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Genetics of Huntington’s disease and related disorders Jean-Marc Burgunder1,2,3 1

Swiss Huntington’s Disease Centre, Department of Neurology, Department of Clinical Research, University of Bern, Switzerland Department of Neurology, West China Hospital, Sichuan University, Chengdu, China 3 Xiangya Hospital, Central South University, Changsha, Sun Yat Sen University, Guangzhou, China 2

Huntington’s disease is the most frequent form of the hereditary choreas and has a multifaceted phenotype including cognitive and psychiatric impairment. The disorder is due to a dynamic mutation, which also influences the onset age of the disorder. Other genetic modifiers of the HD phenotypes have been suggested but often not confirmed by independent studies. Several syndromes with similar presentation have different genetic backgrounds, including the neuroacanthocytoses, mainly choreoacanthocytosis and MacLeod syndrome as a result of mutations in chorein and Kell protein, respectively, but also benign hereditary chorea, owing to mutations in NKX-2-1, and paroxysmal kinesigenic dyskinesia, as a result of recently found mutations in the proline-rich transmembrane protein 2, PRRT2. Chorea can also be a major feature in other neurogenetic disorders, including the spinocerebellar ataxias and also in neurometabolic disorders. Introduction Chorea is a prominent feature of Huntington’s disease (HD), the most frequent cause of hereditary chorea; however the disease has a much more extended phenotype including cases with absent chorea at presentation. The gene involved in this disease was identified 20 years ago [1] and results on the search for genetic modifiers to explain the variable phenotype are being published. Our knowledge on the genetic background of other neurogenetic disorders, which can present with chorea, has also increased. This review presents a short summary of our present understanding of the genetic background of these disorders.

Huntington’s disease In a case of progressive cognitive and behavioural changes with hyperkinetic, choreatic involuntary movements starting at around 40 years old with a positive family history compatible with an autosomal dominant inheritance, the most probable diagnosis is HD. The mutation in the huntingtin (HTT; also named IT15) gene, located on chromosome 4p16, is an elongation of the CAG repeated element in exon 1 [1]. The age at onset is negatively E-mail address: [email protected].

correlated with the number of triplet repeats and this explains about 65% of its variance. However, this variability precludes the use of the number of triplet repeats to predict onset in the clinical setting. A large number of observations have allowed the delineation of the boundaries between normal and elevated triple-repeat numbers. The mean in normal subjects is around 17, and the range up to 27. People with HD have more than 36 repeats, but those with 36–39 have a less severe phenotype owing to a decreased penetrance of the mutation at these allele sizes. Repeat numbers can change from one to the next generation, explaining the frequent observation of a more severe phenotype in the next generations, the so-called anticipation effect. This is specifically relevant for carriers of triplet repeat numbers at the border of the above intervals, and people with alleles with 27–35 repeats could have children with higher repeat numbers now reaching the range associated with the disease [2]. Allelic instability with increase over generations has also been implicated in apparently sporadic cases. Such occurrences of HD in the absence of family history amount to about 8% of new cases [3]. Care must also be taken regarding laboratory quality control; indeed, in a comparison of several local laboratories with a single central one an analysis of the Registry Database collected by the European Huntington’s Disease Network

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GLOSSARY

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ADORA2A adenosine A2a receptor CO1 cytochrome c oxidase 1 DFFB DNA fragmentation factor, 40 kDa, beta polypeptide GluR6/GRIK2 glutamate receptor form A/glutamate receptor, ionotropic, kainate 2 GRIN2A glutamate receptor, ionotropic, N-methyl D-aspartate 2A GRIN2B glutamate receptor, ionotropic, N-methyl D-aspartate 2b HTT huntingtin JPH3 junctophilin-3 MAP3K5 mitogen-activated protein kinase kinase kinase 5 MAP2K6 mitogen-activated protein kinase kinase 6 NKX-2-1 NK2 homeobox 1 NRF1 nuclear respiratory factor 1 PGC1a peroxisome proliferator-activated receptor gamma, coactivator 1 alpha TCERG1 transcription elongation regulator 1 TFAM transcription factor A, mitochondrial TITF1 thyroid nuclear actor 1 TP53 tumor protein p53 XK X-linked Kx blood group

