Correlation of genotype, phenotype and mitochondrial metabolism of patients with Friedreich's ataxia with the aim of implementing innovative therapies

Abstract

Title: Presentation of a cohort of 40 Czech and Slovak patients with Friedreich's ataxia with the aim of introducing innovative therapiesBackground and objectives: Friedreich's ataxia (FA) is an autosomal recessive inherited disease caused by a mutation in the FXN gene for the mitochondrial protein frataxin. As a result of its dysfunction, both neurological symptoms and non-constant damage to other tissues or organs are manifested. Since 1999, 76 genetically confirmed Czech and Slovak patients have been examined at the Center of Hereditary Ataxia in Prague (40 active; 20 died; 16 lost in follow-up). Our aim was to correlate clinical data monitoring the natural course of the disease with metabolic and genetic markers in order to prepare for the application of targeted biological / gene therapies.Methods: Patients with genetically confirmed FA were neurologically examined and underwent clinical assessment including the Scale for the Assessment and Rating of Ataxia (SARA); Activities of Daily Living (ADL); Inventory of Non-Ataxia Signs (INAS); Spino-Cerebellar Ataxia Functional Index (SCAFI); Montreal Cognitive Assessment (MoCA); quality of life assessments; neurocognitive tests; and specific laboratory tests including biosampling, mitochondrial function in isolated platelets (spectrophotometry method) and genetic analysis of the FXN gene by determining the length of GAA expansions (long-range polymerase chain reaction (PCR) with PCR product analysis on an Agilent 4200 TapeStation system).Results: A total of 40 patients with FA were examined with a comprehensive protocol in the period 08/2021 to 06/2022 and their data were entered into the EFACTS registry (European Friedreich's Ataxia Consortium for Translational Studies). Their mean age was 32.3 (8-72) years (6 of them under 18), 22 male / 18 female; average ADL 15.4 (2-27) out of 36 total; average SARA 22.6 (7-40) out of 40 total. The activity of respiratory chain complexes in isolated platelets in 26 patients with Friedreich's ataxia and controls shows decreased cytochrome c oxidase (COX) activity and decreased COX / CS (CS - citrate synthase) ratio.Conclusion: We present a well-defined cohort of Czech patients with FA, which has recently been included in the EFACTS registry and is ready for clinical trials. Further biochemical analysis and longitudinal follow-up is ongoing.