Predicting disease progression in progressive cerebellar ataxias: integrating clinical, imaging, fluid, genetic, and digital biomarkers

Hao Y and Hao X (2026) Predicting disease progression in progressive cerebellar ataxias: integrating clinical, imaging, fluid, genetic, and digital biomarkers. Front. Neurol. 17:1921210. doi: 10.3389/fneur.2026.1921210 

This review synthesizes evidence across five complementary biomarker domains, clinical, imaging, fluid, genetic, and digital, and judges their readiness for forecasting onset and progression. Clinical scales such as SARA capture genotype-specific trajectories but lose sensitivity at the extremes of the disease course. Volumetric, microstructural, and spectroscopic MRI and blood neurofilament light chain change before ataxia onset and predict subsequent decline, whereas repeat length and genetic modifiers set prior risk. Wearable-sensor gait and balance metrics detect change earlier than clinical scales and sharply reduce required sample sizes. We argue that no single modality satisfies every context of use, and that stage-specific, multimodal composites, integrated through harmonized international cohorts and machine learning, offer the most credible path to prognostic enrichment and to shorter, adequately powered, and preventive trials.

Evolution of Friedreich's Ataxia Management Across Established and Emerging Therapies-Systematic Review and Meta-Analysis

Garah B, Aljabri H, Aljohani A, Alnuzha E, Maihoub A, Almuzaini R, Aljohani L, Alshamani L, Alluqmani M. Evolution of Friedreich's Ataxia Management Across Established and Emerging Therapies-Systematic Review and Meta-Analysis. J Clin Med. 2026 Jul 21;15(14):5707. doi: 10.3390/jcm15145707. PMID: 42513621; PMCID: PMC13413417. 

 Friedreich’s ataxia (FRDA) is a challenging neurodegenerative disorder with limited pharmacologic treatment options. Among the therapies reviewed, omaveloxolone was the only agent to demonstrate a statistically significant improvement in neurological outcomes; however, this finding is based on very low-certainty evidence. Consequently, omaveloxolone may be the most promising current pharmacologic option, but its true efficacy remains uncertain and should be confirmed in larger, longer, and well-designed randomized controlled trials. Other pharmacologic agents showed no consistent evidence of benefit. Safety outcomes were broadly comparable between intervention and control groups; however, available safety evidence remains limited by imprecision, small sample sizes, and relatively short follow-up periods. Although no substantial increase in adverse events was observed, confidence in the safety estimates remains limited.

Multi-omics Mendelian randomization integrating GWAS, eQTL, mQTL and pQTL data prioritizes mitochondrial gene FXN as a hypothesis−generating candidate for nephrolithiasis

Wu Y, Ye S, Li P, Wu Z, Guo Z, Bian J, Sheng M and Lai D (2026) Multi-omics Mendelian randomization integrating GWAS, eQTL, mQTL and pQTL data prioritizes mitochondrial gene FXN as a hypothesis−generating candidate for nephrolithiasis. Front. Immunol. 17:1876576. doi: 10.3389/fimmu.2026.1876576 

This multi-omics MR study links mitochondrial genes, particularly FXN, to urolithiasis risk. Although colocalization evidence was weak (PP.H4 = 0.0239) and replication in independent cohorts was not statistically significant, the multi−omics consistency across methylation, expression, and protein levels prioritizes FXN as a hypothesis−generating candidate for further investigation. Because all QTL data are blood− or plasma−derived, this study provides blood/plasma QTL−based genetic prioritization rather than kidney−specific causal inference.

Enhanced frataxin expression in Arabidopsis thaliana modulates iron metabolism and improves growth under iron stress

A. Terenzi, M.A. Pagani, M.V. Busi, D.F. Gomez-Casati, Enhanced frataxin expression in Arabidopsis thaliana modulates iron metabolism and improves growth under iron stress, Plant Physiology and Biochemistry, Volume 238, 2026, 111687, ISSN 0981-9428, doi: 10.1016/j.plaphy.2026.111687.

