Frequency of GAA- FGF14 Ataxia in a Large Cohort of Brazilian Patients With Unsolved Adult-Onset Cerebellar Ataxia

Luiz Eduardo Novis¹, Rodrigo S Frezatti¹, David Pellerin¹, Pedro J Tomaselli¹, Shahryar Alavi¹, Marcus Vinícius Della Coleta¹, Mariana Spitz¹, Marie-Josée Dicaire¹, Pablo Iruzubieta¹, José Luiz Pedroso¹, Orlando Barsottini¹, Andrea Cortese¹, Matt C Danzi¹, Marcondes C França Jr¹, Bernard Brais¹, Stephan Zuchner¹, Henry Houlden¹, Salmo Raskin¹, Wilson Marques¹, Helio A Teive¹

Affiliations

Affiliation

¹ From the Pós-graduação Em Medicina Interna e Ciências da Saúde (L.E.N., H.A.T.), Hospital de Clínicas da Universidade Federal do Paraná, Curitiba, Brazil; Department of Neuromuscular Diseases (L.E.N., D.P., S.A., P.I., A.C., H.H.), UCL Queen Square Institute of Neurology and the National Hospital for Neurology and Neurosurgery, London, UK; Department of Neurology (R.S.F., P.J.T., W.M.), School of Medicine at Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil; Departments of Neurology and Neurosurgery (D.P., M.-J.D., B.B.), Montreal Neurological Hospital and Institute, McGill University, Canada; Departamento de Neurologia (M.V.D.C.), Universidade do Estado do Amazonas, Manaus; Departamento de Especialidades Médicas (M.S.), Serviço de Neurologia, Universidade Estadual do Rio de Janeiro, Brazil; Department of Neurology (P.I.), Donostia University Hospital; Neuroscience Area (P.I.), Biodonostia Health Research Institute, San Sebastian; Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED) (P.I.), Spain; Department of Neurology (J.L.P., O.B.), Ataxia Unit, Universidade Federal de São Paulo, SP, Brazil; Department of Brain and Behavioral Sciences (A.C.), University of Pavia, Italy; Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics (M.C.D., S.Z.), University of Miami Miller School of Medicine; Department of Neurology (M.C.F.), School of Medical Sciences-University of Campinas (UNICAMP), São Paulo, Brazil; Department of Human Genetics (B.B.), McGill University, Montreal, Canada; and Laboratório Genetika (S.R.), Curitiba, PR, Brazil.

PMID: 37646005
PMCID: PMC10461713
DOI: 10.1212/NXG.0000000000200094

Frequency of GAA- FGF14 Ataxia in a Large Cohort of Brazilian Patients With Unsolved Adult-Onset Cerebellar Ataxia

Luiz Eduardo Novis et al. Neurol Genet. 2023.

. 2023 Aug 28;9(5):e200094.

doi: 10.1212/NXG.0000000000200094. eCollection 2023 Oct.

Authors

Affiliation

¹ From the Pós-graduação Em Medicina Interna e Ciências da Saúde (L.E.N., H.A.T.), Hospital de Clínicas da Universidade Federal do Paraná, Curitiba, Brazil; Department of Neuromuscular Diseases (L.E.N., D.P., S.A., P.I., A.C., H.H.), UCL Queen Square Institute of Neurology and the National Hospital for Neurology and Neurosurgery, London, UK; Department of Neurology (R.S.F., P.J.T., W.M.), School of Medicine at Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil; Departments of Neurology and Neurosurgery (D.P., M.-J.D., B.B.), Montreal Neurological Hospital and Institute, McGill University, Canada; Departamento de Neurologia (M.V.D.C.), Universidade do Estado do Amazonas, Manaus; Departamento de Especialidades Médicas (M.S.), Serviço de Neurologia, Universidade Estadual do Rio de Janeiro, Brazil; Department of Neurology (P.I.), Donostia University Hospital; Neuroscience Area (P.I.), Biodonostia Health Research Institute, San Sebastian; Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED) (P.I.), Spain; Department of Neurology (J.L.P., O.B.), Ataxia Unit, Universidade Federal de São Paulo, SP, Brazil; Department of Brain and Behavioral Sciences (A.C.), University of Pavia, Italy; Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics (M.C.D., S.Z.), University of Miami Miller School of Medicine; Department of Neurology (M.C.F.), School of Medical Sciences-University of Campinas (UNICAMP), São Paulo, Brazil; Department of Human Genetics (B.B.), McGill University, Montreal, Canada; and Laboratório Genetika (S.R.), Curitiba, PR, Brazil.

