Longitudinal analysis shows GAA1 length and baseline clinical status as robust predictors of progression in Friedreich ataxia

Manrique L, Martínez-Dubarbie F, Pelayo-Negro AL, Benitez-Calle N, Sanchez-Pelaez MV, Cota-Gonzalez D, Loza R, Martinez-Díaz R, Irure-Ventura J, Sanchez-Quintana C, Sanchez I, Matilla-Dueñas A, Infante J. Longitudinal analysis shows GAA1 length and baseline clinical status as robust predictors of progression in Friedreich ataxia. J Neurol. 2026 Apr 9;273(5):259. doi: 10.1007/s00415-026-13812-2. PMID: 41954755; PMCID: PMC13065527.

Frataxin levels were significantly reduced in patients and correlated with GAA1 length and baseline severity. SARA, FARS–ADL, and INAS worsened significantly over time, while SCAFI and CCFS remained stable. GAA1 length and baseline SARA score emerged as the strongest predictors of progression. CSF NfL was elevated in younger patients and declined with age but did not correlate with severity or progression. These results support GAA1 length and baseline clinical status as robust predictors of progression and suggest limited utility of CSF NfL as a longitudinal biomarker particularly in later disease stages.

Hypomagnetic Fields Influence the Developmental Duration, Fecundity and Temperature Stress Resistance of Drosophila melanogaster via Frataxin-Associated Traits

Kang H, Wan G, Zhang J, Pan W. Hypomagnetic Fields Influence the Developmental Duration, Fecundity and Temperature Stress Resistance of Drosophila melanogaster via Frataxin-Associated Traits. Biology (Basel). 2026 Feb 27;15(5):391. doi: 10.3390/biology15050391. PMID: 41823819; PMCID: PMC12985338. 

 The impact of HMF on temperature stress resistance was particularly specific: it enhanced recovery from chill coma in control (GFP-RNAi) flies, while it accelerated recovery from heat shock in frataxin-silenced (fh-RNAi) flies. The mechanisms through which HMF modulate frataxin-associated phenotypes at a fundamental physical level warrant further investigation.

Arctigenin derivative (ARC-18) improved mitochondrial dysfunction and ameliorated frataxin deficiency symptoms via PGC-1α signaling

Gong Q, Han X, Liu T, Xiong B, Zhang B, Xie Y, Wan H, Ali T, Yang X, Li S. Arctigenin derivative (ARC-18) improved mitochondrial dysfunction and ameliorated frataxin deficiency symptoms via PGC-1α signaling. Genes Dis. 2025 Sep 1;13(4):101838. doi: 10.1016/j.gendis.2025.101838. PMID: 41884717; PMCID: PMC13011025.

Notably, co-treatment with the PGC-1α inhibitor SR-18292 abolished ARC-18 effects, confirming its dependence on PGC-1α activation to rescue mitochondrial deficits in FXN-deficient cells.

Generation of Friedreich's ataxia induced pluripotent stem cells carrying the FXN c.165 + 5G>C splicing mutation

Yameogo P, Gerhart BJ, Sentmanat MF, Neilson A, Cui X, Verma M, Lynch DR, Napierala JS, Napierala M. Generation of Friedreich's ataxia induced pluripotent stem cells carrying the FXN c.165 + 5G>C splicing mutation. Stem Cell Res. 2026 Mar 16;93:103966. doi: 10.1016/j.scr.2026.103966. Epub ahead of print. PMID: 41865460. 

 Friedreich's ataxia (FRDA) is a multisystem, autosomal recessive disease caused by biallelic expansion of GAA repeats in intron 1 of the frataxin gene (FXN). While ∼96% of FRDA patients carry expanded GAA repeats on both FXN alleles, ∼4% are compound heterozygous with expanded GAA repeats on one allele and another mutation on the second allele. We generated induced pluripotent stem cells from blood lymphocytes from a FRDA patient carrying the FXN c.165 + 5G > C point mutation, which interferes with canonical splicing of intron 1 of the FXN gene. These cells allow for development of therapeutic approaches that target splicing defect in FRDA.

Deciphering the missing links between Friedreich ataxia and multiple sclerosis for targeted drug development

Kwa FAA, Anjomani-Virmouni S, Ramchunder Z, Kendal E, Xiao J. Deciphering the missing links between Friedreich ataxia and multiple sclerosis for targeted drug development. Drug Discov Today. 2026 Mar 16;31(3):104644. doi: 10.1016/j.drudis.2026.104644. Epub ahead of print. PMID: 41850598. 