Frataxin plays a crucial role in iron homeostasis, Fe-S cluster, and heme biogenesis. This study investigated the impact of constitutive AtFH overexpression in Arabidopsis thaliana. The results demonstrated significant alterations in Fe-S protein activity, iron distribution, and the expression of genes associated with iron transport, Fe-S cluster assembly, and iron storage. Notably, AtFH-overexpressing plants displayed enhanced growth, with increased rosette area and improved root development, under both iron-deficient and iron-excess conditions. While these findings provide valuable insights into the regulatory potential of frataxin in optimizing plant iron homeostasis, they also highlight the need for tissue-specific and stress-inducible approaches to fully evaluate its application in crop resilience.

Serial assessment of echocardiographic measures in Friedreich ataxia

David R. Lynch, Medina Keita, Katherine Gunther, Courtney Park, Kimberly Schadt, Laura Mercer Rosa, Kimberly Y. Lin, Serial assessment of echocardiographic measures in Friedreich ataxia, American Heart Journal Plus: Cardiology Research and Practice, 2026, 100869, ISSN 2666-6022, doi:10.1016/j.ahjo.2026.100869. 

Overall, FRDA hearts initially showed mild hypertrophy with normal systolic function, and a decrease in systolic function up to 30 years later in the disease course. Markers of maximal hypertrophy, in particular septal wall thickness (IVSTd), moderately correlated with genetic severity (GAA1). GAA1 values predicted later stage cardiac disease manifestations in FRDA (presence of arrhythmias, decreases in ejection fraction to less than 50%). Among echocardiographic parameters, early elevations in septal and posterior wall thickness and a hyperdynamic ejection fraction predicted later adverse outcomes including arrhythmias, decreases in ejection fraction, and death.

Hearing Aid Benefit in Auditory Neuropathy Due to Friedreich Ataxia: A Case Report

Melville IZ, Smith AH, Coad GB, Thorne PR, Roxburgh RH, Taylor RL. Hearing Aid Benefit in Auditory Neuropathy Due to Friedreich Ataxia: A Case Report. J Speech Lang Hear Res. 2026 Aug 26:1-11. doi: 10.1044/2026_JSLHR-25-00671. Epub ahead of print. PMID: 42647417. 

Behavioral and electrophysiological testing confirmed ANSD. Aided testing showed improved speech detection and discrimination for low-intensity sounds in quiet, although benefit in noise was limited. The patient experienced reduced fatigue and reported additional unique hearing benefits that extended beyond speech discrimination. 

Hearing aids have the potential to improve hearing, hearing-related quality of life, and fatigue in patients with Friedreich ataxia and auditory neuropathy, with benefits extending beyond speech discrimination. A trial with an amplification device should be considered for all adults with Friedreich ataxia and hearing loss due to ANSD, verified using subjective and behavioral assessments. Use of open-ended, patient-centered validation tools is recommended to capture the full scope of benefit.

Physiologically Regulated Frataxin Gene Replacement Restores Neurological Function in a Mouse Model of Friedreich Ataxia

Pilotto F, Dall'Agnol L, Reutenauer L, Paschaki M, Puccio H. Physiologically Regulated Frataxin Gene Replacement Restores Neurological Function in a Mouse Model of Friedreich Ataxia. Hum Gene Ther. 2026 Aug 9:10430342261474315. doi: 10.1177/10430342261474315. Epub ahead of print. PMID: 42572232. 

Although gene therapy strategies aimed at restoring FXN have shown promise, excessive expression can lead to mitochondrial dysfunction, emphasizing the importance of maintaining FXN within a physiological range. Here, we evaluated a gene therapy approach based on a human mini-frataxin construct (miniFXN7) incorporating an endogenous regulatory element to enable controlled FXN expression. The construct was delivered systemically using an AAV-PHP.eB vector in the Pvalb-cKO mouse model of FA. MiniFXN7 treatment resulted in widespread neuronal transduction and restoration of FXN expression toward a near-physiological range in the neuronal populations examined. Treated mice exhibited sustained improvements in motor coordination and proprioceptive function, including normalization of H-reflex responses. At the cellular level, miniFXN7 restored succinate dehydrogenase activity, a mitochondrial Fe-S enzyme, and was associated with partial normalization of mitochondrial morphology. In parallel, neuronal integrity was preserved and astrogliosis reduced across the cerebellum. These findings demonstrate that physiologically regulated FXN replacement is sufficient to achieve substantial functional rescue in FA, supporting a gene therapy strategy based on a transgene expression driven by endogenous regulatory elements.

