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Introduction: Friedreich Ataxia (FA) is a multisystem neurodegenerative disease. Affected individuals rely on mobility assistive technologies (MAT) (e.g. wheelchairs) and require long-term treatments and care. To analyse the patients' health-related quality of life (HRQoL), the EuroQol 5 Dimension 3 Level survey (EQ-5D-3L)-a widely used and recommended generic measure-is used in clinical and in health economic studies. Concerns about using the instrument in mobility-impaired individuals who might have difficulties finding appropriate response options for mobility-related items led us to investigate how the 3L dimensions perform in patients with FA using or not using MAT., Methods: Using longitudinal data from 607 patients with FA of the EFACTS study (from baseline to the 3-year follow-up), we analysed the acceptability, distribution properties, validity, and responsiveness of the EQ-5D-3L, focusing on the mobility item. Analyses were stratified for patients without and with different MAT-usage., Results: We identified that n = 177 patients used no MAT, n = 299 a wheelchair and n = 131 walking aids. The mobility item non-response was highest in wheelchair users (6.8%) and lowest in patients without MAT. Walking aid users showed the least variability, all selecting the mid-response option "some problems" for mobility. The mobility item correlated moderately with disease severity (r sp  = 0.35) and the activities of daily living scale (r sp  = 0.36) in wheelchair users. No correlation exists for walking aid users. The strongest health changes occurred for wheelchair users, the weakest for walking aid users. The mobility dimensions showed the highest amount of no changes., Conclusion: The EQ-5D-3L's mobility item has limitations in MAT users, particularly in walking aid users, due to a tendency towards mid-responses. These limitations may affect the efficacy and (cost)effectiveness conclusions drawn from interventions and clinical trials with mobility-impaired individuals. Further research is needed to explore the understanding and interpretation of responses of the EQ-5D in patients with FA with mobility support., Trial Registration: ClinicalTrials.gov identifier NCT02069509., Competing Interests: Declarations. Conflict of Interest: All authors declare that they have no competing interests to declare that are relevant to the content of this article. Michelle Pfaff started a Master Program during the preparation of the manuscript. Therefore, her affiliation changed into School of Public Health, San Diego State University, San Diego, CA, USA. MGE is member of the European Reference Network – Rare Neurological Diseases (ERN‐RND). Ethical Approval: EFACTS was approved by the ethics committees of the participating centres and have been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. Written informed consent was obtained from all study participants of EFACTS., (© 2024. The Author(s).)

This case report presents the management of tachycardiomyopathy (TCM) in a patient with Friedreich ataxia, a hereditary disorder characterized by progressive neurodegeneration and associated cardiac complications. The patient exhibited severe tachycardia-induced cardiac dysfunction, complicating the clinical picture due to the overlapping neurological symptoms of Friedreich ataxia. Utilizing a 3D mapping system, catheter ablation was performed to accurately identify and target the arrhythmogenic foci contributing to the patient's TCM. The procedure resulted in significant symptom relief and improvement in cardiac function, underscoring the potential benefits of advanced electrophysiological techniques in managing complex cases. This report highlights the importance of a multidisciplinary approach in diagnosing and treating cardiac manifestations in patients with Friedreich ataxia, as well as the efficacy of 3D mapping technology in guiding successful ablation therapies., (© 2024 Wiley Periodicals LLC.)

Friedreich's Ataxia (FRDA) is the most common autosomal recessive ataxia worldwide and is caused by biallelic unstable intronic GAA expansions at FXN. With its limited therapy and the recent approval of the first disease-modifying agent for FRDA, the search for biological markers is urgently needed to assist and ease the development of therapies. MiRNAs have emerged as promising biomarkers in various medical fields such as oncology, cardiology, epilepsy and neurology as well. Cell-free plasmatic miRNAs have potential advantages as biomarkers because of their size, stability against blood RNases, relative ease of obtaining, storage and measurement. In this study, we attempted to characterize the plasma miRNA signature (RNA-Seq followed by qRT-PCR) and its clinical/structural correlates in a cohort of Brazilian patients with FRDA. Our results showed that miR-26a-5p is upregulated and miR-15a-5p is downregulated. The first was correlated with age at onset, cerebellum volume, spinal cord cross-sectional area (C2-CSA) and the left ventricle mass (LV_Mass). For the miR-15a-5p, significant correlations were found with cerebellum volume, spinal cord eccentricity and LV_Mass. It has been previously hypothesized that these miRs target BDNF, modulating its expression and, when this gene is downregulated, it leads to neuronal loss, explaining the ataxic phenotype and our results reinforce this hypothesis. The miR-26a-5p was already associated with cardiomyocyte hypertrophy through the increased NLRP3 inflammasome activity, which is indirectly linked with cardiac hypertrophy. Considering that, we propose these miRNAs as possible prognostic biomarkers for FRDA. However, longitudinal studies are still needed to validate their clinical use., Competing Interests: Declarations. Competing Interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Cerebellar transcranial direct current stimulation (ctDCS) has emerged as a promising, non-invasive, and safe neuromodulatory intervention capable of reducing ataxia symptoms and restoring cerebellum-motor connectivity. However, previous studies have only applied ctDCS in isolation, without association with specific training. This study aimed to assess the effect of ctDCS combined with gait training on functional mobility, balance, and symptoms and severity of ataxia. A randomized, triple-blind, sham-controlled, bi-center clinical trial was conducted with forty-four adults with cerebellar ataxia. Volunteers were randomized to receive five daily sessions of either real ctDCS (n = 11; 2 mA for 25 min) or sham ctDCS (n = 11) during gait training. Functional mobility, balance, and symptoms and severity of ataxia were assessed using the Time Up and Go test, the MiniBESTest, and the Scale for the Assessment and Rating of Ataxia (SARA), respectively, before and after the interventions. Both groups showed improvement in functional mobility, but there was no significant difference between the ctDCS and sham groups. However, the ctDCS group demonstrated significant improvements in cerebellar ataxia severity as reflected by SARA scores, particularly in tests of stance, sitting, speech disturbance, nose-finger test, and heel-shin slide test. Notably, no improvements were observed in balance. This study indicates that while ctDCS combined with gait training may improve specific symptoms of cerebellar ataxia, it does not significantly enhance overall functional mobility compared to sham treatment., Competing Interests: Declarations. Ethical Approval: This study was approved by the local research ethics committee (No. ) and registered on clinicaltrials.org (NCT03703830 - https://clinicaltrials.gov/study/NCT03703830 ) in 2018-11-01. Competing Interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Neuropsychiatric symptoms (NPS) are common in hereditary ataxias as a part of the cerebellar cognitive affective syndrome. In Friedreich ataxia (FRDA), one of the most common hereditary ataxias, depressive symptoms were previously reported, but little is known about other NPS. We aimed to study the presence and severity of a broad range of NPS in individuals with FRDA and assess the relationship between the NPS and the disease severity, cognition, and quality of life and to examine the concordance between the NPS reported by the patients and by their informants. Mild Behavioral Impairment Checklist (MBI-C), a questionnaire designed for screening NPS in the early stages of neurodegenerative diseases, was administered to informants of individuals with FRDA and healthy controls and to people with FRDA themselves. Compared to healthy controls, patients with FRDA scored significantly higher in the total MBI-C score, emotion dysregulation domain (corresponding to depression and anxiety), and decreased motivation domain. When assessed by caregiver, the total MBI-C score and several NPS domains correlated with activities of daily living. Only psychotic symptoms were related to ataxia severity and general cognition. When endorsed by patients, only the relation between few MBI-C domains and quality of life was observed. We found slight to moderate agreement between informant-rated and patient-rated scores. NPS, particularly emotion dysregulation and decreased motivation, are common and clinically relevant in FRDA and should receive more attention due to their potential impact on quality of life and the possibility of therapeutic intervention., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Purpose: Friedreich ataxia (FDRA) is a debilitating neurodegenerative disease that can have ophthalmological manifestations including visual dysfunction, nystagmus, and optic atrophy. However, severe photophobia has not been reported nor evaluated with functional magnetic resonance imaging (fMRI)., Methods: A 64-year-old white female with a 37-year history of FDRA presented to the eye clinic with worsening photophobia of 3 years. To measure her visual cortex activation and subjective responses during episodes of photophobia, she underwent event-related fMRI with light stimuli. In comparison, the same protocol was conducted in an individual with photophobia but without FDRA. After the fMRI, both patients were treated with 35 units of BoNT-A applied to the forehead., Results: Analysis of visual cortex activity in response to light stimulus in the FDRA patient showed no correlation between blood oxygen level dependent (BOLD) activation and light stimuli in the first (r = -0.100, p = 0.235), and a weak negative correlation in the second half of the fMRI scan (r = -0.236 p = 0.004). In notable contrast, significant positive correlations were noted between visual cortex activity and the light stimulus (1st half: r = 0.742, p < 0.001, vs. 2nd half: r = 0.614, p < 0.001) in the comparator . Six weeks later, no improvement in photophobia was noted in either patient., Conclusion and Importance: Our study highlights photophobia as one potential ocular manifestation of FDRA and suggests that one underlying contributor may be a decoupled cortical neurovascular response to light. Our study provides novel information that may guide physiologic understanding and future treatments in this disease., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. The authors have no conflict of interest.