PMID: 37646005
PMCID: PMC10461713
DOI: 10.1212/NXG.0000000000200094

Abstract

Objectives: Intronic FGF14 GAA repeat expansions have recently been found to be a common cause of hereditary ataxia (GAA-FGF14 ataxia; SCA27B). The global epidemiology and regional prevalence of this newly reported disorder remain to be established. In this study, we investigated the frequency of GAA-FGF14 ataxia in a large cohort of Brazilian patients with unsolved adult-onset ataxia.

Methods: We recruited 93 index patients with genetically unsolved adult-onset ataxia despite extensive genetic investigation and genotyped the FGF14 repeat locus. Patients were recruited across 4 different regions of Brazil.

Results: Of the 93 index patients, 8 (9%) carried an FGF14 (GAA)_≥250 expansion. The expansion was also identified in 1 affected relative. Seven patients were of European descent, 1 was of African descent, and 1was of admixed American ancestry. One patient carrying a (GAA)₃₇₆ expansion developed ataxia at age 28 years, confirming that GAA-FGF14 ataxia can occur before the age of 30 years. One patient displayed episodic symptoms, while none had downbeat nystagmus. Cerebellar atrophy was observed on brain MRI in 7 of 8 patients (87%).

Discussion: Our results suggest that GAA-FGF14 ataxia is a common cause of adult-onset ataxia in the Brazilian population, although larger studies are needed to fully define its epidemiology.

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Conflict of interest statement

L.E. Novis, R.S. Frezatti, D. Pellerin., P.J. Tomaselli, S. Alavi, M.V. Della Coleta, M. Spitz, M.-J. Dicaire, P. Iruzubieta, J.L. Pedroso, O. Barsottini, A. Cortese, and M.C. Danzi report no disclosures. M.C. França Jr took part as a PI in a clinical trial for Friedreich ataxia, sponsored by PTC, and received research funding from Friedreich ataxia research alliance. None of these related to the current study. B. Brais reports no disclosures. S. Zuchner is a consultant on drug targets for Aeglea BioTherapeutics and consultant on clinical trial design for Applied Therapeutics, all of them unrelated to the work in the present manuscript. H. Houlden, S. Raskin, W. Marques, and H.A. Teive report no disclosures. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/NG.

Figures

**Figure. Allele Distribution and Genetic Analysis of the *FGF14* GAA Repeat Locus**
(A) Allele distribution of the *FGF14* repeat locus in 94 Brazilian patients with unsolved adult-onset ataxia. The repeat length was measured by capillary electrophoresis of fluorescent long-range PCR amplification products. The allele sizes are expressed in numbers of triplet repeat units. Expanded alleles consisting of non-GAA repeats are represented by red triangles. The dashed red line indicates the pathogenic threshold of at least 250 GAA repeat units. The bold dashed black line within the violin plot shows the median allele size. (B) Fragment length analysis results of patient 1.1 carrying an expanded allele of 253 GAA repeat units. (C and D) Results of repeat-primed PCR targeting the (C) 3′-end and (D) 5′-end of the *FGF14* repeat locus in patient 1.1. (E) Excerpt of Sanger sequencing chromatogram showing the GAA motif of the expanded allele of patient 1.1.

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References

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Frequency of GAA- FGF14 Ataxia in a Large Cohort of Brazilian Patients With Unsolved Adult-Onset Cerebellar Ataxia

Affiliation

Frequency of GAA- FGF14 Ataxia in a Large Cohort of Brazilian Patients With Unsolved Adult-Onset Cerebellar Ataxia

Authors

Affiliation

Abstract

Conflict of interest statement

Figures

References

Grants and funding

LinkOut - more resources

Full Text Sources

Miscellaneous