Directional information flow in human frataxin defines allosteric pathways connecting the hydrophobic core to the iron-binding ridge

Kırboğa KK, Küçüksille EU. Directional information flow in human frataxin defines allosteric pathways connecting the hydrophobic core to the iron-binding ridge. FEBS J. 2026 Aug 13. doi: 10.1111/febs.70687. Epub ahead of print. PMID: 42593048. 

We identify LEU47 (LEU136 in UniProt Q16595 numbering) and LEU51 (LEU140) as primary signal sources with net transfer entropy values of 0.415 and 0.249, respectively, connecting the hydrophobic core to the iron-binding acidic ridge. NMR relaxation at 600 and 800 MHz reveals elevated R2/R1 ratios (9.90-10.00) and significant exchange contributions (Rex = 3-5 s-1) specifically at these primary signal source residues, indicating μs-ms dynamics. Hydrogen-deuterium exchange mass spectrometry demonstrates that hub residues possess intermediate protection factors (ln(PF) = 5.97-6.07) optimal for conformational signaling, while iron binding induces bidirectional protection changes propagating through the identified pathway. Systematic mutagenesis confirms that disruption of hub residues reduces iron-binding affinity 1.9-4.2-fold and decreases thermal stability by 4.3-11.2 °C, despite occupying buried-core positions distant from the iron-coordinating acidic-ridge residues (LEU136/LEU140 Cα to ASP122, ASP124, and GLU189 = 6.7 to 11.8 Å in PDB 1EKG). The strong prediction-experiment correlation establishes transfer entropy as a reliable predictor of functionally important allosteric residues and provides a methodological framework applicable to other proteins of biomedical significance.

Myeloid cell replacement induces intercellular mitochondrial transfer and restores metabolism in a mouse model of mitochondrial disease

Cho, H., Sayana, R., Koladiya, A. et al. Myeloid cell replacement induces intercellular mitochondrial transfer and restores metabolism in a mouse model of mitochondrial disease. Nat Commun (2026). doi:10.1038/s41467-026-76775-y 

 Here we show that myeloid cell replacement promotes neurological and cardiac recovery in FA mice through intercellular mitochondrial transfer. Donor-derived mitochondria are transferred from microglia and macrophages to central nervous system cells and cardiomyocytes, increasing oxidative phosphorylation and ATP synthesis gene expression and mitochondrial protein abundance. These molecular changes are accompanied by improved survival and growth in male and female mice and enhanced spontaneous locomotion, strength, coordination and cardiac and function in female mice. In cultured cells, mitochondrial transfer requires direct cell-cell contact and partially restores respiratory capacity in frataxin-deficient recipient cells, which exhibit enhanced mitochondrial uptake, suggesting disease-specific mechanisms that promote mitochondrial acquisition or retention. These findings identify mitochondrial transfer as a mechanism underlying the therapeutic effects of myeloid cell replacement and support hematopoietic transplantation for FA and other mitochondrial disorders.

Allosteric rewiring of mitochondrial stress signaling through Miro1

Drwesh L, Fitzgerald J; Allosteric rewiring of mitochondrial stress signaling through Miro1: Cell Chemical Biology, 33, 1071-1073. doi:10.1016/j.chembiol.2026.07.011 

 Mitochondrial dysfunction is a common feature of both inherited mitochondrial disorders and neurodegenerative diseases. Although these disorders differ clinically, many converge on shared underlying pathobiology, including oxidative damage, impaired mitochondrial homeostasis, and defective mitochondrial quality control. Chandra and colleagues investigate these shared stress pathways in the context of Friedreich’s ataxia.