has demonstrated discrepancies, even some leading to a change in diagnostic category [4]. In a case with typical presentation with family history, at least among Caucasians, molecular diagnostic testing can be offered first line, avoiding additional costs of more-extensive investigations [5]. Of course this needs to be performed after thorough neurogenetic counselling, which should include the family. In a family with proven molecular diagnosis, carrier testing in presymptomatic cases might be offered during a careful, multidisciplinary, stepwise process during which the counselee’s autonomy and her right to know or not is consciously recognised. The quality of the information must be of a high level and is best provided by someone with first-hand, profound knowledge of the disease. It must be given in understandable words adapted to the counselee for them to be able to make their own knowledge-based decision. Risks of presymptomatic carrier testing include suicide and depression, and they are increased in people with a history of psychiatric symptoms and unemployed status; by contrast, established and previously successful coping strategies are associated with a lower risk [6,7]. To minimise the risk of negative outcome during the presymptomatic testing, recommendations have been drawn up and recently revised [2]. After an initial session, time is given for further reflection, followed by a second session during which the test is performed after informed consent. The consellee has the freedom to change his mind about knowing his genetic status, or not, until the opening of the result. Follow-up sessions to assess coping are of high importance. The percentage of people at risk who ask for presymptomatic genetic testing is generally low with, for example, 5–20% in the UK [8]. This figure might change because the prevalence of the disorder has a tendency to increase [9] and if there is more availability of disease-modifying strategies in the future. Presymptomatic testing of minors has usually been rejected, but it is important that they can have access to appropriate genetic counselling and support if they wish [10]. Prenatal testing can be 2

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performed after chorionic villus sampling between week 11 and 13. Preimplantation genetic diagnosis is allowed in certain countries and can be performed in a non-disclosure way, so that the parents would not know their own genetic status. Both need to be performed after thorough consideration of the ethical issues raised. Age of onset can vary widely and this is to be taken into consideration in the use of molecular genetic testing for the HTT gene and also for counselling and care management of the families [11]. In very early onset cases, a completely different phenotype linked to HTT gene mutation is found – closer to a developmental disorder [12]. Juvenile cases have a more akinetic phenotype than in adult cases to compare with other differential diagnoses. The probability of finding CAG in juvenile cases without family history is low [13], therefore testing in these patients should only be part of a comprehensive diagnostic investigation. By contrast, older people have a phenotype with mainly motor symptoms at onset, which can be undistinguishable from senile chorea. The diagnosis is often the first to be made in the family, associated dementia can be of the Alzheimer’s type and death is related to other diseases of old age [14]. Although intermediate triplet numbers between 27 and 35 are not associated with definitive and typical HD, 5% of them have increased apathy and suicidal ideation, whereas their motor, cognitive and other behavioural scores are in the normal range [15].

The search for genetic modifiers Other than the clear influence of the number of repeats in the longer allele on the age at onset, environmental or genetic reasons for HD phenotype variation are not well understood. Although the effect of the longer allele can already be seen in small groups of patients, larger numbers are needed to assess other aspects. In a cohort of more than 4000 patients the smaller allele had no effect on the age at onset, which is determined by the large allele in a fully dominant fashion [16]. Several studies have used a hypothesis-driven approach to search for other genetic modifiers in HD based on knowledge on molecular pathways. So far most of the studies have examined the association of single nucleotide polymorphisms (SNPs) with age of onset. However, age of onset is often difficult to establish and motor symptoms, which are fairly obvious, can wrongly be taken as the beginning of the phenotypic manifestation. Therefore, in Registry 3, the major study of the European Huntington’s Disease Network (EHDN), a more comprehensive catalogue of symptoms that are historically present is being used. This will allow specific assessment of age at onset of different symptoms, which could be associated differentially with particular SNPs. So far, almost 30 studies have examined the association of SNPs with age at onset. They have studied genes coding proteins interacting with HTT (e.g. TCERG1 and HAP1) or involved in neurotransmission (GluR6/ GRIK2, GRIN2A, GRIN2B, ADORA2A), in energy metabolism (PGC1a, CO1, NRF1 and TFAM), in stress response (MAP3K5, MAP2K6, DFFB and TP53) or in other processes [17]. Some of the findings have been further explored in replication studies, and only a few of them have been confirmed. For example association of GRIN2A and GRIN2B could not be replicated in a recent study [18]. Only a few genome-wide associations studies have been performed so far. A replication study confirmed only one of the loci

