Current Knowledge and Future Directions in Huntington’s Disease

Authors

  • Alexander Rodríguez Universidad del Norte
  • Eileeng Morales Medical student, Universidad Metropolitana, Barranquilla, Colombia
  • Camila Herrera Medical student, Universidad Metropolitana, Barranquilla, Colombia
  • Ledys Montaño
  • Karin Martínez Medical student, Universidad Metropolitana, Barranquilla, Colombia
  • María Meza Medical student, Universidad Metropolitana, Barranquilla, Colombia
  • Natalia Del Villar Medical student, Universidad Metropolitana, Barranquilla, Colombia
  • Xilene Mendoza Research advisor, Universidad Metropolitana, Barranquilla, Colombia

DOI:

https://doi.org/10.31157/an.v27i4.346

Keywords:

Age at onset, Huntington disease, Htt protein, Polymorphism

Abstract

Introduction: Huntington's Disease (HD) is a hereditary, neurodegenerative disorder due to abnormal repeats of the CAG triplet in the IT-15 gene. It is characterized by a triad of progressive motor, psychiatric and cognitive symptoms, resulting from striatal neuronal loss. The impact of HD in Latin America is evidenced by the prevalence rates in Maracaibo (Venezuela) and Juan de Acosta (Colombia), which are the highest recorded in the world. This contrasts with the social abandonment and the scarce intervention of local governments.

Aim: Provide an approach to the most relevant aspects of HD from its pathogenesis and associated genetic polymorphisms, to the current treatment options.

Methodology: A literature review was performed of the state of the art of prognosis and treatment strategies in HD, including the identification of different polymorphic markers in the genes coding for UCHL1, HIP1, PGC1α, GRIK2, TBP, BDNF, among others, and its associations in the evolution of the disease in the presence of abnormal CAG repeats.

Conclusion: Even though in the last decades many researchers have focused on the development of curative treatment, there is no effective therapeutic target to prevent the clinical onset of the disease or to delay its progression. Instead, current pharmacological management is palliative, the evidence to generalize the surgical approaches is insufficient. Newly, the fetal neural cell transplantation into the striatum is offered as the surgical option that provides hope for the development of a true disease-modifying treatment.

