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Ophthalmological and Neurologic Manifestations in Pre-clinical and Clinical Phases of Spinocerebellar Ataxia Type 7

  • Pietro B. Azevedo
  • Anastácia G. Rocha
  • Leda M. N. Keim
  • Daniel Lavinsky
  • Gabriel V. Furtado
  • Eduardo P. de Mattos
  • Fernando R. Vargas
  • Vanessa B. Leotti
  • Maria-Luiza Saraiva-Pereira
  • Laura B. JardimEmail author
  • on behalf of Rede Neurogenetica
Original Paper
  • 10 Downloads

Abstract

Spinocerebellar ataxia type 7 (SCA7) is a polyglutamine disease that progressively affects the cerebellum, brainstem, and retina. SCA7 is quite rare, and insights into biomarkers and pre-clinical phases are still missing. We aimed to describe neurologic and ophthalmological findings observed in symptomatic and pre-symptomatic SCA7 subjects. Several neurologic scales, visual acuity, visual fields obtained by computer perimetry, and macular thickness in optical coherence tomography (mOCT) were measured in symptomatic carriers and at risk relatives. Molecular analysis of the ATXN7 was done blindly in individuals at risk. Thirteen symptomatic carriers, 3 pre-symptomatic subjects, and 5 related controls were enrolled. Symptomatic carriers presented scores significantly different from those of controls in most neurologic and ophthalmological scores. Gradual changes from controls to pre-symptomatic and then to symptomatic carriers were seen in mean (SD) of visual fields − 1.34 (1.15), − 2.81 (1.66). and − 9.56 (7.26); mOCT − 1.11 (2.6), − 3.48 (3.54), and − 7.73 (2.56) Z scores; and “Spinocerebellar Ataxia Functional Index (SCAFI)” − 1.16 (0.28), 0.65 (0.56), and − 0.61 (0.44), respectively. Visual fields and SCAFI were significantly correlated with time to disease onset (pre-symptomatic)/disease duration (symptomatic carriers). Visual fields, mOCT, and SCAFI stood out as candidates for state biomarkers for SCA7 since pre-symptomatic stages of disease.

Keywords

Biomarkers Macular thickness Optical coherence tomography SCAFI Spinocerebellar ataxia type 7 Visual fields 

Notes

Acknowledgements

We are very grateful to the patients and families who agreed to participate in the present study.

Funding

This study was supported by Fundo de Incentivo à Pesquisa do Hospital de Clinicas de Porto Alegre HCPA-FIPE (GPPG 16-0093). EPM, GVF, MLSP, and LBJ were supported by CNPq.

Compliance with Ethical Standards

Informed consent was obtained from each participant. This study was approved by the Ethics Committees (EC) from Hospital de Clínicas de Porto Alegre and from Hospital Gaffrée e Guinle (UNIRIO), being registered at Plataforma Brasil as CAAE 52703516.8.0000.5327.

Conflict of Interest

The authors declare that they have no conflict of interest. EPM, GVF, MLSP, and LBJ were supported by the National Council for Research and Development (CNPq), Brazil. MLSP received grant from Fundo de Incentivo à Pesquisa do Hospital de Clínicas de Porto Alegre, Brazil, for performing some of the laboratorial procedures. LBJ received grants from the National Council for Research and Development (CNPq), Fundo de Incentivo à Pesquisa do Hospital de Clínicas de Porto Alegre, and Fundo de Apoio à Pesquisa do Rio Grande do Sul, Brazil.

