Vásquez-Cerdas M, Morales-Montero F

Idioma: Español
Referencias bibliográficas: 49
Paginas: 34-42
Archivo PDF: 129.45 Kb.

RESUMEN

Introducción y objetivos: La enfermedad de Huntington (HD) es la enfermedad neurodegenerativa hereditaria más frecuente, causada por una expansión inestable de la repetición CAG en el gen HTT. Se caracteriza por trastornos del movimiento, deterioro cognitivo y disturbios psiquiátricos y del comportamiento. Un número creciente de enfermedades pueden imitar la presentación de la HD. Se estima que entre 1 y 7% de los pacientes con síntomas y signos sugestivos de HD, son negativos para la mutación en el gen HTT, y se dice que presentan fenotipos similares a la HD ó fenocopias de HD. El objetivo del estudio es contribuir a la correcta clasificación de pacientes costarricenses con un cuadro clínico sugestivo de HD, pero sin la expansión CAG en el gen HTT.
Metodología: Un total de 11 pacientes costarricenses, ocho hombres y tres mujeres, se tamizaron para expansiones de repeticiones en los genes JPH3, TBP, ATN1, ATX1, ATX2, ATX3 y CACNA1A. El análisis molecular se llevó a cabo por medio de la reacción en cadena de la polimerasa (PCR) y electroforesis en geles desnaturalizantes de urea-acrilamida con la posterior tinción con nitrato de plata.
Resultados: Todos los pacientes estudiados con fenotipo similar a la HD resultaron negativos para las expansiones en los genes JPH3, TBP, ATN1, ATX1, ATX2, ATX3 y CACNA1A.
Conclusiones: La causa de la enfermedad en los pacientes analizados sigue siendo desconocida, y no se pudo establecer un diagnóstico o clasificación clínica definitiva. Esto indica lo complejo del diagnóstico diferencial de fenocopias de HD y evidencia que los trastornos del movimiento con fenotipos similares a la HD son clínica y genéticamente heterogéneos.

REFERENCIAS (EN ESTE ARTÍCULO)

1. Novak MJ, Tabrizi SJ. Huntington’s disease: clinical presentation and treatment. Int Rev Neurobiol 2011; 98: 297–323.

2. Vásquez M, Sevilla F, Gutiérrez A et al. Enfermedad de Huntington infantil: reporte del primer caso en Costa Rica confirmado por análisis molecular. Neuroje 2016; 29(2): 18-25.

3. Wild EJ, Mudanohwo EE, Sweeney MG et al. Huntington’s disease phenocopies are clinically and genetically heterogeneous. Mov Disord 2008; 23: 716–20.

4. Wild EJ, Tabrizi SJ. Huntington’s disease phenocopy syndromes. Curr Opin Neurol 2007; 20: 681–687.

5. Rodrigues GR, Walker R, Bader B et al. Clinical and genetic analysis of 29 patients with Huntington’s disease-like phenotype. Arq Neuropsiquiatr 2011; 69: 419-423.

6. Schneider SA, Walker RH, Bhatia KP. The Huntington’s disease-like syndromes: what to consider in patients with a negative Huntington’s disease gene test. Nat Clin Pract Neurol 2007; 3: 517– 525.

7. Marogianni C, Rikos D, Provatas A et al. The role of C9orf72 in neurodegenerative disorders: a systematic review, an updated meta-analysis, and the creation of an online database. Neurobiol Aging 2019; 84: 238.e25-238.e34.

8. Rikos D, Marogianni C, Provatas A et al. Screening for the C9ORF72 Expansion in Greek Huntington Disease Phenocopies and Controls and Meta-analysis of Current Data. Tremor and Other Hyperkinetic Movements 2020; 10(1): 5.

9. Koutsis G, Karadima G, Kartanou C et al. C9ORF72 hexanucleotide repeat expansions are a frequent cause of Huntington disease phenocopies in the Greek population. Neurobiol Aging 2015; 36(1): 547.e13-6.

10. Martino D, Stamelou M, Bhatia K. The differential diagnosis of Huntington’s disease like syndromes: ‘red flags’ for the clinician. J Neurol Neurosurg Psychiatry 2013; 84(4): 650–656.

