lethal neurological disease i n mice expressing reduced levels of huntingtin. Hum Mol Genet 2001; 10 : 2515 \200\22323 . 51. Sun Y, Savanenin A, Reddy PH, Liu YF. Polyglutamine-expanded hunt- ingtin promotes sens itization of N -methyl- d -aspartate receptors via post-synaptic density 95. J Biol Chem 20 01; 276 : 24 713 \200\22318 . 30. Leavitt BR, van Raamsdonk JM, Shehadeh J, et al. Wild-type huntingtin protects neurons from excitotoxicity. J Neurochem 2006; 96 : 1121 \200\2239 . 31. Zuccato C, Ciammola A, Rig amonti D, et al. Loss of huntingtin-mediated BDNF gene transcription in Huntington \200\231 s disease. Science 2001; 293 : 493 \200\2238 . 32. Trushina E, Dyer RB, Badger JD, et al. M utant huntingtin impairs axonal traffi cking in mammalian neurons in vivo and in vitro . Mo l Cell Biol 2004; 24 : 8195 \200\223209 . 52. Bl zquez C, Chiarlone A,Sagredo O, et al. Loss of striatal type 1 cannabi- noid rece ptors is a key pathogenic factor in Huntington \200\231s disease. Brain 2011; 134 : 119 \200\22336 . 53. Cummings DM, Milnerwood AJ, Dall rac GM, et al. Aberrant cortical synaptic plasticit y and dopaminergic dysfunction in a mouse model of Huntington \200\231s disease. Hum Mol Ge net 2006; 15 : 2856 \200\22368 . 33. Th ompson LM, Aiken CT, Kaltenbach LS, et al. IKK phosphorylates huntingtin and targets it for degradation by the proteasome and lyso- some. J Cell Biol 2009; 187 : 1083 \200\223 99 . 54. Tang TS, Tu H, Chan EY, et al. Huntingtin and huntingtin-associated protein 1 infl uenc e neuronal calcium signaling mediated by inositol- (1,4,5) triphosphate receptor type 1. Ne uron 2003; 39 : 227 \200\22339 . 34. Jeong H, Th en F, Melia TJ, Jr, et al. Acetylation targets mutant huntingtin 55. Panov AV, Gutekunst CA, Leavitt BR, et al. Early mitochondrial calcium defects in Hunti ngton \200\231s disease are a direct eff ect of polyglutamines. Nat Neurosci 2002; 5 : 731 \200\2236 . to autophagosomes for degradation. Cell 2009; 137 : 60 \200\22372 . 35. Graham RK, Deng Y, Slow EJ, et al. Cleavage at the caspase-6 site is required for neuro nal dysfunction and degeneration due to mutant huntingtin. Cell 2006; 125 : 1179 \200\22391 . 56. Cui L, Jeong H, Borovecki F, Parkhurst CN, Tanese N, Krainc D. Transcriptional repressi on of PGC-1alpha by mutant huntingtin leads to mitochondrial dysfunction and neurodegenerat ion. Cell 2006; 127 : 59 \200\22369 . 36. DiFiglia M, Sapp E, Chase KO, et al. Aggregation of huntingtin in neuro- nal intranucle ar inclusions and dystrophic neurites in the brain. Science 1997; 277 : 1990 \200\2233 . 57. Bae BI, Xu H, Igarashi S, et al. p53 mediates cellular dysfunction and behav- ioral abn ormalities in Huntington \200\231s disease. Neuron 2005; 47 : 29 \200\22341 . 58. Pavese N, Gerhard A, Tai YF, et al. Microglial activation correlates with severity in Huntington dis ease: a clinical and PET study. Neurology 2006; 66 : 1638 \200\22343 . 37. Martindale D, Hackam A, et al. Length of huntingtin and its poly- glutamine tract infl uences localization and frequency of intracellular aggregates. Nat Genet 1998; 18 : 150 \200\2234 . 