References

1. Scahill RI, Zeun P, Osborne-Crowley K, Johnson EB, Gregory S, Parker C, et al. Biological and clinical characteristics of gene carriers far from predicted onset in the Huntington’s disease Young Adult Study (HD-YAS): a cross-sectional analysis. Lancet Neurol [Internet]. 2020;19(6):502–12. DOI: DOI:https://doi.org/10.1016/S1474-4422(20)30143-5
2. Fernández M. Papel de GSK-3 y Tau en la Enfermedad de Huntington. Universidad Autónoma de Madrid; 2015.
3. Owens GE. Biochemical and Biophysical Characterization of Huntingtin. Thesis by. Vol. 2016. CALIFORNIA INSTITUTE OF TECHNOLOGY; 2016.
4. Migliore S, Jankovic J, Squitieri F. Genetic counseling in Huntington’s disease: Potential new challenges on horizon? Front Neurol. 2019;10(APR):1–6. DOI: 10.3389/fneur.2019.00453
5. Massey TH, Jones L. The central role of DNA damage and repair in CAG repeat diseases. DMM Dis Model Mech. 2018;11(1). DOI: 10.1242/dmm.031930
6. Chao T-K, Hu J, Pringsheim T. Risk factors for the onset and progression of Huntington disease. Neurotoxicology [Internet]. 2017;61:79–99. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0161813X17300165 DOI: 10.1016/j.neuro.2017.01.005
7. Castilhos R, Augustin M, Santos J, Perandones C, Saraiva-Pereira M, Jardim L. Genetic aspects of Huntington’s disease in Latin America. A systematic review on Behalf of Rede Neurogenética. Clin Genet. 2016;89(89):295–303. DOI: 10.1111/cge.12641
8. Cascante L. Análisis de un caso y revisión bibliográfica sobre síntomas psiquiátricos prodrómicos en la Enfermedad de Huntington. Universidad de Costa Rica; 2018.
9. Walker RH, Gatto EM, Bustamante ML, Bernal-Pacheco O, Cardoso F, Castilhos RM, et al. Huntington’s disease-like disorders in Latin America and the Caribbean. Park Relat Disord. 2018;53:10–20. DOI: 10.1016/j.parkreldis.2018.05.021
10. Silva-Paredes G, Urbanos-Garrido RM, Inca-Martinez M, Rabinowitz D, Cornejo-Olivas MR. Economic burden of Huntington’s disease in Peru. BMC Health Serv Res. 2019;19(1):1–10. DOI: 10.1186/s12913-019-4806-6
11. Daniel C, Sepúlveda R, Sierra García N. Enfermedad De Huntington: Estado Del Arte. 2014;
12. Campo M del C, Bute LE. Vulnerable Groups, The Responsibility Of The State To Guarantee The Right To Health: Huntington In Communities Of The Caribbean Region Of Colombia. Perfiles las Ciencias Soc. 2016;3(6):54–99.
13. Raymond LA, André VM, Cepeda C, Gladding CM, Milnerwood AJ, Levine AMS. REVIEW PATHOPHYSIOLOGY OF HUNTINGTON’S DISEASE: TIME-DEPENDENT ALTERATIONS IN SYNAPTIC AND RECEPTOR FUNCTION. NSC. 2011;198:252–73. DOI: 10.1016/j.neuroscience.2011.08.052
14. Blumenstock S, Dudanova I. Cortical and Striatal Circuits in Huntington’s Disease. Front Neurosci. 2020;14(February). DOI: 10.3389/fnins.2020.00082
15. Tasset I, Sánchez F, Túnez I. Bases moleculares de la enfermedad de Huntington: Papel del estrés oxidativo. Rev Neurol. 2009;49(8):424–9. DOI: https://doi.org/10.33588/rn.4908.2009192
16. Plotkin JL, Goldberg JA. Thinking Outside the Box (and Arrow): Current Themes in Striatal Dysfunction in Movement Disorders. Neuroscientist. 2019;25(4):359–79. DOI: 10.1177/1073858418807887
17. De Paepe AE, Sierpowska J, Garcia-Gorro C, Martinez-Horta S, Perez-Perez J, Kulisevsky J, et al. White matter cortico-striatal tracts predict apathy subtypes in Huntington’s disease. NeuroImage Clin [Internet]. 2019;24(March):101965. Available from: https://doi.org/10.1016/j.nicl.2019.101965
18. Langbehn DR, Hayden MR, Paulsen JS, Johnson H, Aylward E, Biglan K, et al. CAG-repeat length and the age of onset in Huntington Disease (HD): A review and validation study of statistical approaches. Am J Med Genet Part B Neuropsychiatr Genet. 2010;153(2):397–408. DOI: 10.1002/ajmg.b.30992