Vatiquinone, a 15-lipoxygenase inhibitor, is in development for patients with Friedreich ataxia. The study determined the effect of vatiquinone on electrocardiogram parameters. This was a 2-part, single-center, randomized, double-blinded, and placebo-controlled study. Part 1 used an adaptive approach to identify a supratherapeutic dose, while Part 2 evaluated the effect of vatiquinone on Fridericia corrected QT interval (QTcF). A safe and tolerated supratherapeutic dose of 1400 mg was identified. Concentration-QTcF analysis confirmed there was no statistically significant relationship between vatiquinone concentration and QTcF. QTcF effect (ie, ΔΔQTcF) exceeding 10 milliseconds was excluded for concentrations up to approximately 11,500 ng/mL. By-time-point analysis confirmed that least-squares mean ΔΔQTcF was below 10 milliseconds. Largest least-squares mean ΔΔQTcF of 1.5 milliseconds was observed at 2 hours after dosing. Vatiquinone did not have a clinically relevant effect on heart rate nor on cardiac conduction (PR interval and QRS interval). No new safety signals were found, as safety data are consistent with the known safety profile of vatiquinone. These findings altogether demonstrated that there is a minimal cardiac risk for vatiquinone concentrations up to the supratherapeutic dose level., (© 2024 The Author(s). Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

Background: Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disorder caused by an expanded GAA repeat in the first intron of the FXN gene., Objective: The aim of this study was to analyze leukocyte telomeres length (LTL) in FRDA to verify the possible relationships between LTL and disease progression. We investigated LTL in a cohort of FRDA biallelic patients (n = 61), heterozygous (n = 29), and age-matched healthy subjects (n = 87)., Methods: LTL was measured by real-time polymerase chain reaction quantitative analysis (qPCR)., Results: The results showed that before 35 years of age, leukocyte telomeres were longer in patients than in controls, whereas the reverse applies in patients above 36 years of age. Interestingly, LTL was greater than controls at any age in heterozygous subjects. This picture mirrors what has been previously observed in vitro in FRDA cultured fibroblasts, showing significantly longer telomeres at early passages because of activation of an alternative lengthening of telomeres (ALT)-like mechanism, but showing accelerated telomere shortening as population doubling increases. GAA1 repeat length is positively correlated with the LTL and negatively correlated with the age at blood sampling. The relationship of LTL with clinical parameters (cardiomyopathy, diabetes, dependence on a wheelchair) was also analyzed. Significantly shorter leukocyte telomeres were associated with the presence of cardiomyopathy, but not with diabetes and the dependence on a wheelchair., Conclusions: Overall, the present study indicates that telomere length analysis in FRDA may be a relevant biomarker for following the stages of the disease. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Friedreich ataxia (FA) is a rare neurodegenerative disease caused by decreased levels of the mitochondrial protein frataxin. Frataxin has been related in iron homeostasis, energy metabolism, and oxidative stress. Ferroptosis has recently been shown to be involved in FA cellular degeneration; however, its role in dorsal root ganglion (DRG) sensory neurons, the cells that are affected the most and the earliest, is mostly unknown. In this study, we used primary cultures of frataxin-deficient DRG neurons as well as DRG from the FXN I151F mouse model to study ferroptosis and its regulatory pathways. A lack of frataxin induced upregulation of transferrin receptor 1 and decreased ferritin and mitochondrial iron accumulation, a source of oxidative stress. However, there was impaired activation of NRF2, a key transcription factor involved in the antioxidant response pathway. Decreased total and nuclear NRF2 explains the downregulation of both SLC7A11 (a member of the system Xc, which transports cystine required for glutathione synthesis) and glutathione peroxidase 4, responsible for increased lipid peroxidation, the main markers of ferroptosis. Such dysregulation could be due to the increase in KEAP1 and the activation of GSK3β, which promote cytosolic localization and degradation of NRF2. Moreover, there was a deficiency in the LKB1/AMPK pathway, which would also impair NRF2 activity. AMPK acts as a positive regulator of NRF2 and it is activated by the upstream kinase LKB1. The levels of LKB1 were reduced when frataxin decreased, in agreement with reduced pAMPK (Thr172), the active form of AMPK. SIRT1, a known activator of LKB1, was also reduced when frataxin decreased. MT-6378, an AMPK activator, restored NRF2 levels, increased GPX4 levels and reduced lipid peroxidation. In conclusion, this study demonstrated that frataxin deficiency in DRG neurons disrupts iron homeostasis and the intricate regulation of molecular pathways affecting NRF2 activation and the cellular response to oxidative stress, leading to ferroptosis., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Cerebellar pathology engenders the disturbance of movement that characterizes Friedreich ataxia (FRDA), yet the impact of cerebellar pathology on cognition in FRDA remains unclear. Numerous studies have unequivocally demonstrated the role of the cerebellar pathology in disturbed cognitive, language and affective regulation, referred to as Cerebellar Cognitive Affective Syndrome (CCAS), and quantified by the CCAS-Scale (CCAS-S). The presence of dysarthria in many individuals with ataxia, particularly FRDA, may confound results on some items of the CCAS-S resulting in false-positive scores. This study explored the relationship between performance on the CCAS-S and clinical metrics of disease severity in 57 adults with FRDA. In addition, this study explored the relationship between measures of intelligibility and naturalness of speech and scores on the CCAS-S in a subgroup of 39 individuals with FRDA. We demonstrated a significant relationship between clinical metrics and performance on the CCAS-S. In addition, we confirmed the items that returned the greatest rate of failure were based on Verbal Fluency Tasks, revealing a significant relationship between these items and measures of speech. Measures of speech explained over half of the variance in the CCAS-S score suggesting the role of dysarthria in the performance on the CCAS-S is not clear. Further work is required prior to adopting the CCAS-S as a cognitive screening tool for individuals with FRDA., (© 2024. The Author(s).)