Supplementary material

12311_2019_1004_MOESM1_ESM.docx (18 kb)
Supplemental table 1. Clinical, molecular, neurological, and ophthalmological characteristics of the carrier of an ATXN7 allele of unknown significance, compared to symptomatic and pre-symptomatic carriers of expanded CAG repeats at ATXN7, and to controls. (DOCX 18 kb)
12311_2019_1004_MOESM2_ESM.docx (16 kb)
Supplemental table 2. Correlations between the a priori parameter of disease severity SARA and best corrected visual acuity (BCVA), and other neurologic and ophthalmological measurements of interest among all ATXN7 CAGexp carriers. (DOCX 16 kb)

References

  1. 1.
    David G, Giunti P, Abbas N, et al. The gene for autosomal dominant cerebellar ataxia type II is located in a 5-cM region in 3p12-p13: genetic and physical mapping of the SCA7 locus. Am J Hum Genet. 1996 Dec;59(6):1328–36.PubMedPubMedCentralGoogle Scholar
  2. 2.
    Garden G. Spinocerebellar ataxia type 7. [updated 2012 Dec 20] , GeneReviews[online]; Aug 27 1998 [Available at http://www.ncbi.nlm.nih.gov/books/NBK1256. Accessed: January 12, 2015].
  3. 3.
    Benton CS, de Silva R, Rutledge SL, Bohlega S, Ashizawa T, Zoghbi HY. Molecular and clinical studies in SCA-7 define a broad clinical spectrum and the infantile phenotype. Neurology. 1998;51:1081–6.CrossRefGoogle Scholar
  4. 4.
    Schöls L, Amoiridis G, Buttner T, Przuntek H, Epplen JT, Riess O. Autosomal dominant cerebellar ataxia: phenotypic differences in genetically defined subtypes? Neurology. 1997;42:924–32.Google Scholar
  5. 5.
    Jin DK, Oh MR, Song SM, Koh SW, Lee M, Kim GM, et al. Frequency of spinocerebellar ataxia types 1,2,3,6,7 and dentatorubral pallidoluysian atrophy mutations in Korean patients with spinocerebellar ataxia. J Neurol. 1999;246:207–10.CrossRefGoogle Scholar
  6. 6.
    de Castilhos RM, Furtado GV, Gheno TC, et al. Spinocerebellar ataxias in Brazil--frequencies and modulating effects of related genes. Cerebellum. 2014 Feb;13(1):17–28.CrossRefGoogle Scholar
  7. 7.
    Simao LM, Lana-Peixoto MA, Araújo CR, Moreira MA, Teixeira AL. The Brazilian version of the 25-Item National Eye Institute Visual Function Questionnaire: translation, reliability and validity. Arq Bras Oftalmol. 2008 Jul-Aug;71(4):540–6.CrossRefGoogle Scholar
  8. 8.
    Schmitz-Hübsch T, du Montcel ST, Baliko L, et al. Scale for the assessment and rating of ataxia: development of a new clinical scale. Neurology. 2006 Jun 13;66(11):1717–20.CrossRefGoogle Scholar
  9. 9.
    Kieling C, Rieder CR, Silva AC, et al. A neurological examination score for the assessment of spinocerebellar ataxia 3 (SCA3). Eur J Neurol. 2008 Apr;15(4):371–6.CrossRefGoogle Scholar
  10. 10.
    du Montcel ST, Charles P, Ribai P, Goizet C, le Bayon A, Labauge P, et al. Composite cerebellar functional severity score: validation of a quantitative score of cerebellar impairment. Brain. 2008 May;131(Pt 5):1352–61.CrossRefGoogle Scholar
  11. 11.
    Schmitz-Hübsch T, Giunti P, Stephenson DA, et al. SCA Functional Index: a useful compound performance measure for spinocerebellar ataxia. Neurology. 2008a Aug 12;71(7):486–92.CrossRefGoogle Scholar
  12. 12.