38. Scherzinger E, Sittler A, Schweiger K, et al. Self-assembly of polyglutamine-containing huntingtin fragments into amyloid-like fi brils: implications for Huntington \200\231s disease pathology. Proc Natl Acad Sci USA 1999; 96 : 4604 \200\2239 . 59. Bj rkqvist M, Wild EJ, Th iele J, et al. A novel pathogenic pathway of immune activa tion detectable before clinical onset in Huntington \200\231s dis- ease. J Exp Med 2008; 20 5 : 1869 \200\22377 . 39. Tydlacka S, Wang CE, Wang X, Li S, Li XJ. Diff erential activities of the ubiquitin-pro teasome system in neurons versus glia may account for the preferential accumulation of misf olded proteins in neurons. 2008; 28 : 13 285 \200\22395 . 60. Zwilling D, Huang SY, Sathyasaikumar KV, et al. Kynurenine 3-monooxygenase inhibition in blood ameliorates neurodegeneration. Cell 2011; 14 5 : 863 \200\22374 . 61. Vonsattel JP, Myers RH, Stevens TJ, et al. Neuropathological classifi cation of Hunting ton \200\231s disease. J Neuropathol Exp Neurol 1985; 44 : 559 \200\22377 . 62. Rosas HD, S alat DH, Lee SY, et al. Cerebral cortex and the clinical expres- sion of Huntington \200 \231s disease: complexity and heterogeneity. Brain 2008; 131 : 1057 \200\22368 . 40. Bodner RA, Outeiro TF, Altmann S, et al. Pharmacological promotion of inclusion formati on: a therapeutic approach for Huntington \200\231s and Parkinson \200\231s diseases. Proc Natl Acad Sci USA 2006; 103 : 4246 \200\22351 . 41. Ravikumar B, Vacher C, Berger Z, et al. Inhibition of mTOR induces autophagy and reduce s toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat G enet 2004; 36 : 585 \200\22395 . 63. Tabrizi SJ, Scahill RI, Durr A, et al. Biological and clinical changes in pre- manifest and early stage Huntington \200\231s disease in the TRACK-HD study: the 12-month longitudi nal analysis. Lancet Neurol 2011; 10 : 31 \200\22342 . 64. Vonsattel JP, DiFiglia M. Huntin gton disease . J Neuropathol Exp Neurol 42. Benn CL, Sun T, Sadri-Vakili G, et al. Huntingtin modulates transcrip- tion, occupies g ene promoters in vivo, and binds directly to DNA in a polyglutamine-dependent manner. J Neu rosci 2008; 28 : 10 720 \200\22333 . 43. Zhai W, Jeong H, Cui L, Krainc D, Tjian R. In vitr o analysis of huntingtin-mediated transcriptional repression reveals multiple tran- scripti on factor targets. Cell 2005; 123 : 1241 \200\22353 . 1998; 57 : 369 \200\22384 . 65. Bates G, Harper P, Jones L. Huntington \200\231s disease (3rd edn). Oxford: Oxford University Press, 2002. 66. Quarrell OWJ, Brewer HM, Squitieri F, Barker RA, Nance MA, Landwehrmeyer GB (eds). Juve nile Huntington \200\231s disease and other trinu- cleotide repeat disorders. Oxford : Oxfo rd University Press , 2009. 44. Nucifora FC, Jr, Sasaki M, Peters MF, et al. Interference by huntingtin and atrophin-1 with cbp-mediated transcription leading to cellular tox- icity. Science 2001; 291 : 2423 \200\2238 . 67. Ho AK, Sahakian BJ, Brown RG, et al. Profi le of cognitive progression in early Huntington \200\231s disease. Neurology 2003; 61 : 1702 \200\2236 . 45. Valenza M, Rigamonti D, Goff redo D, et al. Dysfunction of the choles- terol biosynthet ic pathway in Huntington \200\231s disease. J Neurosci 2005; 25 : 9932 \200\2239 . 