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

• Published in: Journal of human genetics Vol. 65; no. 10; pp. 895 - 902
• Main Authors: Perez Maturo, J., Zavala, L., Vega, P., González-Morón, D., Medina, N., Salinas, V., Rosales, J., Córdoba, M., Arakaki, T., Garretto, N., Rodríguez-Quiroga, S., Kauffman, M. A.
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.10.2020
• Subjects: Adolescent; Adult; Age of Onset; Aged; Aged, 80 and over; Algorithms; Apraxia; Argentina - epidemiology; Ataxia; Cerebellar Ataxia - classification; Cerebellar Ataxia - diagnosis; Cerebellar Ataxia - epidemiology; Cerebellar Ataxia - genetics; Child; Child, Preschool; Chronic Disease; Disease Progression; Epidemiology; Family medical history; Genes; Genes, Dominant; Genes, Recessive; Genetic Heterogeneity; Genetics; Genotype & phenotype; High-Throughput Nucleotide Sequencing; Humans; Middle Aged; Molecular Diagnostic Techniques - methods; Movement disorders; Neurology; Next-generation sequencing; Nystagmus, Pathologic - genetics; Patients; Pediatrics; Phenotypes; Prospective Studies; SCA2 protein; Spinocerebellar ataxia; Young Adult; Argentina
• ISSN: 1434-5161; 1435-232X; 1435-232X
• DOI: 10.1038/s10038-020-0785-z

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.