    Schmitz-Hübsch T, Coudert M, Bauer P, et al. Spinocerebellar ataxia types 1, 2, 3, and 6: disease severity and nonataxia symptoms. Neurology. 2008b Sep 23;71(13):982–9.CrossRefGoogle Scholar
  13. 13.
    Klein R, Klein BE, Moss SE, DeMets D. Inter-observer variation in refraction and visual acuity measurement using a standardized protocol. Ophthalmology. 1983 Nov;90(11):1357–9.CrossRefGoogle Scholar
  14. 14.
    Hu AY, Liu T, Kaines A, Yu F, Schwartz SD, Hubschman J. Normative data for macular thickness and volume measurements using Cirrus HD-optical coherence tomography. Invest Ophthalmol Vis Sci. 2010;51(13):338.Google Scholar
  15. 15.
    TOPCON 3D OCT Series Normative Database. Available at OCT Normative summary H1H4_0930.pdf. Assessed in July 2018.Google Scholar
  16. 16.
    Tezenas du Montcel S, Charles P, Goizet C, Marelli C, Ribai P, Vincitorio C, et al. Factors influencing disease progression in autosomal dominant cerebellar ataxia and spastic paraplegia. Arch Neurol. 2012 Apr;69(4):500–8.CrossRefGoogle Scholar
  17. 17.
    Mattos EP, Leotti VB, Soong Bw, et al. Age at onset prediction in spinocerebellar ataxia type 3 changes according to population of origin. Submitted.Google Scholar
  18. 18.
    Jardim LB, Silveira I, Pereira ML, Ferro A, Alonso I, do Céu Moreira M, et al. A survey of spinocerebellar ataxia in South Brazil - 66 new cases with Machado-Joseph disease, SCA7, SCA8, or unidentified disease-causing mutations. J Neurol. 2001 Oct;248(10):870–6.CrossRefGoogle Scholar
  19. 19.
    Giunti P, Stevanin G, Worth PF, David G, Brice A, Wood NW. Molecular and clinical study of 18 families with ADCA type II: evidence for genetic heterogeneity and de novo mutation. Am J Hum Genet. 1999 Jun;64(6):1594–603.CrossRefGoogle Scholar
  20. 20.
    Bryer A, Krause A, Bill P, Davids V, Bryant D, Butler J, et al. The hereditary adult-onset ataxias in South Africa. J Neurol Sci. 2003 Dec 15;216(1):47–54.CrossRefGoogle Scholar
  21. 21.
    Horton LC, Frosch MP, Vangel MG, Weigel-DiFranco C, Berson EL, Schmahmann JD. Spinocerebellar ataxia type 7: clinical course, phenotype-genotype correlations, and neuropathology. Cerebellum. 2013 Apr;12(2):176–93.CrossRefGoogle Scholar
  22. 22.
    Velázquez-Pérez L, Cerecedo-Zapata CM, Hernández-Hernández O, Martínez-Cruz E, Tapia-Guerrero YS, González-Piña R, et al. A comprehensive clinical and genetic study of a large Mexican population with spinocerebellar ataxia type 7. Neurogenetics. 2015 Jan;16(1):11–21.CrossRefGoogle Scholar
  23. 23.
    Campos-Romo A, Graue-Hernandez EO, Pedro-Aguilar L, Hernandez-Camarena JC, Rivera-de la Parra D, Galvez V, et al. Ophthalmic features of spinocerebellar ataxia type 7. Eye (Lond). 2018 Jan;32(1):120–7.CrossRefGoogle Scholar
  24. 24.
    Schmitz-Hübsch T, Fimmers R, Rakowicz M, et al. Responsiveness of different rating instruments in spinocerebellar ataxia patients. Neurology. 2010 Feb 23;74(8):678–84.CrossRefGoogle Scholar
  25. 25.
    Abe T, Tsuda T, Yoshida M, et al. Macular degeneration associated with aberrant expansion of trinucleotide repeat of the SCA7 gene in 2 Japanese families. Arch Ophthalmol. 2000 Oct;118(10):1415–21.CrossRefGoogle Scholar
  26. 26.