68. Mason SL, Wijeyekoon R, Swain R, et al. Cognitive follow up of a small cohort of Huntin gton \200\231s disease patients over a 5 year period. PLoS Curr 2010; 2 : RRN1174. 46. Zuccato C, Tartari M, Crotti A, et al. Huntingtin interacts with REST/ NRSF to modulate the transcription of NRSE-controlled neuronal genes . Nat Genet 2003; 35 : 76 \200\22383 . 69. van Duijn E, Kingma EM, van der Mast RC. Psychopathology in verifi ed Huntington \200 \231s disease gene carriers. J Neuropsychiatry Clin Neurosci 2007; 19 : 441 \200\2238 . 47. Steff an JS, Bodai L, Palos J, et al. Histone deacetylase inhibitors arrest polyglutami ne-dependent neurodegeneration in Drosophila. Nature 2001; 413 : 739 \200\22343 . 70. Ross CA, Tabrizi SJ. Huntington \200\231s disease: from molecular pathogenesis to clinical treatment. Lancet Neurol 2011; 10 : 83 \200\22398 . 71. Fiedorowicz JG, Mills JA, Ruggle A, et al. Suicidal behavior in prodromal 48. Gauthier LR, Charrin BC, Borrell-Pag s M, et al. Huntingtin controls neurotrophic su pport and survival of neurons by enhancing BDNF vesicular transportation along microtubules . Cell 2004; 118 : 127 \200\22338 . Huntington disease. Neurodegener Dis 2011; 8 : 483 \200\22390 . 72. Bindler L, Travers D, Millet B. Suicide in Huntington \200\231s disease: a review. Rev Med Suisse 2009; 5 : 646 \200\2238 . 49. Shin JY, Fang ZH, Yu ZX, Wang CE, Li SH, Li XJ. Expression of mutant huntingtin in glia l cells contributes to neuronal excitotoxicity. J Cell Biol 2005; 171 : 1001 \200\22312 . 73. Ho AK, Robbins AO, Barker RA. Huntington \200\231s disease patients have selective problems with insight. Mov Disord 2006; 21 : 385 \200\2239 . Oxford Textbook of Movement Disorders 222 84. Huntington Study Group TREND-HD Investigators. Randomized con- trolled trial of ethyl-e icosapentaenoic acid in Huntington disease: the TREND-HD study. Arch Neurol 2008; 65 : 1582 \200\2239 . 74. Goodman AO, Rogers L, Pilsworth S, et al. Asymptomatic sleep abnor- malities are a comm on early feature in patients with Huntington \200\231s dis- ease. Curr Neurol Neurosci Rep 2011; 11 : 211 \200\22317 . 85. Lundin A, Dietrichs E, Haghighi S, et al. Effi cacy and safety of the dopaminergic stab ilizer pridopidine (ACR16) in patients with Huntington \200\231s disease. Clin Neuropharmac ol 2010; 33 : 260 \200\2234 . 75. Morton AJ, Wood NI, Hastings MH, Hurelbrink C, Barker RA, Maywood ES. Disintegration of the sleep \200\223wake cycle and circadian timing in Huntington \200\231s disease. J Neuro sci 2005; 25 : 157 \200\22363 . 86. Kieburtz K, McDermott MP, Voss TS, et al. A randomized, placebo- controlled trial of la trepirdine in Huntington disease. Arch Neurol 2010; 67 : 154 \200\22360 . 76. Goodman AO, Murgatroyd PR, Medina-Gomez G, et al. Th e metabolic profi le of early Hunt ington \200\231s disease \200\224a combined human and transgenic mouse study. Exp Neurol 20 08; 210 : 691 \200\2238 . 87. Sah DW, Aronin N. Oligonucleotide therapeutic approaches for 77. Tibben A. Predictive testing for Huntington \200\231s disease. Brain Res Bull Huntington disease. J Clin Invest 2011; 121 : 500 \200\2237 . 2007; 72 : 165 \200\22371 .