11. Nishi M, Mizushima A, Nakagawara K et al. Characterization of human junctophilin subtype genes. Biochem Biophys Res Commun 2000; 273(3): 920-7.

12. Takeshima H, Komazaki S, Nishi M et al. Junctophilins: a novel family of junctional membrane complex proteins. Mol Cell 2000; 6:11–22.

13. Ito K, Komazaki S, Sasamoto K et al. Deficiency of triad junction and contraction in mutant skeletal muscle lacking junctophilin type 1. J Cell Biol 2001; 154(5): 1059–67.

14. Margolis RL, Holmes SE, Rosenblatt A et al. Huntington’s diseaselike 2 (HDL2) in North America and Japan. Ann Neurol 2004; 56(5): 670-674.

15. Stevanin G, Brice A. Spinocerebellar ataxia 17 (SCA17) and Huntington’s disease-like 4 (HDL4). Cerebellum 2008; 7(2): 170–8.

16. Craig K, Keers SM, Walls TJ et al. Minimum prevalence of spinocerebellar ataxia 17 in the north east of England. J Neurol Sci 2005; 239: 105–109.

17. Toyoshima Y, Yamada M, Onodera O et al. SCA 17 homozygote showing Huntington's disease-like phenotype. Ann Neurol 2004; 55(2): 281-286.

18. Palmer EE, Hong S, Al Zahrani F et al. De novo variants disrupting the HX repeat motif of ATN1 cause a recognizable non-progressive neurocognitive syndrome. Am J Hum Genet 2019; 104: 542-552.

19. Naito H, Oyanagi S. Familial myoclonus epilepsy and choreoathetosis: hereditary dentatorubral-pallidoluysian atrophy. Neurology 1982; 32(8): 798–807.

20. Ikeuchi T, Koide R, Tanaka H et al. Dentatorubral-pallidoluysian atrophy: clinical features are closely related to unstable expansions of trinucleotide (CAG) repeat. Ann Neurol 1995b; 37(6): 769–75.

21. Schols L, Bauer P, Schmidt T et al. Autosomal dominant cerebellar ataxias: clinical features, genetics, and pathogenesis. Lancet Neurol 2004; 3(5): 291–304.

22. Soong B, Paulson HL. Spinocerebellar ataxias: an update. Curr Opin Neurol 2007; 20: 438–446

23. Durr A. Autosomal dominant cerebellar ataxias: polyglutamine expansions and beyond. Lancet 2010; 9: 885-894.

24. Vásquez M, Morales F, Cuenca P. Características clínicas y genético-moleculares de la enfermedad de Huntington en pacientes costarricenses: experiencia de 14 años de diagnóstico molecular. Rev Mex Neuroci 2018; 19(5): 9-18.

25. Sambrook J, Russell DW. Molecular Cloning: a laboratory manual. New York: Cold Spring Harbor Laboratory Press; 2001.

26. Holmes SE, O’Hearn E, Rosenblatt A et al. A repeat expansion in the gene encoding junctophilin-3 is associated with Huntington disease-like 2. Nat Genet 2001; 29(4): 377-378.

27. Koide R, Kobayashi S, Shimohata T et al. A neurological disease caused by an expanded CAG trinucleotide repeat in the TATAbinding protein gene: a new polyglutamine disease? Hum Mol Genet 1999; 8(11): 2047–78.

28. Nagafuchi S, Yanagisawa H, Sato K et al. Dentatorubral and pallidoluysian atrophy expansion of an unstable CAG trinucleotide on chromosome 12p. Nature Genet 1994; 6(1): 14–18.

29. Vásquez M, Fernández H, Cuenca P et al. Diagnóstico molecular de ataxias espinocerebelosas (SCAs) y reporte del primer caso de SCA3 en Costa Rica confirmado por análisis molecular. Neuroeje 2017; 30(1): 19-25

30. Stevanin G, Fujigasaki H, Lebre AS et al. Huntington’s disease-like phenotype due to trinucleotide repeat expansions in the TBP and JPH3 genes. Brain 2003; 126: 1599–1603.

