Recent approaches on Huntington's disease (Review)

Palaiogeorgou,Anastasia Marina; Papakonstantinou,Eleni; Golfinopoulou,Rebecca; Sigala,Markezina; Mitsis,Thanasis; Papageorgiou,Louis; Diakou,Io; Pierouli,Katerina; Dragoumani,Konstantina; Spandidos,Demetrios A.; Bacopoulou,Flora; Chrousos,George P.; Eliopoulos,Elias; Vlachakis,Dimitrios

doi:10.3892/br.2022.1587

Recent approaches on Huntington's disease (Review)

Authors:
- Anastasia Marina Palaiogeorgou
- Eleni Papakonstantinou
- Rebecca Golfinopoulou
- Markezina Sigala
- Thanasis Mitsis
- Louis Papageorgiou
- Io Diakou
- Katerina Pierouli
- Konstantina Dragoumani
- Demetrios A. Spandidos
- Flora Bacopoulou
- George P. Chrousos
- Elias Eliopoulos
- Dimitrios Vlachakis
View Affiliations

Affiliations: Laboratory of Genetics, Department of Biotechnology, School of Applied Biology and Biotechnology, Agricultural University of Athens, 11855 Athens, Greece, Laboratory of Clinical Virology, School of Medicine, University of Crete, 71003 Heraklion, Greece, University Research Institute of Maternal and Child Health and Precision Medicine, and UNESCO Chair on Adolescent Health Care, National and Kapodistrian University of Athens, ‘Aghia Sophia’ Children's Hospital, 11527 Athens, Greece
Published online on: November 21, 2022 https://doi.org/10.3892/br.2022.1587
Article Number: 5
Copyright: © Palaiogeorgou et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Huntington's disease (HD) is a neurodegenerative disorder characterized by severe motor, cognitive and psychiatric symptoms. Patients of all ages can present with a dysfunction of the nervous system, which leads to the progressive loss of movement control and disabilities in speech, swallowing, communications, etc. The molecular basis of the disease is well‑known, as HD is related to a mutated gene, a trinucleotide expansion, which encodes to the huntingtin protein. This protein is linked to neurogenesis and the loss of its function leads to neurodegenerative disorders. Although the genetic cause of the disorder has been known for decades, no effective treatment is yet available to prevent onset or to eliminate the progression of symptoms. Thus, the present review focused on the development of novel methods for the timely and accurate diagnosis of HD in an aim to aid the development of therapies which may reduce the severity of the symptoms and control their progression. The majority of the therapies include gene‑silencing mechanisms of the mutated huntingtin gene aiming to suppress its expression, and the use of various substances as drugs with highly promising results. In the present review, the latest approaches on the diagnosis of HD are discussed along with the need for genetic counseling and an up‑to‑date presentation of the applied treatments.

View Figures

View References

1	Recabarren D and Alarcon M: Gene networks in neurodegenerative disorders. Life Sci. 183:83–97. 2017.PubMed/NCBI View Article : Google Scholar
2	Pihlstrøm L, Wiethoff S and Houlden H: Genetics of neurodegenerative diseases: An overview. Handb Clin Neurol. 145:309–323. 2017.PubMed/NCBI View Article : Google Scholar
3	Shen T, You Y, Joseph C, Mirzaei M, Klistorner A, Graham SL and Gupta V: BDNF polymorphism: A review of its diagnostic and clinical relevance in neurodegenerative disorders. Aging Dis. 9(523)2018.PubMed/NCBI View Article : Google Scholar
4	Guzman-Martinez L, Maccioni RB, Andrade V, Navarrete LP, Pastor MG and Ramos-Escobar N: Neuroinflammation as a common feature of neurodegenerative disorders. Front Pharmacol. 10(1008)2019.PubMed/NCBI View Article : Google Scholar