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[19]. In a replication study by the same group using a new patient cohort, only one of them could be replicated [20]. Four loci have been found in the large Venezuelan kindreds studied during the HTT gene search analysed using a 5858-SNP panel [21]. Some genes of interest, according to the pathways they are involved in, have been found but the data need to be replicated. An important aspect in such studies is the number of cases. Some of the published ones lack power owing to the small number of cases included. This should now be overcome owing to the inclusion of large numbers of cases in HD registries including Registry 3 of the EHDN and the recently launched, (CHDI: combat huntington’s disease initiative)-sponsored global study: EnrollHD. It is hoped that these large cohorts with deep phenotyping data will also enable searching for associations with other aspects of the phenotype.

expansion in the variably spliced exon following exon 1 of the junctophilin-3 (JPH3) gene [27]. Accumulation of the abnormal mRNA and protein as well as loss-of-function is the mechanism involved in neurodegeneration. MLS is X-linked with males presenting with neurological symptoms and signs in their fourth decade. They are often associated with cardiomyopathy, which can have fatal consequences. Female mutation carriers are rarely clinically affected, usually with a less severe phenotype. The XK protein mutated in MLS and linked to the Kell protein in erythrocytes has a membrane location suggesting transport functions. The fact that this complex expresses Kell blood group antigens allows diagnosis by their immunological investigation. However, negative immunological marking does not rule out MLS, which can be further investigated by molecular genetic techniques [25].

Molecular pathogenesis

Benign hereditary chorea

The Htt CAG repeat is translated into a poly glutamine domain, and this is associated with accumulation of an abnormal protein, which can impair cell function and lead to neuronal loss. However, the protein has several cellular functions, specifically in striatal spiny neurons, and they are disturbed by the mutated protein at different levels and within a large number of pathway [22]. These functions include regulation of gene transcription, protein trafficking and autophagy, regulation of cellular energy metabolism and mitochondrial function, modulation of dynamic axonal transport mechanisms through interactions with microtubules, endocytic and vesicular trafficking at the presynaptic sites and modulation of postsynaptic signalling mechanisms. These pathways have all been extensively studied and are now opening up avenues to explore novel treatments.

Benign hereditary chorea is a rare hereditary disorder with early onset chorea and hypotonia with delayed walking ability [28]. Other abnormal movement might be associated, including dystonia and motor tics. The course is nonprogressing and in about onethird of cases an improvement in chorea has been described. Earlier descriptions had pointed to the absence of major cognitive or psychiatric troubles. However, after the discovery of the gene and the description of larger, more homogenous series, several neuropsychiatric features have been recognised. They include attention deficit and hyperactivity as well as learning difficulties. The phenotype is sometime more generalised with hypothyroidism and lung disease. Mutations in the NKX-2-1 (previously called TITF1) gene [29] are found in some but not all families. Most mutations are private ones, which renders the molecular genetic confirmation of diagnosis and genetic counselling more difficult.

Neuroacanthocytosis Several rare genetic conditions are included under the term of neuroacanthocytosis (NA), encompassing disorders with acanthocytosis (i.e. a deformity of erythrocytes with spike-like protrusions, which is not found in absolutely all cases) and movement disorders. The major disorders are chorea-acanthocytosis (ChAC) [23], Huntington’s-disease-like 2 (HDL2) [23] and McLeod syndrome (MLS) [24]. Major additional features in MLS and ChAC include seizures, cognitive and behavioural symptoms and signs, and a neuromuscular involvement. Abnormal laboratory findings include elevated levels of creatine kinase and liver enzymes. ChAC is an autosomal recessive disorder with age onset in the 20s. Besides chorea and feeding dystonia, typical symptoms include tongue protrusion and mutilation of tongue and lips resulting in malnutrition. Mutations are located in chorein, a member of the vacuolar protein sorting (VPS)13 family of proteins, and mutations are found all over the gene, including missense, frameshift, nonsense, splice site and deletions and duplication, but diagnosis can be made more easily by assessing chorein expression on a Western blot of protein extracted from erythrocytes [25]. HDL2 is an autosomal dominant disorder with a phenotype similar to HD found in people from black African ancestry. Acanthocytes are found in about 10% of affected people but, unlike in ChAC and MLS, they do not have seizures or neuromuscular manifestations [26]. The mutation is a CTG/CAG repeat