19. Gusella JF, MacDonald ME, Lee J-M. Genetic modifiers of Huntington’s disease. Mov Disord [Internet]. 2014;29(11):1359–65. Available from: http://doi.wiley.com/10.1002/mds.26001 DOI: 10.1002/mds.26001
20. Tanaka M, Machida Y, Niu S, Ikeda T, Jana NR, Doi H, et al. Trehalose alleviates polyglutamine-mediated pathology in a mouse model of Huntington disease. Nat Med. 2004. DOI: 10.1038/nm985
21. Metzger S, Bauer P, Tomiuk J, Laccone F, DiDonato S, Gellera C, et al. Genetic analysis of candidate genes modifying the age-at-onset in Huntington’s disease. Hum Genet. 2006;120(2):285–92. DOI:10.1007/s00439-006-0221-2
22. Metzger S, Bauer P, Tomiuk J, Laccone F, Didonato S, Gellera C, et al. The S18Y polymorphism in the UCHL1 gene is a genetic modifier in Huntington’s disease. Neurogenetics. 2006;7(1):27–30. DOI: 10.1007/s10048-005-0023-z
23. Xu E he, Tang Y, Li D, Jia J ping. Polymorphism of HD and UCHL-1 genes in Huntington’s disease. J Clin Neurosci [Internet]. 2009;16(11):1473–7. Available from: http://dx.doi.org/10.1016/j.jocn.2009.03.027 DOI: 10.1016/j.jocn.2009.03.027
24. Taherzadeh-Fard E, Saft C, Andrich J, Wieczorek S, Arning L. PGC-1alpha as modifier of onset age in Huntington disease. Mol Neurodegener. 2009;4(1):4–7. DOI: 10.1186/1750-1326-4-10
25. Moss DJH, Pardiñas AF, Langbehn D, Lo K, Leavitt BR, Roos R, et al. Identification of genetic variants associated with Huntington’s disease progression: a genome-wide association study. Lancet Neurol. 2017. DOI: 10.1016/S1474-4422(17)30161-8
26. Lee JH, Lee JM, Ramos EM, Gillis T, Mysore JS, Kishikawa S, et al. TAA repeat variation in the GRIK2 gene does not influence age at onset in Huntington’s disease. Biochem Biophys Res Commun [Internet]. 2012;424(3):404–8. Available from: http://dx.doi.org/10.1016/j.bbrc.2012.06.120. DOI: 10.1016/j.bbrc.2012.06.120
27. Alberch J, López M, Badenas C, Carrasco J, Milà M, Muñoz E, et al. Association between BDNF Val66Met polymorphism and age at onset in Huntington disease. Neurology. 2005. DOI: 10.1212/01.wnl.0000175977.57661.b1
28. Daza J, Coronell C, Brokate A, Caiaffa H, Alfonso H. Characterization of polymorphic sequences of CAG and CCG triplets of Huntington’s disease in Colombian families. 2006;
29. Ncheux C, Mouret J-F, Diirr A, Agid Y, Feingold J, Brice A, et al. Sequence analysis of the CCG polymorphic region adjacent to the CAG triplet repeat of the HD gene in normal and HD chromosomes. JMed Genet Genet. 1995;3232. DOI: 10.1136/jmg.32.5.399
30. Ghosh R, Tabrizi SJ. Clinical features of huntington’s disease. Adv Exp Med Biol. 2018;1049:1–28. DOI: 10.1007/978-3-319-71779-1_1
31. Cano M, Talavera V. Enfermedad de Huntington variedad Westphal: reporte de caso. 2015;16(163):52–7.
32. Dayalu P, Albin RL. Huntington Disease: Pathogenesis and Treatment. Neurol Clin. 2015;33(1):101–14. DOI: 10.1016/j.ncl.2014.09.003
33. Rodríguez J, Díaz V, Rojas Y, Rodríguez Y, Núñez E. Actualización en enfermedad de Huntington. Gen Univ Vladimir Ilich Lenin [Internet]. 2013;17(1):546–57. Available from: http://scielo.sld.cu/pdf/ccm/v17s1/ccm03513.pdf
34. Molano J, Iragorri A, Ucrós G, Bonilla C, Tovar S, Herin D, et al. Obsessive-Compulsive Disorder Symptoms in Huntington’s Disease: A Case Report. Rev Colomb Psiquiatr. 2008;37(4):644–54. DOI: 10.1901/jaba.2008.37-644
35. Shannon K, Hersch S. La enfermedad de Huntington: Serie de Guías Familiares. 1. Tarapata K, editor. New York.; 2010. 24 p.
36. Camargo-Mendoza M, Castillo-Triana N, Fandiño Cardona JM, Mateus-Moreno A, Moreno-Martínez M. Características del habla, el lenguaje y la deglución en la enfermedad de Huntington. Rev la Fac Med. 2017;65(2):343–8. DOI: http://dx.doi.org/10.15446/revfacmed.v65n2.57449