Omaveloxolone (SKYCLARYS ® ) is approved for the treatment of Friedreich ataxia (FA) in patients aged ≥16 years in the United States and European Union (EU). The recommended dosage is 150 mg administered orally once daily as three 50-mg capsules. However, some patients with FA may have oropharyngeal dysphagia or difficulty swallowing whole capsules; therefore, alternate method(s) of administration are needed. A Phase 1 clinical study in 32 healthy volunteers evaluated the relative bioavailability, safety, and tolerability of a single dose of omaveloxolone when capsule contents were sprinkled on and mixed in applesauce compared to when taken as intact capsules. Palatability when sprinkled on and mixed in applesauce was assessed with a questionnaire. After a single 150-mg dose, the peak and overall exposures of omaveloxolone were similar irrespective of administration method, with the 90% CIs of the geometric least squares mean ratio (%) for maximum plasma concentration (C max ), AUC 0-t , and AUC 0-∞ within the 80% to 125% reference intervals. Omaveloxolone was absorbed more slowly as intact capsules (median t max , 10 h) compared with sprinkled capsule contents over applesauce (median t max , 6 h). With chronic daily administration of omaveloxolone to treat FA, the 4-h difference in t max is not considered clinically relevant. Sprinkled omaveloxolone capsule contents on applesauce were well tolerated, with acceptable palatability and no serious adverse events. Given the similar systemic exposure when capsules were swallowed whole, sprinkling omaveloxolone capsule contents on and mixing in applesauce is a feasible alternative method of administering omaveloxolone and has been included in both the United States and EU prescribing information., (© 2024 Biogen, Inc. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

Friedreich's Ataxia (FRDA) is the leading cause of ataxia worldwide, but data on epidemiology and diagnostic journey are scarce, particularly in Latin America. Herein we estimated the prevalence of FRDA in the most populous Brazilian state and characterized the diagnostic odyssey of the disease. We received anonymized data of patients with FRDA from advocacy groups and physicians. Prevalence was estimated dividing the number of patients by the population of the state as reported in the last census. Patients were invited to answer an online survey to describe clinical data and diagnostic journey of the disease. FRDA estimated prevalence was 0.367:100,000, with a slight predominance of women (58.2% vs 41.7%). One hundred and four patients answered the survey (mean age of 37.3 ± 13.8 years; 75.9% classical and 24.0% late onset). On average, 6.2 ± 4.1 physicians were visited before reaching the diagnosis. Mean diagnostic delay was 7.8 ± 6.7 years; no difference between classical and LOFA groups was found. Most of the patients reported unsteadiness and gait abnormalities as the first symptom. Neurologists and orthopedical surgeons were the main specialties first sought by patients. We found a prevalence of 0.36:100,000 for FRDA in the state of São Paulo, Brazil. The disease is characterized by remarkable diagnostic delay, with no relevant differences between classical and LOFA patients., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Friedreich ataxia is a hereditary neurodegenerative disorder resulting from reduced levels of the protein frataxin due to an expanded GAA repeat in the FXN gene. This deficiency causes progressive degeneration of specific neuronal populations in the cerebellum and the consequent loss of movement coordination and equilibrium, which are some of the main symptoms observed in affected individuals. Like in other neurodegenerative diseases, previous studies suggest that glial cells could be involved in the neurodegenerative process and disease progression in patients with Friedreich ataxia. In this work, we followed and characterized the progression of changes in the cerebellar cortex in the latest version of Friedreich ataxia humanized mouse model, YG8-800 (Fxn null :YG8s(GAA) >800 ), which carries a human FXN transgene containing >800 GAA repeats. Comparative analyses of behavioral, histopathological, and biochemical parameters were conducted between the control strain Y47R and YG8-800 mice at different time points. Our findings revealed that YG8-800 mice exhibit an ataxic phenotype characterized by poor motor coordination, decreased body weight, cerebellar atrophy, neuronal loss, and changes in synaptic proteins. Additionally, early activation of glial cells, predominantly astrocytes and microglia, was observed preceding neuronal degeneration, as was increased expression of key proinflammatory cytokines and downregulation of neurotrophic factors. Together, our results show that the YG8-800 mouse model exhibits a stronger phenotype than previous experimental murine models, reliably recapitulating some of the features observed in humans. Accordingly, this humanized model could represent a valuable tool for studying Friedreich ataxia molecular disease mechanisms and for preclinical evaluation of possible therapies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Friedreich Ataxia (FRDA) is an inherited neuromuscular disorder triggered by a deficit of the mitochondrial protein frataxin. At a cellular level, frataxin deficiency results in insufficient iron-sulfur cluster biosynthesis and impaired mitochondrial function and adenosine triphosphate production. The main clinical manifestation is a progressive balance and coordination disorder which depends on the involvement of peripheral and central sensory pathways as well as of the cerebellum. Besides the neurological involvement, FRDA affects also the striated muscles. The most prominent manifestation is a hypertrophic cardiomyopathy, which also represents the major determinant of premature mortality. Moreover, FRDA displays skeletal muscle involvement, which contributes to the weakness and marked fatigue evident throughout the course of the disease. Herein, we review skeletal muscle findings in FRDA generated by functional imaging, histology, as well as multiomics techniques in both disease models and in patients. Altogether, these findings corroborate a disease phenotype in skeletal muscle and support the notion of progressive mitochondrial damage as a driver of disease progression in FRDA. Furthermore, we highlight the relevance of skeletal muscle investigations in the development of biomarkers for early-phase trials and future therapeutic strategies in FRDA.

Introduction: The last decade has witnessed major breakthroughs in identifying novel genetic causes of hereditary ataxias, deepening our understanding of disease mechanisms, and developing therapies for these debilitating disorders., Areas Covered: This article reviews the currently approved and most promising candidate pharmacotherapies in relation to the known disease mechanisms of the most prevalent autosomal recessive ataxias. Omaveloxolone is an Nrf2 activator that increases antioxidant defense and was recently approved for treatment of Friedreich ataxia. Its therapeutic effect is modest, and further research is needed to find synergistic treatments that would halt or reverse disease progression. Promising approaches include upregulation of frataxin expression by epigenetic mechanisms, direct protein replacement, and gene replacement therapy. For ataxia-telangiectasia, promising approaches include splice-switching antisense oligonucleotides and small molecules targeting oxidative stress, inflammation, and mitochondrial function. Rare recessive ataxias for which disease-modifying therapies exist are also reviewed, emphasizing recently approved therapies. Evidence supporting the use of riluzole and acetyl-leucine in recessive ataxias is discussed., Expert Opinion: Advances in genetic therapies for other neurogenetic conditions have paved the way to implement feasible approaches with potential dramatic benefits. Particularly, as we develop effective treatments for these conditions, we may need to combine therapies, consider newborn testing for pre-symptomatic treatment, and optimize non-pharmacological approaches.

The translocator protein TSPO is an evolutionary conserved mitochondrial protein overexpressed in various contexts of neurodegeneration. Friedreich Ataxia (FA) is a neurodegenerative disease due to GAA expansions in the FXN gene leading to decreased expression of frataxin, a mitochondrial protein involved in the biosynthesis of iron-sulfur clusters. We previously reported that Tspo was overexpressed in a Drosophila model of this disease generated by CRISPR/Cas9 insertion of approximately 200 GAA in the intron of fh, the fly frataxin gene. Here, we describe a new Drosophila model of FA with 42 GAA repeats, called fh-GAAs. The smaller expansion size allowed to obtain adults exhibiting hallmarks of the FA disease, including short lifespan, locomotory defects and hypersensitivity to oxidative stress. The reduced lifespan was fully rescued by ubiquitous expression of human FXN, confirming that both frataxins share conserved functions. We observed that Tspo was overexpressed in heads and decreased in intestines of these fh-GAAs flies. Then, we further overexpressed Tspo specifically in glial cells and observed improved survival. Finally, we investigated the effects of Tspo overexpression in healthy flies. Increased longevity was conferred by glial-specific overexpression, with opposite effects in neurons. Overall, this study highlights protective effects of glial TSPO in Drosophila both in a neurodegenerative and a healthy context., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: A drug repositioning effort supported the possible use of the anti-HIV drug etravirine as a disease-modifying drug for Friedreich ataxia (FRDA). Etravirine increases frataxin protein and corrects the biochemical defects in cells derived from FRDA patients. Because of these findings, and since etravirine displays a favorable safety profile, we conducted a pilot open-label phase 2 clinical trial assessing the safety and potential efficacy of etravirine in FRDA patients., Methods: Thirty-five patients were stratified into three severity groups and randomized to etravirine 200 mg/day or 400 mg/day. They were treated for 4 months. Safety endpoints were the number and type of adverse events and number of dropouts. Efficacy endpoints were represented by changes in peak oxygen uptake and workload as measured by incremental exercise test, SARA score, cardiac measures, measures of QoL and disability. Data were collected 4 months before the start of the treatment (T - 4), at the start (T0), at the end (T4) and 4 months after the termination of the treatment (T + 4)., Results: Etravirine was reasonably tolerated, and adverse events were generally mild. Four months of etravirine treatment did not significantly increase the peak oxygen uptake but was associated with a change in the progression of the SARA score ( p value < 0.001), compared to the 4 months pre- and post-treatment. It also significantly increased peak workload ( p value = 0.021). No changes in the cardiac measures were observed. Health and QoL measures showed a worsening at the suspension of the drug., Conclusions: In this open trial etravirine treatment was safe, reasonably well tolerated and appreciably improved neurological function and exercise performance. Even though a placebo effect cannot be ruled out, these results suggest that etravirine may represent a potential therapeutic agent in FRDA deserving testing in a randomized placebo-controlled clinical trial.