31. Keckarevic M, Savic D, Svetel M et al. Yugoslav HD phenocopies analyzed on the presence of mutations in PrP, ferritin, and Jp-3 genes. Int J Neurosci 2005; 115(2): 299–301.

32. Costa Mdo C, Teixeira-Castro A, Constante M et al. Exclusion of mutations in the PRNP, JPH3, TBP, ATN1, CREBBP, POU3F2 and FTL genes as a cause of disease in Portuguese patients with a Huntington- like phenotype. J Hum Genet 2006; 51(8): 645–651.

33. Sułek-Piatkowska A, Krysa W, Zdzienicka E et al. Searching for mutation in the JPH3, ATN1 and TBP genes in Polish patients suspected of Huntington’s disease and without mutation in the IT15 gene. Neurol Neurochir Pol 2008; 42(3): 203-209.

34. Koutsis G, Karadima G, Pandraud A et al. Genetic screening of Greek patients with Huntington’s disease phenocopies identifies an SCA8 expansion. J Neurol 2012; 259(9): 1874–1878.

35. Rosenblatt A, Ranen NG, Rubinsztein DC et al. Patients with features similar to Huntington’s disease, without CAG expansion in huntingtin. Neurology 1998; 51: 215-220.

36. Vuillaume I, Meynieu P, Schraen-Maschke S et al. Absence of unidentified CAG repeat expansion in patients with Huntington’s disease-like phenotype. J Neurol Neurosurg Psychiatry 2000; 68(5): 672-675

37. Bauer I, Gencik M, Laccone F et al. Trinucleotide repeat expansions in the junctophilin-3 gene are not found in Caucasian patients with a Hunting-ton’s disease-like phenotype. Ann Neurol 2002; 51(5): 662.

38. Bauer P, Laccone F, Rolfs A et al. Trinucleotide repeat expansion in SCA17/ TBP in white patients with Huntington’s disease-like phenotype. J Med Genet 2004; 41(3): 230-232.

39. Cellini E, Forleo P, Nacmias B et al. Spinocerebellar ataxia type 17 repeat in patients with Huntington’s disease-like and ataxia. Ann Neurol 2004; 56(1): 163.

40. Krause A, Hetem C, Holmes SE et al. HDL2 mutations are an important cause of Huntington’s disease in patients with African ancestry. J Neurol Neurosurg Psychiatr 2005; 76(Suppl 4): S17.

41. Rodriguez-Revenga L, Santos MM, Sánchez A et al. Screening for FXTAS in 95 Spanish patients negative for Huntington disease. Genet Test 2008; 12: 135-138.

42. Schneider SA, Bird T. Huntington's Disease, Huntington's Disease Look-Alikes, and Benign Hereditary Chorea: What's New? Mov Disord Clin Pract 2016; 3(4): 342-354.

43. Holmes SE, O’Hearn E, Rosenblatt A et al. A repeat expansion in the gene encoding junctophilin-3 is associated with Huntington disease-like 2. Nat Genet 2001; 29(4): 377–378.

44. Hensman DJ, Poulter M, Beck J et al. C9orf72 expansions are the most common genetic cause of Huntington disease phenocopies. Neurology 2014; 82(4): 292–299.

45. Kostic VS, Dobricic V, Stankovic I et al. C9orf72 expansion as a possible genetic cause of Huntington disease phenocopy syndrome. J Neurol 2014; 261(10): 1917– 1921.

46. Babić Leko M, Župunski V, Kirincich J et al. Molecular Mechanisms of Neurodegeneration Related to C9orf72 Hexanucleotide Repeat Expansion. Behav Neurol 2019: 2909168.

47. Moens TG, Partridge L, Isaacs AM. Genetic models of C9orf72: what is toxic? Curr Opin Genet Dev 2017; 44: 92-101.

48. Majounie E, Renton AE, Mok K et al. Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study. Lancet Neurology. 2012b; 11: 323–330.

49. Malek, N, Newman EJ. Hereditary chorea—What else to consider when the huntington’s disease genetics test is negative? Acta Neurol Scand 2017; 135: 25–33.