5	Ma MW, Wang J, Zhang Q, Wang R, Dhandapani KM, Vadlamudi RK and Brann DW: NADPH oxidase in brain injury and neurodegenerative disorders. Mol Neurodegener. 12(7)2017.PubMed/NCBI View Article : Google Scholar
6	Mendez MF: Early-onset Alzheimer disease and its variants. Continuum (Minneap Minn). 25:34–51. 2019.PubMed/NCBI View Article : Google Scholar
7	Bakels HS, Roos RAC, van Roon-Mom WMC and de Bot ST: Juvenile-Onset huntington disease pathophysiology and neurodevelopment: A review. Mov Disord. 37:16–24. 2022.PubMed/NCBI View Article : Google Scholar
8	Kumar A, Kumar V, Singh K, Kumar S, Kim YS, Lee YM and Kim JJ: Therapeutic advances for Huntington's disease. Brain Sci. 10(43)2020.PubMed/NCBI View Article : Google Scholar
9	Yanagisawa N: The spectrum of motor disorders in Huntington's disease. Clin Neurol Neurosurg. 94 (Suppl):S182–S184. 1992.PubMed/NCBI View Article : Google Scholar
10	Bonner-Jackson A, Long JD, Westervelt H, Tremont G, Aylward E and Paulsen JS: PREDICT-HD Investigators and Coordinators of the Huntington Study Group. Cognitive reserve and brain reserve in prodromal Huntington's disease. J Int Neuropsychol Soc. 19:739–750. 2013.PubMed/NCBI View Article : Google Scholar
11	Harrington DL, Liu D, Smith MM, Mills JA, Long JD, Aylward EH and Paulsen JS: Neuroanatomical correlates of cognitive functioning in prodromal Huntington disease. Brain Behav. 4:29–40. 2014.PubMed/NCBI View Article : Google Scholar
12	Epping EA, Mills JA, Beglinger LJ, Fiedorowicz JG, Craufurd D, Smith MM, Groves M, Bijanki KR, Downing N, Williams JK, et al: Characterization of depression in prodromal Huntington disease in the neurobiological predictors of HD (PREDICT-HD) study. J Psychiatr Res. 47:1423–1431. 2013.PubMed/NCBI View Article : Google Scholar
13	van Dijk JG, van der Velde EA, Roos RA and Bruyn GW: Juvenile huntington disease. Hum Genet. 73:235–239. 1986.PubMed/NCBI View Article : Google Scholar
14	Siesling S, Vegter-van der Vlis M and Roos RA: Juvenile Huntington disease in the Netherlands. Pediatr Neurol. 17:37–43. 1997.PubMed/NCBI View Article : Google Scholar
15	Wexler NS, Lorimer J, Porter J, Gomez F, Moskowitz C, Shackell E, Marder K, Penchaszadeh G, Roberts SA, Gayán J, et al: Venezuelan kindreds reveal that genetic and environmental factors modulate Huntington's disease age of onset. Proc Natl Acad Sci USA. 101:3498–3503. 2004.PubMed/NCBI View Article : Google Scholar
16	Quarrell OWJ, Brewer HM, Squitieri F, Barker R, Nance MA and Lanswehrmeyer BG: ‘Juvenile Huntington's Disease (and other trinucleotide repeat disorders)’. Oxford University Press, Oxford, 2009.
17	Gatto EM, Parisi V, Etcheverry JL, Sanguinetti A, Cordi L, Binelli A, Persi G and Squitieri F: Juvenile Huntington disease in Argentina. Arq Neuropsiquiatr. 74:50–54. 2016.PubMed/NCBI View Article : Google Scholar
18	Tereshchenko A, Magnotta V, Epping E, Mathews K, Espe-Pfeifer P, Martin E, Dawson J, Duan W and Nopoulos P: Brain structure in juvenile-onset Huntington disease. Neurology. 92:e1939–e1947. 2019.PubMed/NCBI View Article : Google Scholar
19	van der Plas E, Langbehn DR, Conrad AL, Koscik TR, Tereshchenko A, Epping EA, Magnotta VA and Nopoulos PC: Abnormal brain development in child and adolescent carriers of mutant huntingtin. Neurology. 93:e1021–e1030. 2019.PubMed/NCBI View Article : Google Scholar
20	Gusella JF, Wexler NS, Conneally PM, Naylor SL, Anderson MA, Tanzi RE, Watkins PC, Ottina K, Wallace MR, Sakaguchi AY, et al: A polymorphic DNA marker genetically linked to Huntington's disease. Nature. 306:234–238. 1983.PubMed/NCBI View Article : Google Scholar
