Friedreich's Ataxia and Cesarean Delivery: A Case Report of Epidural Anesthesia With Ropivacaine.

Friedreich's ataxia (FRDA), a rare inherited neurodegenerative disease, presents distinctive complexities in obstetrical anesthesia. Available research about FRDA in obstetrics is extremely limited. In this report, the anesthetic management of a 40-year-old primigravida with FRDA undergoing cesarean delivery is presented. An uneventful cesarean delivery with effective epidural anesthesia with ropivacaine at the L2-L3 intervertebral space was performed in our case. Neither hypotension nor bradycardia was observed, and vital signs remained stable, with no need for administration of vasoactive drugs. After discharge, the parturient reported no change in her neurologic symptoms. Conclusive recommendations are contingent upon more extensive studies. Overall management and the choice to proceed with neuraxial anesthesia in a woman with FRDA should be based on comprehensive consultations in both cardio-obstetrics and pre-anesthetic evaluations.

The importance of synthetic pharmacotherapy for recessive cerebellar ataxias.

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 Regulation of the Disease-Causing Gene FXN.

Friedreich's ataxia (FRDA) is a progressive neurodegenerative disease caused in almost all patients by expanded guanine-adenine-adenine (GAA) trinucleotide repeats within intron 1 of the FXN gene. This results in a relative deficiency of frataxin, a small nucleus-encoded mitochondrial protein crucial for iron-sulfur cluster biogenesis. Currently, there is only one medication, omaveloxolone, available for FRDA patients, and it is limited to patients 16 years of age and older. This necessitates the development of new medications. Frataxin restoration is one of the main strategies in potential treatment options as it addresses the root cause of the disease. Comprehending the control of frataxin at the transcriptional, post-transcriptional, and post-translational stages could offer potential therapeutic approaches for addressing the illness. This review aims to provide a general overview of the regulation of frataxin and its implications for a possible therapeutic treatment of FRDA.

An In Silico Analysis of Genetic Variants and Structural Modeling of the Human Frataxin Protein in Friedreich's Ataxia.

Friedreich's Ataxia (FRDA) stands out as the most prevalent form of hereditary ataxias, marked by progressive movement ataxia, loss of vibratory sensitivity, and skeletal deformities, severely affecting daily functioning. To date, the only medication available for treating FRDA is Omaveloxolone (Skyclarys®), recently approved by the FDA. Missense mutations within the human frataxin (FXN) gene, responsible for intracellular iron homeostasis regulation, are linked to FRDA development. These mutations induce FXN dysfunction, fostering mitochondrial iron accumulation and heightened oxidative stress, ultimately triggering neuronal cell death pathways. This study amalgamated 226 FXN genetic variants from the literature and database searches, with only 18 previously characterized. Predictive analyses revealed a notable prevalence of detrimental and destabilizing predictions for FXN mutations, predominantly impacting conserved residues crucial for protein function. Additionally, an accurate, comprehensive three-dimensional model of human FXN was constructed, serving as the basis for generating genetic variants I154F and W155R. These variants, selected for their severe clinical implications, underwent molecular dynamics (MD) simulations, unveiling flexibility and essential dynamic alterations in their N-terminal segments, encompassing FXN42, FXN56, and FXN78 domains pivotal for protein maturation. Thus, our findings indicate potential interaction profile disturbances in the FXN42, FXN56, and FXN78 domains induced by I154F and W155R mutations, aligning with the existing literature.

Relative Bioavailability of Omaveloxolone When Capsules Are Sprinkled Over and Mixed in Applesauce Compared With Administration as Intact Omaveloxolone Capsules: A Phase 1, Randomized, Open-Label, Single-Dose, Crossover Study in Healthy Adults.

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 (Cmax), AUC0-t, and AUC0-∞ within the 80% to 125% reference intervals. Omaveloxolone was absorbed more slowly as intact capsules (median tmax, 10 h) compared with sprinkled capsule contents over applesauce (median tmax, 6 h). With chronic daily administration of omaveloxolone to treat FA, the 4-h difference in tmax 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.