    Aleman TS, Cideciyan AV, Volpe NJ, Stevanin G, Brice A, Jacobson SG. Spinocerebellar ataxia type 7 (SCA7) shows a cone-rod dystrophy phenotype. Exp Eye Res. 2002 Jun;74(6):737–45.CrossRefGoogle Scholar
  27. 27.
    Ahn JK, Seo JM, Chung H, Yu HG. Anatomical and functional characteristics in atrophic maculopathy associated with spinocerebellar ataxia type 7. Am J Ophthalmol. 2005 May;139(5):923–5.CrossRefGoogle Scholar
  28. 28.
    Manrique RK, Noval S, Aguilar-Amat MJ, Arpa J, Rosa I, Contreras I. Ophthalmic features of spinocerebellar ataxia type 7. J Neuroophthalmol. 2009 Sep;29(3):174–9.CrossRefGoogle Scholar
  29. 29.
    Hugosson T, Gränse L, Ponjavic V, Andréasson S. Macular dysfunction and morphology in spinocerebellar ataxia type 7 (SCA 7). Ophthalmic Genet. 2009 Mar;30(1):1–6.CrossRefGoogle Scholar
  30. 30.
    Ramachandran PS, Bhattarai S, Singh P, Boudreau RL, Thompson S, LaSpada AR, et al. RNA interference-based therapy for spinocerebellar ataxia type 7 retinal degeneration. PLoS One. 2014 Apr 23;9(4):e95362.CrossRefGoogle Scholar
  31. 31.
    Scholefield J, Watson L, Smith D, Greenberg J, Wood MJ. Allele-specific silencing of mutant ataxin-7 in SCA7 patient-derived fibroblasts. Eur J Hum Genet. 2014 Dec;22(12):1369–75.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Pietro B. Azevedo
    • 1
    • 2
  • Anastácia G. Rocha
    • 3
  • Leda M. N. Keim
    • 4
  • Daniel Lavinsky
    • 2
    • 5
  • Gabriel V. Furtado
    • 6
    • 7
  • Eduardo P. de Mattos
    • 6
    • 7
  • Fernando R. Vargas
    • 4
    • 8
  • Vanessa B. Leotti
    • 9
  • Maria-Luiza Saraiva-Pereira
    • 6
    • 7
    • 10
    • 11
  • Laura B. Jardim
    • 1
    • 3
    • 6
    • 7
    • 11
    • 12
    • 13
    Email author return OK on get
  • on behalf of Rede Neurogenetica
  1. 1.Programa de Pós-Graduação em Ciências MédicasUniversidade Federal do Rio Grande do SulPorto AlegreBrazil
  2. 2.Serviço de OftalmologiaHospital de Clínicas de Porto AlegrePorto AlegreBrazil
  3. 3.Faculdade de MedicinaUniversidade Federal do Rio Grande do SulPorto AlegreBrazil
  4. 4.Hospital Gaffrée e GuinleUniversidade Federal do Estado do Rio de JaneiroRio de JaneiroBrazil
  5. 5.Departamento de Oftalmologia e OtorrinolaringologiaUniversidade Federal do Rio Grande do SulPorto AlegreBrazil
  6. 6.Programa de Pós-Graduação em Genética e Biologia MolecularUniversidade Federal do Rio Grande do SulPorto AlegreBrazil
  7. 7.Laboratório de Investigação GenéticaHospital de Clínicas de Porto AlegrePorto AlegreBrazil
  8. 8.Laboratório de Epidemiologia de Malformações Congênitas, Fundação Oswaldo CruzInstituto Oswaldo CruzRio de JaneiroBrazil
  9. 9.Departamento de EstatísticaUniversidade Federal do Rio Grande do SulPorto AlegreBrazil
  10. 10.Departamento de BioquímicaUniversidade Federal do Rio Grande do SulPorto AlegreBrazil
  11. 11.Serviço de Genética MédicaHospital de Clínicas de Porto AlegrePorto AlegreBrazil
  12. 12.Departamento de Medicina InternaUniversidade Federal do Rio Grande do SulPorto AlegreBrazil
  13. 13.Medical Genetics ServiceHospital de Clínicas de Porto AlegrePorto AlegreBrazil

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