Background: Friedreich ataxia is a rare genetic disorder associated with progressive mitochondrial dysfunction leading to widespread sequelae including ataxia, muscle weakness, hypertrophic cardiomyopathy, diabetes mellitus, and neuromuscular scoliosis. Children with Friedreich ataxia are at high risk for periprocedural complications during posterior spinal fusion due to their comorbidities., Aim: To describe our single-center perioperative management of patients with Friedreich ataxia undergoing posterior spinal fusion., Methods: Adolescent patients with Friedreich ataxia presenting for spinal deformity surgery between 2007 and 2023 were included in this retrospective case series performed at the Children's Hospital of Philadelphia. Perioperative outcomes were reviewed along with preoperative characteristics, intraoperative anesthetic management, and postoperative medical management., Results: Seventeen patients were included in the final analysis. The mean age was 15 ± 2 years old and 47% were female. Preoperatively, 35% were wheelchair dependent, 100% had mild-to-moderate hypertrophic cardiomyopathy with preserved systolic function and no left ventricular outflow tract obstruction, 29% were on cardiac medications, and 29% were on pain medications. Intraoperatively, 53% had transesophageal echocardiography monitoring; 12% had changes in volume status on echo but no changes in function. Numerous combinations of total intravenous anesthetic agents were used, most commonly propofol, remifentanil, and ketamine. Baseline neuromonitoring signals were poor in four patients and one patient lost signals, resulting in 4 (24%) wake-up tests. The majority (75%) were extubated in the operating room. Postoperative complications were high (88%) and ranged from minor complications like nausea/vomiting (18%) to major complications like hypotension/tachycardia (29%) and need for extracorporeal membrane oxygenation support in one patient (6%)., Conclusions: Patients with Friedreich ataxia are at high risk for perioperative complications when undergoing posterior spinal fusion and coordinated multidisciplinary care is required at each stage. Future research should focus on the utility of intraoperative echocardiography, optimal anesthetic agent selection, and targeted fluid management to reduce postoperative cardiac complications., (© 2024 The Authors. Pediatric Anesthesia published by John Wiley & Sons Ltd.)

Background: Calcitriol, the active form of vitamin D (also known as 1,25-dihydroxycholecalciferol), improves the phenotype and increases frataxin levels in cell models of Friedreich ataxia (FRDA)., Objectives: Based on these results, we aimed measuring the effects of a calcitriol dose of 0.25 mcg/24h in the neurological function and frataxin levels when administered to FRDA patients for a year., Methods: 20 FRDA patients where recluted and 15 patients completed the treatment for a year. Evaluations of neurological function changes (SARA scale, 9-HPT, 8-MWT, PATA test) and quality of life (Barthel Scale and Short Form (36) Health Survey [SF-36] quality of life questionnaire) were performed. Frataxin amounts were measured in isolated platelets obtained from these FRDA patients, from heterozygous FRDA carriers (relatives of the FA patients) and from non-heterozygous sex and age matched controls., Results: Although the patients did not experience any observable neurological improvement, there was a statistically significant increase in frataxin levels from initial values, 5.5 to 7.0 pg/μg after 12 months. Differences in frataxin levels referred to total protein levels were observed among sex- and age-matched controls (18.1 pg/μg), relative controls (10.1 pg/μg), and FRDA patients (5.7 pg/μg). The treatment was well tolerated by most patients, and only some of them experienced minor adverse effects at the beginning of the trial., Conclusions: Calcitriol dosage used (0.25 mcg/24 h) is safe for FRDA patients, and it increases frataxin levels. We cannot rule out that higher doses administered longer could yield neurological benefits. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Friedreich ataxia (FRDA) is a life-threatening hereditary ataxia; its incidence is 1:50,000 individuals in the Caucasian population. A unique therapeutic drug for FRDA, the antioxidant Omaveloxolone, has been recently approved by the US Food and Drug Administration (FDA). FRDA is a multi-systemic neurodegenerative disease; in addition to a progressive neurodegeneration, FRDA is characterized by hypertrophic cardiomyopathy, diabetes mellitus and musculoskeletal deformities. Cardiomyopathy is the predominant cause of premature death. The onset of FRDA typically occurs between the ages of 5 and 15. Given the complexity and heterogeneity of clinical features and the variability of their onset, the identification of biomarkers capable of assessing disease progression and monitoring the efficacy of treatments is essential to facilitate decision making in clinical practice. We conducted an RNA-seq analysis in peripheral blood mononuclear cells from FRDA patients and healthy donors, identifying a signature of small non-coding RNAs (sncRNAs) capable of distinguishing healthy individuals from the majority of FRDA patients. Among the differentially expressed sncRNAs, microRNAs are a class of small non-coding endogenous RNAs that regulate posttranscriptional silencing of target genes. In FRDA plasma samples, hsa-miR-148a-3p resulted significantly upregulated. The analysis of the Receiver Operating Characteristic (ROC) curve, combining the circulating expression levels of hsa-miR-148a-3p and hsa-miR-223-3p (previously identified by our group), revealed an Area Under the Curve (AUC) of 0.86 (95%, Confidence Interval 0.77-0.95; p-value < 0.0001). An in silico prediction analysis indicated that the IL6ST gene, an interesting marker of neuroinflammation in FRDA, is a common target gene of both miRNAs. Our findings support the evaluation of combined expression levels of different circulating miRNAs as potent epi-biomarkers in FRDA. Moreover, we found hsa-miR-148a-3p significantly over-expressed in Intermediate and Late-Onset Friedreich Ataxia patients' group (IOG and LOG, respectively) compared to healthy individuals, indicating it as a putative prognostic biomarker in this pathology., (© 2024. The Author(s).)

Introduction: Friedreich ataxia (FRDA) is a rare autosomal recessive disease, marked by loss of coordination as well as impaired neurological, endocrine, orthopedic, and cardiac function. There are many symptomatic medications for FRDA, and many clinical trials have been performed, but only one FDA-approved medication exists., Areas Covered: The relative absence of the frataxin protein (FXN) in FRDA causes mitochondrial dysfunction, resulting in clinical manifestations. Currently, the only approved treatment for FRDA is an Nrf2 activator called omaveloxolone (Skyclarys). Patients with FRDA also rely on various symptomatic medications for treatment. Because there is only one approved medication for FRDA, clinical trials continue to advance in FRDA. Although some trials have not met their endpoints, many current and upcoming clinical trials provide exciting possibilities for the treatment of FRDA., Expert Opinion: The approval of omaveloxolone provides a major advance in FRDA therapeutics. Although well tolerated, it is not curative. Reversal of deficient frataxin levels with gene therapy, protein replacement, or epigenetic approaches provides the most likely prospect for enduring, disease-modifying therapy in the future.