Long non-coding RNA TUG1 is downregulated in Friedreich's ataxia.

Friedreich's ataxia is a neurodegenerative disorder caused by reduced frataxin levels. It leads to motor and sensory impairments and has a median life expectancy of around 35 years. As the most common inherited form of ataxia, Friedreich's ataxia lacks reliable, non-invasive biomarkers, prolonging and inflating the cost of clinical trials. This study proposes TUG1, a long non-coding RNA, as a promising blood-based biomarker for Friedreich's ataxia, which is known to regulate various cellular processes. In a previous study using a frataxin knockdown mouse model, we observed several hallmark Friedreich's ataxia symptoms. Building on this, we hypothesized that a dual-source approach-comparing the data from peripheral blood samples from Friedreich's ataxia patients with tissue samples from affected areas in Friedreich's ataxia knockdown mice, tissues usually unattainable from patients-would effectively identify robust biomarkers. A comprehensive reanalysis was conducted on gene expression data from 183 age- and sex-matched peripheral blood samples of Friedreich's ataxia patients, carriers and controls and 192 tissue data sets from Friedreich's ataxia knockdown mice. Blood and tissue samples underwent RNA isolation and quantitative reverse transcription polymerase chain reaction, and frataxin knockdown was confirmed through enzyme-linked immunosorbent assays. Tug1 RNA interaction was explored via RNA pull-down assays. Validation was performed in serum samples on an independent set of 45 controls and 45 Friedreich's ataxia patients and in blood samples from 66 heterozygous carriers and 72 Friedreich's ataxia patients. Tug1 and Slc40a1 emerged as potential blood-based biomarkers, confirmed in the Friedreich's ataxia knockdown mouse model (one-way ANOVA, P ≤ 0.05). Tug1 was consistently downregulated after Fxn knockdown and correlated strongly with Fxn levels (R 2 = 0.71 during depletion, R 2 = 0.74 during rescue). Slc40a1 showed a similar but tissue-specific pattern. Further validation of Tug1's downstream targets strengthened its biomarker candidacy. In additional human samples, TUG1 levels were significantly downregulated in both whole blood and serum of Friedreich's ataxia patients compared with controls (Wilcoxon signed-rank test, P < 0.05). Regression analyses revealed a negative correlation between TUG1 fold-change and disease onset (P < 0.0037) and positive correlations with disease duration and functional disability stage score (P < 0.04). This suggests that elevated TUG1 levels correlate with earlier onset and more severe cases. This study identifies TUG1 as a potential blood-based biomarker for Friedreich's ataxia, showing consistent expression variance in human and mouse tissues related to disease severity and key Friedreich's ataxia pathways. It correlates with frataxin levels, indicating its promise as an early, non-invasive marker. TUG1 holds potential for Friedreich's ataxia monitoring and therapeutic development, meriting additional research.

Efficacy and Safety of Coenzyme Q10 Supplementation in Neonates, Infants and Children: An Overview.

To date, there have been no review articles specifically relating to the general efficacy and safety of coenzyme Q10 (CoQ10) supplementation in younger subjects. In this article, we therefore reviewed the efficacy and safety of CoQ10 supplementation in neonates (less than 1 month of age), infants (up to 1 year of age) and children (up to 12 years of age). As there is no rationale for the supplementation of CoQ10 in normal younger subjects (as there is in otherwise healthy older subjects), all of the articles in the medical literature reviewed in the present article therefore refer to the supplementation of CoQ10 in younger subjects with a variety of clinical disorders; these include primary CoQ10 deficiency, acyl CoA dehydrogenase deficiency, Duchenne muscular dystrophy, migraine, Down syndrome, ADHD, idiopathic cardiomyopathy and Friedreich's ataxia.

Revisiting Friedreich's Ataxia: Phenotypic and Imaging Characteristics.