Paroxysmal kinesigenic dyskinesia Several names had been used in the past for the autosomal dominant disorder now called paroxysmal kinesigenic dystonia, including paroxysmal kinesigenic choreathetosis, epidodic kinesigenic dyskinesia type 1 (EKD1), dystonia familial paroxysmal (DFP) and dystonia type 10 (DYT10). Sudden movements typically induce unilateral or bilateral attacks of chorea, sometimes associated with dystonia, ballism and/or myoclonus, which last for a couple of seconds. Sometimes patients also suffer from epileptic seizures and symptoms respond well to carbamazepine treatment. The disorder is rare, but has been reported more often in China than in the West. Linkage was reported in 2000 [30], but a long search was needed until this locus was confirmed in Chinese families [31] and the gene recently confirmed [32,33]. Several mutations in prolinerich transmembrane protein 2 (PRRT2) have been reported, and some are associated disorders including benign familial infantile convulsions (BFIC) and infantile convulsion and choreathetosis (ICCA).

Other disorders Huntington-like disorders were discovered after families with HD were found not to have the CAG triplet repeat expansions in the Htt gene. The first was in a single family with autosomal-dominant inheritance and the cause is an octapeptide repetition in the prion gene [34]. However, other cases with the same mutation turned www.drugdiscoverytoday.com

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out to have a variable phenotype, highlighting the problems associated with such a nomenclature [35]. HDL3 was found in one family and HDL4 turned out to be to a variation of spinocerebellar ataxia Type 17 (SCA17) [35,36]. Other spinocerebellar ataxias can have a predominant choreatic presentation rather than ataxia, they include SCA3, most commonly found in many ethnic backgrounds, and also SCA1 [37], SCA2 [38] and SCA8 [39]. Dentatorubralpallidoluysian atrophy (DRPLA) is another triplet repeat disorder with chorea as a predominant feature, at least in cases with adult onset. It was first described in the Japanese population but is found in other populations as well [40]. Furthermore, several neurogenetic disorders can occur together in the same family, as has been described for hereditary spastic paraplegia (HSP) [41] and SCA8 [42]. Chorea is also a major feature of disorders with brain iron accumulation (NBIA) and pantothenate kinase-associated neurodegeneration (PKAN), caused by mutations in the PKAN2 gene [43] as the most frequent one. PKAN is an autosomal-recessive disorder typically with childhood chorea onset, together with dystonia, parkinsonism and spasticity [43]. Chorea with neuropsychiatric abnormalities can be found in several other disorders, specifically in neurometabolic disorders, for example in Lesch–Nyhan syndrome, an X-linked disorder caused by impaired hypoxanthine guanin phophoribosyl transferase activity. Chorea, together with other abnormal movements usually follows hypotonia,

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self-injuring behaviour and developmental delay in affected children [44]. Hypericemia is typically found and diagnosis is established by enzymatic testing. Usually, these disorders can be recognised and distinguished from neurodegenerative choreatic disorders by the clinical and laboratory phenotype.

Concluding remarks Molecular genetic investigations have recently led to the identification of the cause of a large number of hereditary choreatic disorders. There certainly remain some yet unexplained instances, but these could soon be uncovered owing to the newly developed and increasingly fast techniques. A more complex task will be to find the genetic cause for the phenotypic variation in these disorders. Furthermore, it is also hoped that the genetic background underlying the susceptibility to develop chorea after brain insults, including metabolic, toxic and pharmacological influence, will be understood better. All of this knowledge is needed to develop novel therapies and also strategies to influence the occurrence of chorea. Indeed, gene therapy strategies, for example leading to a decrease in the expression of the elongated HTT transcript and huntingtin protein, should be tested in the near future.