The exciting news about the US FDA approval of omaveloxolone as the first-ever drug to be approved for an inherited ataxia is welcome news for patients and families that deal with this devastating disease as well as for health care providers and investigators with an interest in this and other rare diseases. This event is the culmination of long and fruitful collaboration between patients, their families, clinicians, laboratory researchers, patient advocacy organizations, industry, and regulatory agencies. The process has generated intense discussion about outcome measures, biomarkers, trial design, and the nature of approval process for such diseases. It also has brought hope and enthusiasm for increasingly better therapies for genetic diseases in general., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Quantitative measurement of physical activity may complement neurological evaluation and provide valuable information on patients' daily life. We evaluated longitudinal changes of physical activity in patients with Friedreich ataxia (FRDA) using remote monitoring with wearable sensors. We performed an observational study in 26 adult patients with FRDA and 13 age-sex matched healthy controls (CTR). Participants were asked to wear two wearable sensors, at non-dominant wrist and at waist, for 7 days during waking hours. Evaluations were performed at baseline and at 1-year follow-up. We analysed the percentage of time spent in sedentary or physical activities, the Vector Magnitude on the 3 axes (VM3), and average number of steps/min. Study participants were also evaluated with ataxia clinical scales and functional tests for upper limbs dexterity and walking capability. Baseline data showed that patients had an overall reduced level of physical activity as compared to CTR. Accelerometer-based measures were highly correlated with clinical scales and disease duration in FRDA. Significantly changes from baseline to l-year follow-up were observed in patients for the following measures: (i) VM3; (ii) percentage of sedentary and light activity, and (iii) percentage of Moderate-Vigorous Physical Activity (MVPA). Reduction in physical activity corresponded to worsening in gait score of the Scale for Assessment and Rating of Ataxia. Real-life activity monitoring is feasible and well tolerated by patients. Accelerometer-based measures can quantify disease progression in FRDA over 1 year, providing objective information about patient's motor activities and supporting the usefulness of these data as complementary outcome measure in interventional trials., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Fichera, Nanetti, Monelli, Castaldo, Marchini, Neri, Vukaj, Marzorati, Porcelli and Mariotti.)

Background: Friedreich's ataxia (FA) is a rare multisystemic disorder which can cause premature death., Objectives: To investigate predictors of survival in FA., Methods: Within a prospective registry established by the European Friedreich's Ataxia Consortium for Translational Studies (EFACTS; ClinicalTrials.gov identifier NCT02069509) we enrolled genetically confirmed FA patients at 11 tertiary centers and followed them in yearly intervals. We investigated overall survival applying the Kaplan-Meier method, life tables, and log-rank test. We explored prognostic factors applying Cox proportional hazards regression and subsequently built a risk score which was assessed for discrimination and calibration performance., Results: Between September 2010 and March 2017, we enrolled 631 FA patients. Median age at inclusion was 31 (range, 6-76) years. Until December 2022, 44 patients died and 119 terminated the study for other reasons. The 10-year cumulative survival rate was 87%. In a multivariable analysis, the disability stage (hazard ratio [HR] 1.51, 95% CI 1.08-2.12, P = 0.02), history of arrhythmic disorder (HR 2.93, 95% CI 1.34-6.39, P = 0.007), and diabetes mellitus (HR 2.31, 95% CI 1.05-5.10, P = 0.04) were independent predictors of survival. GAA repeat lengths did not improve the survival model. A risk score built on the previously described factors plus the presence of left ventricular systolic dysfunction at echocardiography enabled identification of four trajectories to prognosticate up to 10-year survival (log-rank test P < 0.001)., Conclusions: 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. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Friedreich's ataxia is degenerative disease frequently starting around puberty and it's characterized by a progressive gait ataxia, limb weakness, apparition of Babinsky sign, loss of deep tendon reflex, dysarthria and skeletal deformities. The development of vestibular pathology is common but not completely understood. A 16 years old woman with early vestibular defects in relation to a latter Friedreich's ataxia diagnosis is reported., Competing Interests: Conflict of InterestThere are no conflicts of interest or supports for writing and preparing this paper., (© Association of Otolaryngologists of India 2023. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Background: The neurological phenotype of Friedreich ataxia (FRDA) is characterized by neurodegeneration and neuroinflammation in the cerebellum and brainstem. Novel neuroimaging approaches quantifying brain free-water using diffusion magnetic resonance imaging (dMRI) are potentially more sensitive to these processes than standard imaging markers., Objectives: To quantify the extent of free-water and microstructural change in FRDA-relevant brain regions using neurite orientation dispersion and density imaging (NODDI), and bitensor diffusion tensor imaging (btDTI)., Method: Multi-shell dMRI was acquired from 14 individuals with FRDA and 14 controls. Free-water measures from NODDI (FISO) and btDTI (FW) were compared between groups in the cerebellar cortex, dentate nuclei, cerebellar peduncles, and brainstem. The relative sensitivity of the free-water measures to group differences was compared to microstructural measures of NODDI intracellular volume, free-water corrected fractional anisotropy, and conventional uncorrected fractional anisotropy., Results: In individuals with FRDA, FW was elevated in the cerebellar cortex, peduncles (excluding middle), dentate, and brainstem (P < 0.005). FISO was elevated primarily in the cerebellar lobules (P < 0.001). On average, FW effect sizes were larger than all other markers (mean η ρ 2  = 0.43), although microstructural measures also had very large effects in the superior and inferior cerebellar peduncles and brainstem (η ρ 2  > 0.37). Across all regions and metrics, effect sizes were largest in the superior cerebellar peduncles (η ρ 2  > 0.46)., Conclusions: Multi-compartment diffusion measures of free-water and neurite integrity distinguish FRDA from controls with large effects. Free-water magnitude in the brainstem and cerebellum provided the greatest distinction between groups. This study supports further applications of multi-compartment diffusion modeling, and investigations of free-water as a measure of disease expression and progression in FRDA. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Characterizing bedside oculomotor deficits is a critical factor in defining the clinical presentation of hereditary ataxias. Quantitative assessments are increasingly available and have significant advantages, including comparability over time, reduced examiner dependency, and sensitivity to subtle changes. To delineate the potential of quantitative oculomotor assessments as digital-motor outcome measures for clinical trials in ataxia, we searched MEDLINE for articles reporting on quantitative eye movement recordings in genetically confirmed or suspected hereditary ataxias, asking which paradigms are most promising for capturing disease progression and treatment response. Eighty-nine manuscripts identified reported on 1541 patients, including spinocerebellar ataxias (SCA2, n = 421), SCA3 (n = 268), SCA6 (n = 117), other SCAs (n = 97), Friedreich ataxia (FRDA, n = 178), Niemann-Pick disease type C (NPC, n = 57), and ataxia-telangiectasia (n = 85) as largest cohorts. Whereas most studies reported discriminatory power of oculomotor assessments in diagnostics, few explored their value for monitoring genotype-specific disease progression (n = 2; SCA2) or treatment response (n = 8; SCA2, FRDA, NPC, ataxia-telangiectasia, episodic-ataxia 4). Oculomotor parameters correlated with disease severity measures including clinical scores (n = 18 studies (SARA: n = 9)), chronological measures (e.g., age, disease duration, time-to-symptom onset; n = 17), genetic stratification (n = 9), and imaging measures of atrophy (n = 5). Recurrent correlations across many ataxias (SCA2/3/17, FRDA, NPC) suggest saccadic eye movements as potentially generic quantitative oculomotor outcome. Recommendation of other paradigms was limited by the scarcity of cross-validating correlations, except saccadic intrusions (FRDA), pursuit eye movements (SCA17), and quantitative head-impulse testing (SCA3/6). This work aids in understanding the current knowledge of quantitative oculomotor parameters in hereditary ataxias, and identifies gaps for validation as potential trial outcome measures in specific ataxia genotypes., (© 2023. The Author(s).)

Heart, dentate nucleus, and dorsal root ganglia (DRG) are targets of tissue damage in Friedreich ataxia (FA). This report summarizes the histology and histopathology of iron in the main tissues affected by FA. None of the affected anatomical sites reveals an elevation of total iron levels. In the myocardium, a small percentage of fibers shows iron-reactive granular inclusions. The accumulation of larger iron aggregates and fiber invasion cause necrosis and damage to the contractile apparatus. In the dentate nucleus, the principal FA-caused tissue injury is neuronal atrophy and grumose reaction. X-ray fluorescence mapping of iron in the dentate nucleus in FA shows retention of the metal in the center of the collapsed structure. Immunohistochemistry of ferritin, a surrogate marker of tissue iron, confirms strong expression in oligodendrocytes of the efferent white matter of the dentate nucleus and abundance of ferritin-positive microglia in the atrophic gray matter. Iron dysmetabolism in DRG is complex and consists of prominent expression of ferritin in hyperplastic satellite cells and residual nodules, also a loss of the iron export protein ferroportin from the cytoplasm of the remaining DRG nerve cells., Competing Interests: The author declares no conflict of interest., (© 2024 The Author(s). Published by IMR Press.)