Background and Aim: Friedreich's ataxia (FRDA) is a common cause of autosomal recessive cerebellar ataxia. The phenotype is dependent on the repeat size and duration of the disease. We aimed to study the clinical, electrophysiologic, and radiologic profiles in a large Indian cohort of genetically proven FRDA patients. Subjects and Methods: A retrospective cross-sectional, descriptive analysis of genetically proven FRDA patients was performed. A detailed review of all the hospital case records was done to analyze the clinical, radiologic, and electrophysiologic details. Results: A total of 100 FRDA patients were selected for the analysis. Eighty-six patients had an age at onset between 5 and 25 years. Eight patients (8%) were classified as late-onset FRDA and six patients (6%) as early-onset FRDA. The median age at presentation was 19 years. The median age at onset was 14 years, and the median duration of illness was 4 years. All patients had gait ataxia as the initial symptom. Gait ataxia, loss of proprioception, and areflexia were seen in all patients. Dysarthria, nystagmus, amyotrophy, spasticity, extensor plantars, pes cavus, and scoliosis occurred in one-third of patients. Cardiomyopathy (18%) and diabetes (5%) were less common. Sensory polyneuropathy (87.5%) was the most common nerve conduction abnormality. Cortical somatosensory evoked responses were absent in all 43 tested patients (100%). Brainstem auditory evoked response test was done in 24 patients and it showed absent reactions in six patients (25%). Visual evoked potential was tested in 24 patients and it showed absent P100 responses in five patients (21%). Cerebellar and cord atrophy was seen on magnetic resonance imaging in 50% of patients. Conclusion: Most FRDA patients (86%) had an age at onset of less than 25 years, with typical symptoms of gait ataxia, areflexia, and loss of proprioception found in all patients. Dysarthria, nystagmus, amyotrophy, spasticity, extensor plantars, pes cavus, scoliosis, cardiomyopathy, and diabetes were not seen in all patients. Cerebellar atrophy can occur in FRDA patients. Knowledge regarding the clinical, radiologic, and electrophysiologic profile of FRDA will aid in proper phenotypic characterization.

Glial overexpression of Tspo extends lifespan and protects against frataxin deficiency in Drosophila.

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.

An RNA-seq study in Friedreich ataxia patients identified hsa-miR-148a-3p as a putative prognostic biomarker of the disease.

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.

Calcitriol Treatment Is Safe and Increases Frataxin Levels in Friedreich Ataxia Patients.

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.

Ferrostatin-1 specifically targets mitochondrial iron-sulfur clusters and aconitase to improve cardiac function in Sirtuin 3 cardiomyocyte knockout mice.

AIMS: Ferroptosis is a form of iron-regulated cell death implicated in ischemic heart disease. Our previous study revealed that Sirtuin 3 (SIRT3) is associated with ferroptosis and cardiac fibrosis. In this study, we tested whether the knockout of SIRT3 in cardiomyocytes (SIRT3cKO) promotes mitochondrial ferroptosis and whether the blockade of ferroptosis would ameliorate mitochondrial dysfunction. METHODS AND RESULTS: Mitochondrial and cytosolic fractions were isolated from the ventricles of mice. Cytosolic and mitochondrial ferroptosis were analyzed by comparison to SIRT3loxp mice. An echocardiography study showed that SIRT3cKO mice developed heart failure as evidenced by a reduction of EF% and FS% compared to SIRT3loxp mice. Comparison of mitochondrial and cytosolic fractions of SIRT3cKO and SIRT3loxp mice revealed that, upon loss of SIRT3, mitochondrial, but not cytosolic, total lysine acetylation was significantly increased. Similarly, acetylated p53 was significantly upregulated only in the mitochondria. These data demonstrate that SIRT3 is the primary mitochondrial deacetylase. Most importantly, loss of SIRT3 resulted in significant reductions of frataxin, aconitase, and glutathione peroxidase 4 (GPX4) in the mitochondria. This was accompanied by a significant increase in levels of mitochondrial 4-hydroxynonenal. Treatment of SIRT3cKO mice with the ferroptosis inhibitor ferrostatin-1 (Fer-1) for 14 days significantly improved preexisting heart failure. Mechanistically, Fer-1 treatment significantly increased GPX4 and aconitase expression/activity, increased mitochondrial iron­sulfur clusters, and improved mitochondrial membrane potential and Complex IV activity. CONCLUSIONS: Inhibition of ferroptosis ameliorated cardiac dysfunction by specifically targeting mitochondrial aconitase and iron­sulfur clusters. Blockade of mitochondrial ferroptosis may be a novel therapeutic target for mitochondrial cardiomyopathies.