 FA and MS appear to share some overlapping molecular mechanisms, including iron and lipid dysregulation, mitochondrial dysfunction, oxidative stress, and neuroinflammation. Recent research, including comparative transcriptomic analyses, offers valuable insights into shared disease pathways, with implications for potential biomarkers and therapeutic targets. In this review, we explore the shared pathological features and disease mechanisms in FA and MS, highlighting how delineating these shared pathways could inform early diagnostic strategies and support the development of targeted, mechanism-based interventions, including opportunities for drug repurposing.

Advancing a novel ASO therapy for Friedreich ataxia cardiomyopathy using a pre-clinical human vascularised cardiac organoid model

Jarmon G. Lees, Li Li, Haoxiang Zhang, Anne M. Kong, Andrew Treller, Geraldine M. Mitchell, Mirella Dottori, Alice Pebay, Stephen Wilcox, Mark Chong, Roger Peverill, Martin Delatyki, Jeffrey M. Pullin, Davis McCarthy, Jill S. Napierala, Marek Napierala, Shiang Y. Lim, Advancing a novel ASO therapy for Friedreich ataxia cardiomyopathy using a pre-clinical human vascularised cardiac organoid model, Journal of Molecular and Cellular Cardiology Plus, Volume 15, Supplement, 2026, 100527, ISSN 2772-9761, doi:10.1016/j.jmccpl.2025.100527. 

ASO-mediated knockdown of MEG3 reversed EC angiogenic dysfunction, limited SMC migration, reversed mitochondrial dysfunction, and prevented cardiac injury in a human vascularized cardiac organoid model. These findings suggest that MEG3 may be a promising novel therapy for treating cardiovascular disease in FA.

Fronto-Cerebellar Connectivity Disruptions and Functional Reorganization in Friedreich’s Ataxia: A Structural and Resting-State fMRI Study

Ravi Dadsena, Sandro Romanzetti, Stella Andrea Lischewski, Yingua Jing, Dagmar Timmann, Jennifer Faber, Jörg B. Schulz, Kathrin Reetz, Imis Dogan, Fronto-Cerebellar Connectivity Disruptions and Functional Reorganization in Friedreich’s Ataxia: A Structural and Resting-State fMRI Study, NeuroImage, 2026, 121872, ISSN 1053-8119, doi:10.1016/j.neuroimage.2026.121872.

While regional atrophy is known to be associated with symptoms, functional network alterations may represent a critical pathological mechanism; however, their specific contribution to motor and cognitive impairment remains unclear.

Advanced Heart Failure in Friedreich's Ataxia: A Story of Challenges, Opportunities, and Hope

Advanced Heart Failure in Friedreich's Ataxia: A Story of Challenges, Opportunities, and Hope. Satoshi Miyashita, Anthony Zaki, Kaitlin Schlabach, Gabriel Kim, Juliane K. Vierecke, David Lynch, Carmela Tan, Eileen Hsich, and Paulino Alvarez; JACC: Case Reports, 2026, 107391, ISSN 2666-0849, doi:10.1016/j.jaccas.2026.107391.

Heart failure is the leading cause of death in patients with FRDA. For those with high-risk features for adverse cardiovascular outcomes, careful monitoring of disease progression and early evaluation for advanced heart failure therapies are warranted.

Peripheral frataxin levels govern long-term clinical progression in Friedreich ataxia

Rummey C, Blair IA, Mesaros C, Rojsajjakul T, Dong Y, Wilmot G, et al. Peripheral frataxin levels govern long-term clinical progression in Friedreich ataxia. BMJ Neurology Open. 2026;8:e001561. doi:10.1136/bmjno-2026-001561 

 The present study demonstrates that frataxin levels directly correlate with all major clinical outcomes in FRDA, including not only cross-sectional markers such as AOO and disease severity, but also LoA as a disease milestone and long-term progression slopes of mFARS and USS. The associations were observed consistently across two independent cohorts and two distinct assay platforms, providing robust support for peripheral frataxin level as a clinically meaningful biomarker in both natural history studies and interventional trials.

Friedreich ataxia transcriptomic dysregulation and identification of cell type-specific biomarkers: A systematic review and meta-analysis

Friedreich ataxia transcriptomic dysregulation and identification of cell type-specific biomarkers: A systematic review and meta-analysis Marnie L Maddock, Sara Miellet, Anjila Dongol, Amy J Hulme, Chloe K Kennedy, Louise A Corben, Rocio K Finol-Urdaneta, Alberto Nettel-Aguirre, Chiara Dionsi, Martin B Delatycki, Joel M Gottesfeld, Massimo Pandolfo, Elisabetta Soragni, Sanjay I Bidichandani, Jarmon G Lees, Shiang Y Lim, Jill S Napierala, Marek Napierala, Mirella Dottori bioRxiv 2026.03.18.712785; doi: 10.64898/2026.03.18.712785 

Together, these findings implicate cell type specific transcriptional programs as potential drivers of selective vulnerability and establish a framework for prioritising biomarkers in FRDA.