Background: Friedreich's Ataxia (FRDA) is a rare hereditary neurodegenerative disorder characterized by progressive ataxia, cardiomyopathy, and diabetes. The disease is caused by a deficiency of frataxin, a mitochondrial protein involved in iron-sulfur cluster synthesis and iron metabolism., Objective: This review aims to summarize recent advances in the development of treatment strategies for FRDA, with a focus on potential drug candidates and their mechanisms of action., Methods: A comprehensive literature search was conducted using various authentic scientific databases to identify studies published in the last decade that investigated potential treatment strategies for FRDA. The search terms used included "Friedreich's ataxia", "treatment", "drug candidates", and "mechanisms of action"., Results: To date, only one drug got approval from US-FDA in the year 2023; however, significant developments were achieved in FRDA-related research focusing on diverse therapeutic interventions that could potentially alleviate the symptoms of this disease. Several promising drug candidates have been identified for the treatment of FRDA, which target various aspects of frataxin deficiency and aim to restore frataxin levels, reduce oxidative stress, and improve mitochondrial function. Clinical trials have shown varying degrees of success, with some drugs demonstrating significant improvements in neurological function and quality of life in FRDA patients., Conclusion: While there has been significant progress in the development of treatment strategies for FRDA, further research is needed to optimize these approaches and identify the most effective and safe treatment options for patients. The integration of multiple therapeutic strategies may be necessary to achieve the best outcomes in FRDA management., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

A major manifestation of Friedreich ataxia (FRDA) is cardiomyopathy, caused by mitochondrial proliferation in myocytes. Because the lifespan for patients with FRDA improves with better treatment modalities, more patients are becoming pregnant, meaning that more medical providers must know how to care for this population. This report provides a review of the literature on multidisciplinary management of pregnant patients with FRDA and cardiomyopathy from preconception through lactation. A cardio-obstetrics team, including cardiology, anesthesiology, and obstetrics, should be involved for this entire period. All patients should be counseled on pregnancy risk using elements of existing stratification systems, and contraception should be discussed, highlighting the safety of intrauterine devices. Electrocardiogram should be obtained at baseline and each trimester, looking for atrial arrhythmias and ST-segment changes, as should transthoracic echocardiogram, with a focus on left ventricular ejection fraction-which is typically normal in FRDA cardiomyopathy-and relative wall thickness and global longitudinal strain-which tend to decrease as cardiomyopathy progresses. Brain natriuretic peptide is also a helpful marker to detect adverse events. If heart failure develops, it should be treated like any other etiology of heart failure during pregnancy. Atrial arrhythmias should be treated with β blockers or electrical cardioversion and anticoagulation, as necessary. Most patients with FRDA can deliver vaginally, and neuraxial analgesia is recommended during labor because of the risks associated with general anesthesia. Breastfeeding is encouraged, even for those taking cardiac medications., Competing Interests: Declaration of Competing Interest The authors have no competing interest to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Friedreich ataxia (FA) is a rare, recessive neuro-cardiodegenerative disease caused by deficiency of the mitochondrial protein frataxin. Mitochondrial dysfunction, a reduction in the activity of iron-sulfur enzymes, iron accumulation, and increased oxidative stress have been described. Dorsal root ganglion (DRG) sensory neurons are among the cellular types most affected in the early stages of this disease. However, its effect on mitochondrial function remains to be elucidated. In the present study, we found that in primary cultures of DRG neurons as well as in DRGs from the FXN I151F mouse model, frataxin deficiency resulted in lower activity and levels of the electron transport complexes, mainly complexes I and II. In addition, altered mitochondrial morphology, indicative of degeneration was observed in DRGs from FXN I151F mice. Moreover, 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 FXN I151F 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 Fe 2+ 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., (© 2023. The Author(s).)

Gene therapy is a potential treatment for Friedreich ataxia, with multiple programs on the horizon. The purpose of this study was to collect opinions about gene therapy from individuals 14 years or older with Friedreich ataxia or parents/caregivers of Friedreich ataxia patients who were diagnosed as children 17 or younger. Participants were asked to complete a survey after reading brief educational materials regarding gene therapy. Most of the patients captured in this survey have an early-onset (classical) presentation of the disease. Participants expressed urgency in participating in gene therapy clinical trials despite the associated risks. About half of the respondents believed that gene therapy would cease progression or minimize symptoms, whereas nearly one-fourth expected to be cured. The survey also revealed how participants perceive their symptom burden, because a substantial majority reported that balance/walking issues most interfere with their quality of life and would be the symptom they would prioritize treating. Although not statistically significant, more caregivers prioritized treating cardiomyopathy than patients. This study provides valuable information on priorities, beliefs, and expectations regarding gene therapy and serves to guide future gene therapy opinion studies and gene therapy trial design., Competing Interests: M.C. and B.J.B. are co-founders of AavantiBio, which supported the employee at ClinicalMind who provided graphical support for the educational material written by the study team. The survey was completed before the acquisition of AavantiBio by Solid Biosciences. None of the authors have any financial, commercial, legal, or professional relationship with Solid Biosciences. There was no commercial support for this study. The study was developed and conducted by the academic team at the University of Florida. Thus, the authors declare that they have no competing interests., (© 2023 The Author(s).)

Objectives: Friedreich Ataxia (FRDA) is the most common recessive ataxia disorder. Yet, little is known of the prevalence in Sweden. In the future, there may be effective disease-modifying therapies, and use of clinical rating scales as well as possible biomarkers in serum or cerebrospinal fluid may be of importance. We evaluated the axonal protein neurofilament light in plasma ( p -NfL) as a possible biomarker for disease severity in FRDA., Materials & Methods: We searched for all possible genetically confirmed FRDA cases in the Västra Götaland Region (VGR) of Sweden, and investigated each patient clinically and obtained blood sample for analysis of p -NfL., Results: We found eight patients corresponding to 1/170.000 adults in the VGR, and 5 of these participated in the study. Three out of the five FRDA patients displayed a small or moderate increase in the p -NfL value, compared to the age-adjusted cut-offs for p -NfL established in the Clinical Neurochemistry Laboratory at our hospital. The two others were the oldest and most severely affected, displayed normal values according the cut-off values. The cohort is too small to make any statistically significant correlation between the five p -NfL values with regard to disease severity., Conclusions: FRDA is less prevalent in our region of Sweden than could be assumed. In concordance with previous studies from other authors, we find that p -NfL may be increased in patients with FRDA, but less so in older more clinically affected patients. Thus, we conclude that on an individual basis, p -NFL is of uncertain clinical value as a suitable biomarker., Competing Interests: HZ has served at scientific advisory boards and/or as a consultant for AbbVie, Acumen, Alector, Alzinova, ALZPath, Annexon, Apellis, Artery Therapeutics, AZTherapies, CogRx, Denali, Eisai, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure, Biogen, and Roche, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). KB has served as a consultant, at advisory boards, or at data monitoring committees for Abcam, Axon, Biogen, Julius Clinical, Lilly, MagQu, Novartis, Roche Diagnostics, and Siemens Healthineers, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB. (BBS), which is a part of the GU Ventures Incubator Program. CL has served as a consultant, at advisory boards for PTC therapeutics and Biogen. MJ declare no financial or other conflicts of interest in relation to this work., (© 2023 The Authors. Published by Elsevier Ltd.)