Mapping Novel Frataxin Mitochondrial Networks Through Protein- Protein Interactions.

Friedreich's Ataxia (FRDA) is a neuromuscular degenerative disorder caused by trinucleotide expansions in the first intron of the frataxin (FXN) gene, resulting in insufficient levels of functional FNX protein. Deficits in FXN involve mitochondrial disruptions including iron-sulfur cluster synthesis and impaired energetics. These studies were to identify unique protein-protein interactions with FXN to better understand its function and design therapeutics. Two complementary approaches were employed, BioID and Co-IP, to identify protein interactions with FXN at the direct binding, indirect binding, and non-proximal levels. Forty-one novel protein interactions were identified by BioID and IP techniques. The FXN protein landscape was further analyzed incorporating both interaction type and functional pathways using a maximum path of 6 proteins with a potential direct interaction between FXN and NFS1. Probing the intersection between FXN-protein landscape and biological pathways associated with FRDA, we identified 41 proteins of interest. Peroxiredoxin 3 (Prdx3) was chosen for further analysis because of its role in mitochondrial oxidative injury. Our data has demonstrated the strengths of employing complementary methods to identify a unique interactome for FXN. Our data provides new insights into FXN function and regulation, a potential direct interaction between FXN and NFS1, and pathway interactions between FXN and Prdx3.

Pharmacotherapeutic strategies for Friedreich Ataxia: a review of the available data.

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.

Accelerometer-based measures in Friedreich ataxia: a longitudinal study on real-life activity.

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.

The Role of Verbal Fluency in the Cerebellar Cognitive Affective Syndrome Scale in Friedreich Ataxia.

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.

Genetic Determined Iron Starvation Signature in Friedreich's Ataxia.

BACKGROUND: Early studies in cellular models suggested an iron accumulation in Friedreich's ataxia (FA), yet findings from patients are lacking. OBJECTIVES: The objective is to characterize systemic iron metabolism, body iron storages, and intracellular iron regulation in FA patients. METHODS: In FA patients and matched healthy controls, we assessed serum iron parameters, regulatory hormones as well as the expression of regulatory proteins and iron distribution in peripheral blood mononuclear cells (PBMCs). We applied magnetic resonance imaging with R2*-relaxometry to quantify iron storages in the liver, spleen, and pancreas. Across all evaluations, we assessed the influence of the genetic severity as expressed by the length of the shorter GAA-expansion (GAA1). RESULTS: We recruited 40 FA patients (19 women). Compared to controls, FA patients displayed lower serum iron and transferrin saturation. Serum ferritin, hepcidin, mean corpuscular hemoglobin and mean corpuscular volume in FA inversely correlated with the GAA1-repeat length, indicating iron deficiency and restricted availability for erythropoiesis with increasing genetic severity. R2*-relaxometry revealed a reduction of splenic and hepatic iron stores in FA. Liver and spleen R2* values inversely correlated with the GAA1-repeat length. FA PBMCs displayed downregulation of ferritin and upregulation of transferrin receptor and divalent metal transporter-1 mRNA, particularly in patients with >500 GAA1-repeats. In FA PBMCs, intracellular iron was not increased, but shifted toward mitochondria. CONCLUSIONS: We provide evidence for a previously unrecognized iron starvation signature at systemic and cellular levels in FA patients, which is related to the underlying genetic severity. These findings challenge the use of systemic iron lowering therapies in FA. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Perioperative management and outcomes for posterior spinal fusion in patients with Friedreich ataxia: A single-center, retrospective study.

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.

Recent Advances in the Treatment Strategies of Friedreich's Ataxia: A Review of Potential Drug Candidates and their Underlying Mechanisms.

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.

Vestibular Pathology as Early Finding of Friedreich's Ataxia in a 16 Years Old Woman.

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.