37. Arango J, Iglesias J, Lopera F. Características clínicas y neuropsicológicas de la enfermedad de Huntington: Una revisión. Vol. 37, Revista de Neurologia. 2003. p. 758–65. DOI: https://doi.org/10.33588/rn.3708.2003010
38. Damiano M, Galvan L, Déglon N, Brouillet E. Mitochondria in Huntington’s disease. Biochim Biophys Acta - Mol Basis Dis. 2010;1802(1):52–61. DOI: 10.1016/j.bbadis.2009.07.012
39. Parra-Bolaños N, Benjumea-Garcés JS, Gallego-Tavera SY. Alteraciones Neurofisiológicas producidas por la Enfermedad de Huntington sobre la Calidad de Vida. 2016;11(2):45–50. DOI: 10.5839/rcnp.2016.11.02.08
40. López-Mora DA, Camacho V, Pérez-Pérez J, Martínez-Horta S, Fernández A, Sampedro F, et al. Striatal hypometabolism in premanifest and manifest Huntington’s disease patients. Eur J Nucl Med Mol Imaging. 2016;43(12):2183–9. DOI: 10.1007/s00259-016-3445-y
41. Quintana J. Neuropsiquiatría: Pet Y Spect. Rev Shilena Radiol. 2002;8. DOI: http://dx.doi.org/10.4067/S0717-93082002000200005
42. Bennett R. Testing for Huntington Disease: Making and Informed Choice. Medical Genetics. 2008.
43. Roos R. Huntington’s disease: a clinical review. Orphanet J Rare Dis. 2010;5(1):40. DOI: 10.1186/1750-1172-5-40
44. Dickey AS, Spada AR. Therapy development in Huntington disease: From current strategies to emerging opportunities. Am J Med Genet. 2018;176(12):139–48. DOI: 10.1002/ajmg.a.38494
45. Potkin KT, Potkin SG. New directions in therapeutics for Huntington disease. Future Neurol. 2018;13(2):101–21. DOI: 10.2217/fnl-2017-0035
46. Frank S, Stamler D, Kayson E, Claassen DO, Colcher A, Davis C, et al. Safety of converting from tetrabenazine to deutetrabenazine for the treatment of Chorea. JAMA Neurol. 2017;74(8):977–82. DOI: 10.1001/jamaneurol.2017.1352
47. Claassen DO, Carroll B, De Boer LM, Wu E, Ayyagari R, Gandhi S, et al. Indirect tolerability comparison of Deutetrabenazine and Tetrabenazine for Huntington disease. J Clin Mov Disord. 2017;4(1):1–11. DOI: 10.1186/s40734-017-0051-5
48. Rodrigues FB, Duarte GS, Costa J, Ferreira JJ, Wild EJ. Tetrabenazine Versus Deutetrabenazine for Huntington’s Disease: Twins or Distant Cousins? Mov Disord Clin Pract. 2017;4(4):582–5. DOI: 10.1002/mdc3.12483
49. Ayton S, Lei P, Appukuttan AT, Renoir T, Foliaki S, Chen F, et al. Brain Zinc Deficiency Exacerbates Cognitive Decline in the R6/1 Model of Huntington’s Disease. Neurotherapeutics. 2020;17(1):243–51. DOI: 10.1007/s13311-019-00785-6
50. Andrew Feigin MEIM y PF para P y T del M-NLMC. VX15/2503 Treatment for Huntington’s Disease (SIGNAL). 2015.
51. Southwell AL, Franciosi S, Villanueva EB, Xie Y, Winter LA, Veeraraghavan J, et al. Neurobiology of Disease Anti-semaphorin 4D immunotherapy ameliorates neuropathology and some cognitive impairment in the YAC128 mouse model of Huntington disease. Neurobiol Dis. 2015;76:46–56. DOI: 10.1016/j.nbd.2015.01.002
52. Wild EJ, Tabrizi SJ. Therapies targeting DNA and RNA in Huntington’s disease. The Lancet Neurology. 2017. DOI: 10.1016/S1474-4422(17)30280-6
53. Ionis Pharmaceuticals I. New Data from IONIS-HTT Rx Phase 1/2 Study Demonstrates Correlation Between Reduction of Disease-causing Protein and Improvement in Clinical Measures of Huntington’s Disease. 2018.
54. Besusso D, Schellino R, Boido M, Belloli S, Parolisi R, Conforti P, et al. Stem Cell-Derived Human Striatal Progenitors Innervate Striatal Targets and Alleviate Sensorimotor Deficit in a Rat Model of Huntington Disease. Stem cell reports. 2020;14(5):876–91. DOI: 10.1016/j.stemcr.2020.03.018