Introduction: The relevance of rehabilitation in progressive neurological disorders, such as Friedreich's Ataxia (FRDA), has yet to be convincingly proven. FRDA is characterized by ataxia, loss of gait, scoliosis, cardiomyopathy, dysarthria and dysphagia, with reduced life expectancy. The disease onset is usually in adolescence, leading to progressive disability. Omaveloxolone has been recently approved as the first pharmacological treatment for FRDA in adults and adolescents aged 16 years and older. Regarding non-pharmacological therapies, neurorehabilitation is a valuable aid in addressing the symptoms and in maintaining the residual functioning. We performed a prospective observational cohort study to evaluate the efficacy of inpatient rehabilitation (IR) for people with FRDA., Methods: A total of 42 individuals (29 adults and 13 children) with FRDA were recruited. There were 27 ambulant and 15 non-ambulant participants. The patients underwent IR of 3 and 4 weeks in children and adults, respectively. The IR treatment was designed to be applied within a multidisciplinary setting, so FRDA patients underwent, in addition to physiotherapy, also occupational therapy, practical manual activities and psychological support aiming to enhance transferable skills useful in the activities of daily living. The primary outcome was the Scale for the Assessment and Rating of Ataxia (SARA). Other measures were: Friedreich Ataxia Rating Scale (FARS) and Nine Hole Peg Test (NHPT). Furthermore, we used the 6 Minute Walk Test (6MWT), the Timed Up and Go (TUG) and the Berg Balance Scale (BBS) only on ambulant subjects. Outcomes were evaluated at baseline and at the end of the treatment., Results: We report that the IR significantly improves motor performance and ataxia symptoms in patients with FRDA. Our study shows significant functional improvement in all the outcome measures used, except for NHPT bilaterally. FARS and SARA scores post-IR are significatively reduced when compared ( p  < 0.001)., Discussion: We demonstrate that IR programs in FRDA can provide a meaningful clinical improvement in terms of outcome measures. These findings could be useful when approaching progressive neurological disorders., Competing Interests: NP collaborates with Revelo Datalabs Srl. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Paparella, Stragà, Vavla, Pesenti, Merotto, Martorel, Zalunardo, Armellin, Comiotto and Martinuzzi.)

In this paper, we describe the development of a Dictyostelium discoideum strain deficient in frataxin protein (FXN). We investigated the conservation of function between humans and D. discoideum and showed that DdFXN can substitute the human version in the interaction and activation of the Fe-S assembly supercomplex. We edited the D. discoideum fxn locus and isolated a defective mutant, clone 8, which presents landmarks of frataxin deficiency, such as a decrease in Fe-S cluster-dependent enzymatic functions, growth rate reduction, and increased sensitivity to oxidative stress. In addition, the multicellular development is affected as well as growing on bacterial lawn. We also assessed the rescuing capacity of DdFXN-G122V, a version that mimics a human variant present in some FA patients. While the expression of DdFXN-G122V rescues growth and enzymatic activity defects, as DdFXN does, multicellular development defects were only partially rescued. The results of the study suggest that this new D. discoideum strain offers a wide range of possibilities to easily explore diverse FA FXN variants. This can facilitate the development of straightforward drug screenings to look for new therapeutic strategies., (© 2023 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

Friedreich's ataxia (FRDA) is the most common inherited recessive ataxia. Cardiomyopathy (CM) with myocardial hypertrophy is the predominant cause of death. The presence of CM is variable and the risk factors for cardiac involvement are not entirely clear. Markers of collagen degradation, such as C-terminal cross-linked telopeptide of type I collagen (CTX-I), seem to be associated with unfavorable cardiovascular outcomes. The aim of our study was to measure serum CTX-I as a marker of cardiac fibrosis in FRDA patients. We measured serum CTX value in twenty-five FRDA patients (mean age, 31.3 ± 14.7 years) and nineteen healthy controls (mean age, 34.0 ± 13.5 years). Patients underwent echocardiography and SARA scale evaluation. CTX values were significantly higher in the patients than in the control group (31.82 ± 2.27 vs 16.44 ± 1.6 μg/L; p = 0.006). CTX-I was inversely correlated with age (R =  - 0,535; n = 44; p < 0.001). The regression model identified disease duration and TT3 levels to be independent predictors of CTX-I (model R 2  = 0.938; intercept - 64.0, p = 0.071; disease duration coefficient =  - 2.34, p = 0.005; TT3 coefficient = 127.17, p = 0.011). CTX-I, a biomarkers of collagen turnover, is elevated in FRDA and should provide complementary information to identify patients with high cardiological risk even if longitudinal studies are needed to define the role of this serologic marker of collagen metabolism in the natural history of cardiomyopathy in FRDA patients., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Scientists and pharmaceutical companies are working toward delivering gene therapy (GT) for Friedreich ataxia (FRDA). Understanding the views of people with lived experience of FRDA and their parents toward GT is essential to inform trial design and identify potential barriers to participation in clinical trials. The goals of this study were to identify the attitudes toward GT held by individuals with FRDA and parents of individuals with FRDA, and to explore how these may impact future trials for this condition. Audiorecorded, semistructured, qualitative interviews with 19 Australians explored experiences of FRDA, knowledge about clinical trials, views on GT, including risks and benefits, and potential barriers to participation in trials. Participants included thirteen individuals living with FRDA aged between 15-43 years, and six parents of children with FRDA aged 4-12 years of age. Thematic analysis of the interviews identified six main themes. Findings from this study indicate there is strong desire for information regarding GT in FRDA, however the current level of uncertainty around GT makes decision making challenging. The desire to maintain functional status and avoid additional risk of deterioration from an investigational treatment was apparent. Importantly, neurological targets were identified as preferred for GT trials. Further research is required to identify if attitudes and perceptions differ according to geographical location and disease stage.

Cardiomyopathy is often fatal in Friedreich ataxia (FA). However, FA hearts maintain adequate function until advanced disease stages, suggesting initial adaptation to the loss of frataxin (FXN). Conditional cardiac knockout mouse models of FXN show transcriptional and metabolic profiles of the mitochondrial integrated stress response (ISRmt), which could play an adaptive role. However, the ISRmt has not been investigated in models with disease-relevant, partial decrease in FXN. We characterized the heart transcriptomes and metabolomes of three mouse models with varying degrees of FXN depletion: YG8-800, KIKO-700 and FXNG127V. Few metabolites were changed in YG8-800 mice, which did not provide a signature of cardiomyopathy or ISRmt; several metabolites were altered in FXNG127V and KIKO-700 hearts. Transcriptional changes were found in all models, but differentially expressed genes consistent with cardiomyopathy and ISRmt were only identified in FXNG127V hearts. However, these changes were surprisingly mild even at advanced age (18 months), despite a severe decrease in FXN levels to 1% of those of wild type. These findings indicate that the mouse heart has low reliance on FXN, highlighting the difficulty in modeling genetically relevant FA cardiomyopathy., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2023. Published by The Company of Biologists Ltd.)

Friedreich ataxia (FRDA) is a rare genetic multisystem disorder caused by a pathological GAA trinucleotide repeat expansion in the FXN gene. The numerous drawbacks of historical cellular and rodent models of FRDA have caused difficulty in performing effective mechanistic and translational studies to investigate the disease. The recent discovery and subsequent development of induced pluripotent stem cell (iPSC) technology provides an exciting platform to enable enhanced disease modelling for studies of rare genetic diseases. Utilising iPSCs, researchers have created phenotypically relevant and previously inaccessible cellular models of FRDA. These models enable studies of the molecular mechanisms underlying GAA-induced pathology, as well as providing an exciting tool for the screening and testing of novel disease-modifying therapies. This review explores how the use of iPSCs to study FRDA has developed over the past decade, as well as discussing the enormous therapeutic potentials of iPSC-derived models, their current limitations and their future direction within the field of FRDA research., (© 2023. Ruijin Hospital, Shanghai Jiao Tong University.)

Competing Interests: The authors declare no conflicts of interest.

