CO105 A Retrospective Study Characterizing Age at Loss of Ambulation Among Patients With Friedreich Ataxia Using Health Administrative Claims Data in the United States

A. Salvucci, C. Qian, L. Powell, D. Lynch, G. Vasco, K. Johnston, I. Tomazos, CO105 A Retrospective Study Characterizing Age at Loss of Ambulation Among Patients With Friedreich Ataxia Using Health Administrative Claims Data in the United States, Value in Health, Volume 26, Issue 12, Supplement, 2023, Pages S33-S34, ISSN 1098-3015, doi:10.1016/j.jval.2023.09.177. 

 In this cross-sectional analysis, most patients who were diagnosed with FA before the ages of 24 years experienced LOA and wheelchair use before the age of 16 years. While limitations exist in ascertainment of LOA using claims data, findings suggest that those who had earlier onset of FA also had earlier LOA.

Mitochondrial impairment, decreased sirtuin activity and protein acetylation in dorsal root ganglia in Friedreich Ataxia models

Arabela Sanz-Alcázar, Elena Britti, Fabien Delaspre, Marta Medina-Carbonero, Maria Pazos-Gil, Jordi Tamarit, Joaquim Ros & Elisa Cabiscol​. Mitochondrial impairment, decreased sirtuin activity and protein acetylation in dorsal root ganglia in Friedreich Ataxia models. Cell. Mol. Life Sci. 81, 12 (2024). doi:10.1007/s00018-023-05064-4 

 The NAD+/NADH ratio was reduced and sirtuin activity was impaired. We identified alpha tubulin as the major acetylated protein from DRG homogenates whose levels were increased in FXNI151F mice compared to WT mice. In the mitochondria, superoxide dismutase (SOD2), a SirT3 substrate, displayed increased acetylation in frataxin-deficient DRG neurons. Since SOD2 acetylation inactivates the enzyme, and higher levels of mitochondrial superoxide anion were detected, oxidative stress markers were analyzed. Elevated levels of hydroxynonenal bound to proteins and mitochondrial Fe2+ accumulation was detected when frataxin decreased. Honokiol, a SirT3 activator, restores mitochondrial respiration, decreases SOD2 acetylation and reduces mitochondrial superoxide levels. Altogether, these results provide data at the molecular level of the consequences of electron transport chain dysfunction, which starts negative feedback, contributing to neuron lethality. This is especially important in sensory neurons which have greater susceptibility to frataxin deficiency compared to other tissues.

Predictors of Survival in Friedreich's Ataxia: A Prospective Cohort Study

Indelicato, E., Reetz, K., Maier, S., Nachbauer, W., Amprosi, M., Giunti, P., Mariotti, C., Durr, A., de Rivera Garrido, F.J.R., Klopstock, T., Schöls, L., Klockgether, T., Bürk, K., Pandolfo, M., Didszun, C., Grobe-Einsler, M., Nanetti, L., Nenning, L., Kiechl, S., Dichtl, W., Ulmer, H., Schulz, J.B., Boesch, S. and (2023), Predictors of Survival in Friedreich's Ataxia: A Prospective Cohort Study. Mov Disord. doi:10.1002/mds.29687 

Arrhythmias, progressive neurological disability, and diabetes mellitus influence the overall survival in FA. We built a survival prognostic score which identifies patients meriting closer surveillance and who may benefit from early invasive cardiac monitoring and therapy.

Generation and characterization of two human iPSC lines, IGIBi014-A and IGIBi015-A, from Friedreich's ataxia (FRDA) patients with pathogenic (GAA/TTC)n repeat expansion in first intron of the Frataxin (FXN) gene

Ahmad I, Kapoor H, Kumar Srivastava A, Faruq M. Generation and characterization of two human iPSC lines, IGIBi014-A and IGIBi015-A, from Friedreich's ataxia (FRDA) patients with pathogenic (GAA/TTC)n repeat expansion in first intron of the Frataxin (FXN) gene. Stem Cell Res. 2023 Dec 16;74:103289. doi: 10.1016/j.scr.2023.103289. Epub ahead of print. PMID: 38141359. 

We generated two iPSC lines from FRDA patients with biallelic expansion of GAA repeats in the first intron ofFXNgene.IGIBi014-A and IGIBi015-Aboth iPSC lines demonstrated characteristics of pluripotency, normal karyotypes (46, XY),the capacity to differentiate into all three germ layers, and the ability to sustain the GAA repeat expansion with decreased FXN mRNA expression. These cell lines will be utilized to comprehend the pathophysiology of the illness and the FRDA's predictive phenotypes.