Conflicts of interest There is no conflict of interest.

References 1 (1993) The Huntington’s Disease Collaborative Research Group. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell 72, 971–983 2 Losekoot, M. et al. (2013) EMQN/CMGS best practice guidelines for the molecular genetic testing of Huntington disease. Eur. J. Hum. Genet. 21, 480–486 3 Ramos-Arroyo, M. et al. (2005) Incidence and mutation rates of Huntington’s disease in Spain: experience of 9 years of direct genetic testing. J. Neurol. Neurosurg. Psychiatry 76, 337–342 4 Quarrell, O.W. et al. (2012) Discrepancies in reporting the CAG repeat lengths for Huntington’s disease. Eur. J. Hum. Genet. 20, 20–26 5 Harbo, H.F. et al. (2009) EFNS guidelines on the molecular diagnosis of neurogenetic disorders: general issues, Huntington’s disease, Parkinson’s disease and dystonias. Eur. J. Neurol. 16, 777–785 6 Almqvist, E.W. et al. (1999) A worldwide assessment of the frequency of suicide, suicide attempts, or psychiatric hospitalization after predictive testing for Huntington disease. Am. J. Hum. Genet. 64, 1293–1304 7 Almqvist, E.W. et al. (2003) Psychological consequences and predictors of adverse events in the first 5 years after predictive testing for Huntington’s disease. Clin. Genet. 64, 300–309 8 Harper, P.S. et al. (2000) Ten years of presymptomatic testing for Huntington’s disease: the experience of the UK Huntington’s Disease Prediction Consortium. J. Med. Genet. 37, 567–571 9 Evans, S.J. et al. (2013) Prevalence of adult Huntington’s disease in the UK based on diagnoses recorded in general practice records. J. Neurol. Psychiatry Neurosurg. 84, 1156–1160 10 Macleod, R. et al. (2013) Recommendations for the predictive genetic test in Huntington’s disease. Clin. Genet. 83, 221–231 11 Burgunder, J.-M. (2013) Recent advances in the management of choreas. Ther. Adv. Neurol. Disord. 6, 117–127 12 Nicolas, G. et al. (2011) Juvenile Huntington disease in an 18-month-old boy revealed by global developmental delay and reduced cerebellar volume. Am. J. Med. Genet. A 155, 815–818 13 Koutsis, G. et al. (2013) The challenge of juvenile Huntington disease: to test or not to test. Neurology 80, 990–996 14 Lipe, H. and Bird, T. (2009) Late onset Huntington disease: clinical and genetic characteristics of 34 cases. J. Neurol. Sci. 276, 159–162

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15 Killoran, A. et al. (2013) Characterization of the Huntington intermediate CAG repeat expansion phenotype in PHAROS. Neurology 80, 2022–2027 16 Lee, J.M. et al. (2012) CAG repeat expansion in Huntington disease determines age at onset in a fully dominant fashion. Neurology 78, 690–695 17 Arning, L. and Epplen, J.T. (2012) Genetic modifiers of Huntington’s disease. Future Neurol. 7, 93–109 18 Ramos, E.M. et al. (2013) Candidate glutamatergic and dopaminergic pathway gene variants do not influence Huntington’s disease motor onset. Neurogenetics 14, 173–179 19 Li, J.L. et al. (2003) A genome scan for modifiers of age at onset in Huntington disease: the HD MAPS study. Am. J. Hum. Genet. 73, 682–687 20 Li, J.L. et al. (2006) Genome-wide significance for a modifier of age at neurological onset in Huntington’s disease at 6q23–24: the HD MAPS study. BMC Med. Genet. 7, 71 21 Gayan, J. et al. (2008) Genomewide linkage scan reveals novel loci modifying age of onset of Huntington’s disease in the Venezuelan HD kindreds. Genet. Epidemiol. 32, 445–453 22 Munoz-Sanjuan, I. and Bates, G.P. (2011) The importance of integrating basic and clinical research toward the development of new therapies for Huntington disease. J. Clin. Invest. 121, 476–483 23 Walker, R.H. et al. (2007) Neurologic phenotypes associated with acanthocytosis. Neurology 68, 92–98 24 Hewer, E. et al. (2007) McLeod myopathy revisited: more neurogenic and less benign. Brain 130, 3285–3296 25 Pagon, R. et al. (1993) GeneReviews. University of Washington, Seattle, WA [Internet] 26 Jung, H.H. et al. (2011) Neuroacanthocytosis syndromes. Orphanet. J. Rare Dis. 6, 68 27 Holmes, S.E. et al. (2001) A repeat expansion in the gene encoding junctophilin-3 is associated with Huntington disease-like 2. Nat. Genet. 29, 377–378 28 Mahajnah, M. et al. (2007) Benign hereditary chorea: clinical, neuroimaging, and genetic findings. J. Child Neurol. 22, 1231–1234 29 Breedveld, G.J. et al. (2002) Mutations in TITF-1 are associated with benign hereditary chorea. Hum. Mol. Genet. 11, 971–979 30 Valente, E.M. et al. (2000) A second paroxysmal kinesigenic choreoathetosis locus (EKD2) mapping on 16q13-q22.1 indicates a family of genes which give rise to paroxysmal disorders on human chromosome 16. Brain 123, 2040–2045