Introduction: Friedreich Ataxia (FRDA) is an autosomal recessive neurodegenerative disorder that causes gait and limb ataxia, dysarthria, and impaired vibratory sense, with cardiomyopathy being the predominant cause of death. There is no approved therapy, which results in the use of symptomatic treatments and the chronic support of physiotherapy. Dimethyl fumarate (DMF) is a fumaric acid ester used for the treatment of psoriasis and Multiple Sclerosis (MS). It induces Nrf2 in vitro and in vivo , and it increases frataxin in FRDA patient lymphoblasts, in mouse models, and in MS treated patients., Methods: The aim of our study is to investigate if DMF can increase the expression of the FXN gene and frataxin protein and ameliorate in-vivo detectable measures of mitochondrial dysfunction in FRDA. The study is composed of a screening visit and two sequential 12-week phases: a core phase and an extension phase. During the first phase (core), patients will be randomly assigned to either the DMF or a placebo group in a 1:1 ratio. During the first week, patients will receive a total daily dose of 240 mg of DMF or placebo; from the second week of treatment, the dose will be increased to two 120 mg tablets BID for a total daily dose of 480 mg. During the second phase (extension), all patients will be treated with DMF. EudraCT number 2021-006274-23., Endpoints: The primary endpoint will be a change in FXN gene expression level after 12 weeks of treatment. Secondary endpoints will be frataxin protein level, c ardiopulmonary exercise test outputs, echocardiographic measures, Nrf2 pathway and mitochondrial biogenesis gene expression, safety, clinical scales, and quality of life scales., Conclusions: This is the first study aimed at exploring the ability of DMF, an already available treatment for MS and psoriasis, to correct the biological deficits of FRDA and potentially improve mitochondrial respiration in-vivo ., Competing Interests: FS received public speaking honoraria from Alexion, argenx, Genpharm, Medison, Novartis. He also received compensation for Advisory boards or consultation fees from Alexion, Almirall, argenx, Avexis, Dianthus, Lexeo Therapeutics, Novartis, Novatek, Reata, Takeda. He has acted as Principal Investigator in trials from Alexion, argenx, Immunovant, Novartis, Sanofi. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Pane, Marra, Aliberti, Campanile, Coscetta, Crisci, D'Assante, Marsili, Puorro, Salzano, Cittadini and Saccà.)

Friedreich ataxia (FRDA) is a progressive neurodegenerative disease caused by a GAA repeat in the intron 1 of the frataxin gene (FXN) leading to a lower expression of the frataxin protein. The YG8sR mice are Knock-Out (KO) for their murine frataxin gene but contain a human frataxin transgene derived from an FRDA patient with 300 GAA repeats. These mice are used as a FRDA model but even with a low frataxin concentration, their phenotype is mild. We aimed to find an optimized mouse model with a phenotype comparable to the human patients to study the impact of therapy on the phenotype. We compared two mouse models: the YG8sR injected with an AAV. PHP.B coding for a shRNA targeting the human frataxin gene and the YG8-800, a new mouse model with a human transgene containing 800 GAA repeats. Both mouse models were compared to Y47R mice containing nine GAA repeats that were considered healthy mice. Behavior tests (parallel rod floor apparatus, hanging test, inverted T beam, and notched beam test) were carried out from 2 to 11 months and significant differences were noticed for both YG8sR mice injected with an anti-FXN shRNA and the YG8-800 mice compared to healthy mice. In conclusion, YG8sR mice have a slight phenotype, and injecting them with an AAV-PHP.B expressing an shRNA targeting frataxin does increase their phenotype. The YG8-800 mice have a phenotype comparable to the human ataxic phenotype.

Introduction: Friedreich ataxia (FA) is the most common hereditary ataxia in Europe, characterised by progressively worsening movement and speech impairments with a typical onset before the age of 25 years. The symptoms affect the patients' health-related quality of life (HRQoL) and psychosocial health. FA leads to an increasing need for care, associated with an economic burden. Little is known about the impact of FA on daily lives and HRQoL. To fill that gap, we will assess patient-reported, psychosocial and economic outcomes using momentary data assessment via a mobile health application (app)., Methods and Analysis: The PROFA Study is a prospective observational study. Patients with FA (n=200) will be recruited at six European study centres (Germany, France and Austria). We will interview patients at baseline in the study centre and subsequently assess the patients' health at home via mobile health app. Patients will self-report ataxia severity, HRQoL, speech and hearing disabilities, coping strategies and well-being, health services usage, adverse health events and productivity losses due to informal care on a daily to monthly basis on the app for 6 months. Our study aims to (1) validate measurements of HRQoL and psychosocial health, (2) assess the usability of the mobile health app, and (3) use descriptive and multivariate statistics to analyse patient-reported and economic outcomes and the interaction effects between these outcomes. Insights into the app's usability could be used for future studies using momentary data assessments to measure outcomes of patients with FA., Ethics and Dissemination: Ethical approval has been obtained from the Ethics Committee of the University Medicine of Greifswald, (BB096/22a, 26 October 2022) and from all local ethics committees of the participating study sites. Findings of the study will be published in peer-reviewed journals, presented at relevant international/national congresses and disseminated to German and French Patient Advocacy Organizations., Trial Registration Number: ClinicalTrials.gov Registry (NCT05943002); Pre-results., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Hypertrophic cardiomyopathy is a myocardial disease defined by an increased left ventricular wall thickness not solely explained by abnormal loading conditions. It is often genetically determined, with sarcomeric gene mutations accounting for around 50% of cases. Several conditions, including syndromic, metabolic, infiltrative, and neuromuscular diseases, may present with left ventricular hypertrophy, mimicking the hypertrophic cardiomyopathy phenotype but showing a different pathophysiology, clinical course, and outcome. Despite being rare, they are collectively responsible for a large proportion of patients presenting with hypertrophic heart disease, and their timely diagnosis can significantly impact patients' management. The understanding of disease pathophysiology has advanced over the last few years, and several therapeutic targets have been identified, leading to a new era of tailored treatments applying to different etiologies associated with left ventricular hypertrophy. This review aims to provide an overview of the existing and emerging therapies for the principal causes of hypertrophic heart disease, discussing the potential impact on patients' management and clinical outcome., Competing Interests: Disclosures None.

Apart from its role in motor coordination, the importance of the cerebellum in cognitive and affective processes has been recognized in the past few decades. Spinocerebellar ataxias (SCA) and Friedreich ataxia (FRDA) are rare neurodegenerative diseases of the cerebellum presenting mainly with a progressive loss of gait and limb coordination, dysarthria, and other motor disturbances, but also a range of cognitive and neuropsychiatric symptoms. This narrative review summarizes the current knowledge on neuropsychiatric impairment in SCA and FRDA. We discuss the prevalence, clinical features and treatment approaches in the most commonly reported domains of depression, anxiety, apathy, agitation and impulse dyscontrol, and psychosis. Since these symptoms have a considerable impact on patients' quality of life, we argue that further research is mandated to improve the detection and treatment options of neuropsychiatric co-morbidities in ataxia patients., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Individuals with Friedreich's ataxia (FRDA) display significantly lower performances in many cognitive domains with a pattern of impairment that falls within the cerebellar cognitive affective syndrome (CCAS)., Objective: To assess in a large cohort of individuals with FRDA, the main determinant of the CCAS using multiple variable regression models., Methods: This is a monocentric observational study that included 39 individuals with FRDA. Ataxic motor symptoms were evaluated with the SARA and cognitive functions with the CCAS-Scale (CCAS-S). Age, SARA, GAA1, Age of symptoms onset (ASO), Age and disease duration (DD) were chosen as covariates in a linear regression model to predict CCAS-S failed items and covariates in a logistic regression model to predict definite CCAS., Results: Patients mean age, SARA score, ASO, DD and GAA1 were respectively of 29 ± 14, 22 ± 10, 14 ± 11, 15 ± 9 and 712 ± 238 (4 point-mutations). Mean CCAS-S raw score was of 86 ± 16, mean number of failed items was 2.9 ± 1.6. Twenty-three individuals had definite CCAS. The multiple linear regression model with age, SARA, ASO, DD & GAA1 as covariates was statistically significant to predict CCAS-S failed items. The SARA was the only significant coefficient in regression models for predicting CCAS-S failed items number and the definite CCAS occurrence., Conclusions: CCAS is highly prevalent in adult individuals with FRDA. CCAS is predicted by ataxic motor symptoms severity. This finding supports common core cerebellar pathophysiology in both cognitive and motor symptoms in FRDA and warrants screening for CCAS, especially in patients with SARA > 20., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)