21	A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. The Huntington's Disease Collaborative Research Group. Cell. 72:971–983. 1993.PubMed/NCBI View Article : Google Scholar
22	Saudou F and Humbert S: The biology of Huntingtin. Neuron. 89:910–926. 2016.PubMed/NCBI View Article : Google Scholar
23	Schultz JL, van der Plas E, Langbehn DR, Conrad AL and Nopoulos PC: Age-Related cognitive changes as a function of CAG repeat in child and adolescent carriers of mutant Huntingtin. Ann Neurol. 89:1036–1040. 2021.PubMed/NCBI View Article : Google Scholar
24	Andrew SE, Goldberg YP, Kremer B, Telenius H, Theilmann J, Adam S, Starr E, Squitieri F, Lin B, Kalchman MA, et al: The relationship between trinucleotide (CAG) repeat length and clinical features of Huntington's disease. Nat Genet. 4:398–403. 1993.PubMed/NCBI View Article : Google Scholar
25	Squitieri F and Jankovic J: Huntington's disease: How intermediate are intermediate repeat lengths? Mov Disord. 27:1714–1717. 2012.PubMed/NCBI View Article : Google Scholar
26	Ho LW, Brown R, Maxwell M, Wyttenbach A and Rubinsztein DC: Wild type Huntingtin reduces the cellular toxicity of mutant Huntingtin in mammalian cell models of Huntington's disease. J Med Genet. 38:450–452. 2001.PubMed/NCBI View Article : Google Scholar
27	Shirasaki DI, Greiner ER, Al-Ramahi I, Gray M, Boontheung P, Geschwind DH, Botas J, Coppola G, Horvath S, Loo JA and Yang XW: Network organization of the huntingtin proteomic interactome in mammalian brain. Neuron. 75:41–57. 2012.PubMed/NCBI View Article : Google Scholar
28	Nuzzo MT and Marino M: Estrogen/Huntingtin: A novel pathway involved in neuroprotection. Neural Regen Res. 11:402–403. 2016.PubMed/NCBI View Article : Google Scholar
29	Leavitt BR, van Raamsdonk JM, Shehadeh J, Fernandes H, Murphy Z, Graham RK, Wellington CL, Raymond LA and Hayden MR: Wild-type huntingtin protects neurons from excitotoxicity. J Neurochem. 96:1121–1129. 2006.PubMed/NCBI View Article : Google Scholar
30	Ismailoglu I, Chen Q, Popowski M, Yang L, Gross SS and Brivanlou AH: Huntingtin protein is essential for mitochondrial metabolism, bioenergetics and structure in murine embryonic stem cells. Dev Biol. 391:230–240. 2014.PubMed/NCBI View Article : Google Scholar
31	Guedes-Dias P, Pinho BR, Soares TR, de Proença J, Duchen MR and Oliveira JM: Mitochondrial dynamics and quality control in Huntington's disease. Neurobiol Dis. 90:51–57. 2016.PubMed/NCBI View Article : Google Scholar
32	Brustovetsky N: Mutant huntingtin and elusive defects in oxidative metabolism and mitochondrial calcium handling. Mol Neurobiol. 53:2944–2953. 2016.PubMed/NCBI View Article : Google Scholar
33	Grima JC, Daigle JG, Arbez N, Cunningham KC, Zhang K, Ochaba J, Geater C, Morozko E, Stocksdale J, Glatzer JC, et al: Mutant Huntingtin disrupts the nuclear pore complex. Neuron. 94:93–107.e6. 2017.PubMed/NCBI View Article : Google Scholar
34	Zeitlin S, Liu JP, Chapman DL, Papaioannou VE and Efstratiadis A: Increased apoptosis and early embryonic lethality in mice nullizygous for the Huntington's disease gene homologue. Nat Genet. 11:155–163. 1995.PubMed/NCBI View Article : Google Scholar
35	McKinstry SU, Karadeniz YB, Worthington AK, Hayrapetyan VY, Ozlu MI, Serafin-Molina K, Risher WC, Ustunkaya T, Dragatsis I, Zeitlin S, et al: Huntingtin is required for normal excitatory synapse development in cortical and striatal circuits. J Neurosci. 34:9455–9472. 2014.PubMed/NCBI View Article : Google Scholar