55. Kim HS, Jeon I, Noh J-E, Lee H, Hong KS, Lee N, et al. Intracerebral Transplantation of BDNF-overexpressing Human Neural Stem Cells (HB1.F3.BDNF) Promotes Migration, Differentiation and Functional Recovery in a Rodent Model of Huntington’s Disease. Exp Neurobiol. 2020;29(2):130–7. DOI: 10.5607/en20011
56. Barker RA, Swain RA. Neural Transplantation for the Treatment of Huntington’s Disease. 2010. DOI: http://doi.org/10.17925/ENR.2010.05.02.41
57. Choi KA, Choi Y, Hong S. Stem cell transplantation for Huntington’s diseases. Methods. 2017;1–9. DOI: 10.1016/j.ymeth.2017.08.017
58. Huntington G. Medical and Surgical Reporter. On Chorea. 1872;1(789):320–1.
59. Yamamoto A, Lucas JJ, Hen R. Reversal of Neuropathology and Motor Dysfunction in a Conditional Model of Huntington’s Disease. Cell. 2000;101(1):57–66. DOI: 10.1016/S0092-8674(00)80623-6
60. Fernandes J. La enfermedad de Huntington : una visión biomolecular. 2001;32(8):762–7. DOI: https://doi.org/10.33588/rn.3208.2000484
61. Rosas HD, Liu AK, Hersch S, Glessner M, Ferrante RJ, Salat DH, et al. Regional and progressive thinning of the cortical ribbon in Huntington’s disease. Neurology. 2002;58(5):695–701. DOI: 10.1212/wnl.58.5.695
62. Laks J, Rocha M, Capitao C, Domingues RC, Ladeia G, Lima M, et al. Functional and motor response to low dose olanzapine in Huntington’s disease: case report. Arq Neuropsiquiatr. 2004;62(4):1092–4. DOI:10.1590/S0004-282X2004000600030
63. Vásquez M. Diagnostico molecular de la EH en Costa Rica. 2005.
64. Rosenblatt A. Neuropsychiatry of Huntington’s disease. Dialogues Clin Neurosci. 2007. DOI: 10.31887/DCNS.2007.9.2/arosenblatt
65. Altamirano Ley J, Estrada G. Demencias valoradas con tomografía por emisión de positrones y 18 F-fluordesoxiglucosa. 2009.
66. Kordasiewicz HB, Stanek LM, Wancewicz E V., Mazur C, McAlonis MM, Pytel KA, et al. Sustained Therapeutic Reversal of Huntington’s Disease by Transient Repression of Huntingtin Synthesis. Neuron. 2012;74(6):1031–44. DOI: 10.1016/j.neuron.2012.05.009
67. Li JY, Conforti L. Axonopathy in Huntington’s disease. Exp Neurol. 2013;246:62–71. DOI: 10.1016/j.expneurol.2012.08.010
68. Frank S. Treatment of Huntington’s Disease. Neurotherapeutics. 2014;11(1):153–60. DOI: 10.1007/s13311-013-0244-z
69. Kumar A, Kumar Singh S, Kumar V, Kumar D, Agarwal S, Rana MK. Huntington’s disease: An update of therapeutic strategies. Gene. 2015;556(2):91–7. DOI: 10.1016/j.gene.2014.11.022
70. Kobal J, Cankar K, Pretnar J, Zaletel M, Kobal L, Teran N, et al. Functional impairment of precerebral arteries in Huntington disease. J Neurol Sci [Internet]. 2016;372:363–8. DOI: https://doi.org/10.1016/j.jns.2016.10.033
71. Mirallave A, Morales M, Cabib C, Muñoz EJ, Santacruz P, Gasull X, et al. Sensory processing in Huntington’s disease. Clin Neurophysiol. 2017;128(5):689–96. DOI: 10.1016/j.clinph.2017.01.009
72. Minkova L, Gregory S, Scahill RI, Abdulkadir A, Kaller CP, Peter J, et al. Cross-sectional and longitudinal voxel-based grey matter asymmetries in Huntington’s disease. NeuroImage Clin. 2017. DOI: https://doi.org/10.1016/j.nicl.2017.10.023
73. Chattopadhyay B, Ghosh S, Gangopadhyay PK, Das SK, Roy T, Sinha KK, et al. Modulation of age at onset in Huntington’s disease and spinocerebellar ataxia type 2 patients originated from eastern India. Neurosci Lett. 2003. DOI: DOI: 10.1016/s0304-3940(03)00436-1

Additional Files

Published

2022-05-31

How to Cite

Rodríguez, A., Morales, E., Herrera, C., Montaño, L., Martínez, K., Meza, M., Del Villar, N., & Mendoza, X. (2022). Current Knowledge and Future Directions in Huntington’s Disease. Archivos De Neurociencias, 27(4). https://doi.org/10.31157/an.v27i4.346

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Section

Evidence synthesis