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31 Wang, X. et al. (2010) Paroxysmal kinesigenic choreoathetosis: evidence of linkage to the pericentromeric region of chromosome 16 in four Chinese families. Eur. J. Neurol. 17, 800–807 32 Chen, W.J. et al. (2011) Exome sequencing identifies truncating mutations in PRRT2 that cause paroxysmal kinesigenic dyskinesia. Nat. Genet. 43, 1252–1255 33 Wang, J.L. et al. (2011) Identification of PRRT2 as the causative gene of paroxysmal kinesigenic dyskinesias. Brain 134, 3493–3501 34 Moore, R.C. et al. (2001) Huntington disease phenocopy is a familial prion disease. Am. J. Hum. Genet. 69, 1385–1388 35 Walker, R.H. (2012) Update on the non-Huntington’s disease choreas with comments on the current nomenclature. Tremor Other Hyperkinet. Mov. (N. Y.) 2 pii: tre-02-49-211-1 36 Wild, E.J. et al. (2008) Huntington’s disease phenocopies are clinically and genetically heterogeneous. Mov. Disord. 23, 716–720 37 Namekawa, M. et al. (2001) Choreiform movements in spinocerebellar ataxia type 1. J. Neurol. Sci. 187, 103–106

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38 Geschwind, D.H. et al. (1997) The prevalence and wide clinical spectrum of the spinocerebellar ataxia type 2 trinucleotide repeat in patients with autosomal dominant cerebellar ataxia. Am. J. Hum. Genet. 60, 842–850 39 Koutsis, G. et al. (2012) Genetic screening of Greek patients with Huntington’s disease phenocopies identifies an SCA8 expansion. J. Neurol. 259, 1874–1878 40 Wardle, M. et al. (2008) Dentatorubral pallidoluysian atrophy in South Wales. J. Neurol. Neurosurg. Psychiatry 79, 804–807 41 Panas, M. et al. (2011) Co-segregation of Huntington disease and hereditary spastic paraplegia in 4 generations. Neurologist 17, 211–212 42 Roxburgh, R.H. et al. (2013) The unique co-occurrence of spinocerebellar ataxia type 10 (SCA10) and Huntington disease. J. Neurol. Sci. 324, 176–178 43 Zhou, B. et al. (2001) A novel pantothenate kinase gene (PANK2) is defective in Hallervorden-Spatz syndrome. Nat. Genet. 28, 345–349 44 Torres, R.J. et al. (2012) Update on the phenotypic spectrum of Lesch-Nyhan disease and its attenuated variants. Curr. Rheumatol. Rep. 14, 189–194

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Drug Discovery Today  Volume 00, Number 00  April 2014

Genetics of Huntington's disease and related disorders.

Huntington's disease is the most frequent form of the hereditary choreas and has a multifaceted phenotype including cognitive and psychiatric impairme...
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