36	Mehler MF, Petronglo JR, Arteaga-Bracho EE, Gulinello ME, Winchester ML, Pichamoorthy N, Young SK, DeJesus CD, Ishtiaq H, Gokhan S and Molero AE: Loss-of-Huntingtin in medial and lateral ganglionic lineages differentially disrupts regional interneuron and projection neuron subtypes and promotes Huntington's disease-associated behavioral, cellular, and pathological Hallmarks. J Neurosci. 39:1892–1909. 2019.PubMed/NCBI View Article : Google Scholar
37	Jung R, Lee Y, Barker D, Correia K, Shin B, Loupe J, Collins RL, Lucente D, Ruliera J, Gillis T, et al: Mutations causing Lopes-Maciel-Rodan syndrome are huntingtin hypomorphs. Hum Mol Genet. 30:135–148. 2021.PubMed/NCBI View Article : Google Scholar
38	Lackie RE, Maciejewski A, Ostapchenko VG, Marques-Lopes J, Choy WY, Duennwald ML, Prado VF and Prado MAM: The Hsp70/Hsp90 chaperone machinery in neurodegenerative diseases. Front Neurosci. 11(254)2017.PubMed/NCBI View Article : Google Scholar
39	Qi L, Zhang XD, Wu JC, Lin F, Wang J, DiFiglia M and Qin ZH: The role of chaperone-mediated autophagy in huntingtin degradation. PLoS One. 7(e46834)2012.PubMed/NCBI View Article : Google Scholar
40	Keum JW, Shin A, Gillis T, Mysore JS, Abu Elneel K, Lucente D, Hadzi T, Holmans P, Jones L, Orth M, et al: The HTT CAG-Expansion mutation determines age at death but not disease duration in huntington disease. Am J Hum Genet. 98:287–298. 2016.PubMed/NCBI View Article : Google Scholar
41	Dulski J, Sulek A, Krygier M, Radziwonik W and Slawek J: False-negative tests in Huntington's disease: A new variant within primer hybridization site. Eur J Neurol. 28:2103–2105. 2021.PubMed/NCBI View Article : Google Scholar
42	De Luca A, Morella A, Consoli F, Fanelli S, Thibert JR, Statt S, Latham GJ and Squitieri F: A Novel Triplet-Primed PCR assay to detect the full range of trinucleotide CAG repeats in the huntingtin gene (HTT). Int J Mol Sci. 22(1689)2021.PubMed/NCBI View Article : Google Scholar
43	Langfelder P, Gao F, Wang N, Howland D, Kwak S, Vogt TF, Aaronson JS, Rosinski J, Coppola G, Horvath S and Yang XW: MicroRNA signatures of endogenous Huntingtin CAG repeat expansion in mice. PLoS One. 13(e0190550)2018.PubMed/NCBI View Article : Google Scholar
44	Reed ER, Latourelle JC, Bockholt JH, Bregu J, Smock J, Paulsen JS and Myers RH: PREDICT-HD CSF Ancillary Study Investigators. MicroRNAs in CSF as prodromal biomarkers for Huntington disease in the PREDICT-HD study. Neurology. 90:e264–e272. 2018.PubMed/NCBI View Article : Google Scholar
45	Glidden AM, Luebbe EA, Elson MJ, Goldenthal SB, Snyder CW, Zizzi CE, Dorsey ER and Heatwole CR: Patient-reported impact of symptoms in Huntington disease: PRISM-HD. Neurology. 94:e2045–e2053. 2020.PubMed/NCBI View Article : Google Scholar
46	Paulsen JS, Miller AC, Hayes T and Shaw E: Cognitive and behavioral changes in Huntington disease before diagnosis. Handb Clin Neurol. 144:69–91. 2017.PubMed/NCBI View Article : Google Scholar
47	Oosterloo M, de Greef BTA, Bijlsma EK, Durr A, Tabrizi SJ, Estevez-Fraga C, de Die-Smulders CEM and Roos RAC: Disease onset in Huntington's disease: When is the conversion? Mov Disord Clin Pract. 8:352–360. 2021.PubMed/NCBI View Article : Google Scholar
48	Squadrone S, Brizio P, Abete MC and Brusco A: Trace elements profile in the blood of Huntington' disease patients. J Trace Elem Med Biol. 57:18–20. 2020.PubMed/NCBI View Article : Google Scholar
49	Caron NS, Wright GEB and Hayden MR: Huntington Disease. 1998 Oct 23 (updated 2020 Jun 11). In: GeneReviews^® (Internet). Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Mirzaa G and Amemiya A (eds). University of Washington, Seattle, WA, 1993-2021.
