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Overwhelming genetic heterogeneity and exhausting molecular diagnostic process in chronic and progressive ataxias: facing it up with an algorithm, a gene, a panel at a time

Journal of Human Genetics volume 65, pages 895–902 (2020)Cite this article

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Abstract

Ataxias are one of the most frequent complaints in Neurogenetics units worldwide. Currently, more than 50 subtypes of spinocerebellar ataxias and more than 60 recessive ataxias are recognized. We conducted an 11-year prospective, observational, analytical study in order to estimate the frequency of pediatric and adult genetic ataxias in Argentina, to describe the phenotypes of this cohort and evaluate the diagnostic yield of the algorithm used in our unit. We included 334 ataxic patients. Our diagnostic approach was successful in one-third of the cohort. A final molecular diagnosis was reached in 113 subjects. This rate is significantly higher in the subgroup of patients with a positive family history, where the diagnostic yield increased to 55%. The most prevalent dominant and recessive ataxias in Argentina were SCA-2 (36% of dominant ataxias) and FA (62% of recessive ataxias), respectively. Next generation sequencing-based assays were diagnostic in the 65% of the patients requiring these tests. These results provide relevant epidemiological information, bringing a comprehensive knowledge of the most prevalent subtypes of genetic ataxias and their phenotypes in our territory and laying the groundwork for rationally implementing genetic diagnostic programs for these disorders in our country.

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Acknowledgements

We thank the patients and families for their support and collaboration.

Funding

This study was funded by a grant from the Ministry of Science and Technology of Argentina.

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Author notes

  1. These authors contributed equally: J. Perez Maturo, L. Zavala

  2. These authors jointly supervised this work: S. Rodríguez-Quiroga, M.A. Kauffman

Authors and Affiliations

  1. Neurogenetics Unit, Neurology Division, J.M. Ramos Mejía Hospital, University Center of Neurology “J. M. Ramos Mejía,” Faculty of Medicine, University of Buenos Aires, Buenos Aires, Argentina

    J. Perez Maturo, L. Zavala, P. Vega, D. González-Morón, N. Medina, V. Salinas, J. Rosales, M. Córdoba, S. Rodríguez-Quiroga & M. A. Kauffman

  2. Precision Medicine and Genomics Group, IIMT-CONICET and Faculty of Biomedical Sciences-Austral University, Buenos Aires, Argentina

    J. Perez Maturo, V. Salinas & M. A. Kauffman

  3. Movement Disorders Area, Neurology Division, J.M. Ramos Mejía Hospital, University Center of Neurology “J. M. Ramos Mejía,” Faculty of Medicine, University of Buenos Aires, Buenos Aires, Argentina

    T. Arakaki, N. Garretto & S. Rodríguez-Quiroga

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  1. J. Perez Maturo
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Contributions

All authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by LZ, JPM, and SRQ. The first draft of the paper was written by LZ and JPM and all authors commented on previous versions of the paper. All authors read and approved the final paper. LZ and JPM contributed equally and should be considered both first authors in this work, while SRQ, and MK contributed equally and should be considered both as the last authors.

Corresponding author

Correspondence to S. Rodríguez-Quiroga.

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Conflict of interest

JPM and VS have received scholarship support from Argentinean National Science Council (CONICET). MK has received grant support from Ministry of Health of Buenos Aires City, Argentinean National Science Council (CONICET) and Argentinean Ministry of Science and Technology. He serves as Associate Editor of the journal Neurologia Argentina. The rest of the authors declare that they have no conflict of interest.

Ethics approval

This study was approved by the Institutional Ethics Committee of the Hospital J.M. Ramos Mejia of Buenos Aires, Argentina. All patients and parents provided written informed consent for genetic analyses and use of their anonymized data. All experiments and methods were carried out in accordance with the relevant guidelines and regulations of the Institutional Ethics Committee of the Hospital J.M. Ramos Mejia of Buenos Aires, Argentina. All clinical investigations have been conducted in accordance with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent for genetic analyses and use of their anonymized data was obtained from all individual participants and/or parents included in the study. Patients signed informed consent regarding publishing their data.

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Perez Maturo, J., Zavala, L., Vega, P. et al. Overwhelming genetic heterogeneity and exhausting molecular diagnostic process in chronic and progressive ataxias: facing it up with an algorithm, a gene, a panel at a time. J Hum Genet 65, 895–902 (2020). https://doi.org/10.1038/s10038-020-0785-z

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