50	Shoulson I and Young AB: Milestones in huntington disease. Mov Disord. 26:1127–1133. 2011.PubMed/NCBI View Article : Google Scholar
51	Pringsheim T, Wiltshire K, Day L, Dykeman J, Steeves T and Jette N: The incidence and prevalence of Huntington's disease: A systematic review and meta-analysis. Mov Disord. 27:1083–1091. 2012.PubMed/NCBI View Article : Google Scholar
52	Sobel SK and Cowan DB: Impact of genetic testing for Huntington disease on the family system. Am J Med Genet. 90:49–59. 2000.PubMed/NCBI View Article : Google Scholar
53	Migliore S, Jankovic J and Squitieri F: Genetic Counseling in Huntington's disease: Potential new challenges on Horizon? Front Neurol. 10(453)2019.PubMed/NCBI View Article : Google Scholar
54	MacLeod R, Metcalfe A and Ferrer-Duch M: A family systems approach to genetic counseling: Development of narrative inter-ventions. J Genet Couns. 30:22–29. 2021.PubMed/NCBI View Article : Google Scholar
55	Pierron L, Hennessy J, Tezenas du Montcel S, Coarelli G, Heinzmann A, Schaerer E, Herson A, Petit E, Gargiulo M and Durr A: Informing about genetic risk in families with Huntington disease: Comparison of attitudes across two decades. Eur J Hum Genet. 29:672–679. 2021.PubMed/NCBI View Article : Google Scholar
56	Barker RA, Fujimaki M, Rogers P and Rubinsztein DC: Huntingtin-lowering strategies for Huntington's disease. Expert Opin Investig Drugs. 29:1125–1132. 2020.PubMed/NCBI View Article : Google Scholar
57	Aziz NA, van der Burg JMM, Tabrizi SJ and Landwehrmeyer GB: Overlap between age-at-onset and disease-progression determinants in Huntington disease. Neurology. 90:e2099–e2106. 2018.PubMed/NCBI View Article : Google Scholar
58	Tabrizi SJ, Ghosh R and Leavitt BR: Huntingtin lowering strategies for disease modification in Huntington's disease,. Neuron. 101:801–819. 2019.PubMed/NCBI View Article : Google Scholar
59	Lane RM, Smith A, Baumann T, Gleichmann M, Norris D, Bennett CF and Kordasiewicz H: Translating antisense technology into a treatment for Huntington's disease. Methods Mol Biol. 1780:497–523. 2018.PubMed/NCBI View Article : Google Scholar
60	Tabrizi SJ, Leavitt BR, Landwehrmeyer GB, Wild EJ, Saft C, Barker RA, Blair NF, Craufurd D, Priller J, Rickards H, et al: Targeting Huntingtin expression in patients with Huntington's disease. N Engl J Med. 380:2307–2316. 2019.PubMed/NCBI View Article : Google Scholar
61	Harper SQ, Staber PD, He X, Eliason SL, Martins IH, Mao Q, Yang L, Kotin RM, Paulson HL and Davidson BL: RNA interference improves motor and neuropathological abnormalities in a Huntington's disease mouse model. Proc Natl Acad Sci USA. 102:5820–5825. 2005.PubMed/NCBI View Article : Google Scholar
62	DiFiglia M, Sena-Esteves M, Chase K, Sapp E, Pfister E, Sass M, Yoder J, Reeves P, Pandey RK, Rajeev KG, et al: Therapeutic silencing of mutant huntingtin with siRNA attenuates striatal and cortical neuropathology and behavioral deficits. Proc Natl Acad Sci USA. 104:17204–17209. 2007.PubMed/NCBI View Article : Google Scholar
63	Keiser MS, Kordasiewicz HB and McBride JL: Gene suppression strategies for dominantly inherited neurodegenerative diseases: Lessons from Huntington's disease and spinocerebellar ataxia. Hum Mol Genet. 25(R1):R53–R64. 2016.PubMed/NCBI View Article : Google Scholar
64	Yu D, Pendergraff H, Liu J, Kordasiewicz HB, Cleveland DW, Swayze EE, Lima WF, Crooke ST, Prakash TP and Corey DR: Single-stranded RNAs use RNAi to potently and allele-selectively inhibit mutant huntingtin expression. Cell. 150:895–908. 2012.PubMed/NCBI View Article : Google Scholar
65	Dufour BD, Smith CA, Clark RL, Walker TR and McBride JL: Intrajugular vein delivery of AAV9-RNAi prevents neuropathological changes and weight loss in Huntington's disease mice. Mol Ther. 22:797–810. 2014.PubMed/NCBI View Article : Google Scholar
66	Miniarikova J, Zanella I, Huseinovic A, van der Zon T, Hanemaaijer E, Martier R, Koornneef A, Southwell AL, Hayden MR, van Deventer SJ, et al: Design, Characterization, and lead selection of therapeutic miRNAs targeting huntingtin for development of gene therapy for Huntington's disease. Mol Ther Nucleic Acids. 5(e297)2016.PubMed/NCBI View Article : Google Scholar
67	Devi S, Kumar V, Singh SK, Dubey AK and Kim JJ: Flavonoids: Potential candidates for the treatment of neurodegenerative disorders. Biomedicines. 9(99)2021.PubMed/NCBI View Article : Google Scholar
68	Huntington Study Group. Tetrabenazine as antichorea therapy in Huntington disease: A randomized controlled trial. Neurology. 66:366–372. 2006.PubMed/NCBI View Article : Google Scholar
69	Arora A, Kumar S, Ali J and Baboota S: Intranasal delivery of tetrabenazine nanoemulsion via olfactory region for better treatment of hyperkinetic movement associated with Huntington's disease: Pharmacokinetic and brain delivery study. Chem Phys Lipids. 230(104917)2020.PubMed/NCBI View Article : Google Scholar
70	Catanesi M, Caioni G, Castelli V, Benedetti E, d'Angelo M and Cimini A: Benefits under the Sea: The role of marine compounds in neurodegenerative disorders. Mar Drugs. 19(24)2021.PubMed/NCBI View Article : Google Scholar
71	Jabłońska M, Grzelakowska K, Wiśniewski B, Mazur E, Leis K and Gałązka P: Pridopidine in the treatment of Huntington's disease. Rev Neurosci. 31:441–451. 2020.PubMed/NCBI View Article : Google Scholar
72	Squitieri F, Di Pardo A, Favellato M, Amico E, Maglione V and Frati L: Pridopidine, a dopamine stabilizer, improves motor performance and shows neuroprotective effects in Huntington disease R6/2 mouse model. J Cell Mol Med. 19:2540–2548. 2015.PubMed/NCBI View Article : Google Scholar
73	Garcia-Miralles M, Geva M, Tan JY, Yusof NABM, Cha Y, Kusko R, Tan LJ, Xu X, Grossman I, Orbach A, et al: Early pridopidine treatment improves behavioral and transcriptional deficits in YAC128 Huntington disease mice. JCI insight. 2(e95665)2017.PubMed/NCBI View Article : Google Scholar
74	Bartl S, Oueslati A, Southwell AL, Siddu A, Parth M, David LS, Maxan A, Salhat N, Burkert M, Mairhofer A, et al: Inhibiting cellular uptake of mutant huntingtin using a monoclonal antibody: Implications for the treatment of Huntington's disease. Neurobiol Dis. 141(104943)2020.PubMed/NCBI View Article : Google Scholar
75	Connor B: Concise review: The use of stem cells for understanding and treating Huntington's disease. Stem Cells. 36:146–160. 2018.PubMed/NCBI View Article : Google Scholar
76	Fritz NE, Rao AK, Kegelmeyer D, Kloos A, Busse M, Hartel L, Carrier J and Quinn L: Physical therapy and exercise interventions in Huntington's disease: A mixed methods systematic review. J Huntingtons Dis. 6:217–235. 2017.PubMed/NCBI View Article : Google Scholar
77	Roos RA: Huntington's disease: A clinical review. Orphanet J Rare Dis. 5(40)2010.PubMed/NCBI View Article : Google Scholar