In the late 1800s, Nikolaus Friedreich first described "degenerative atrophy of the posterior columns of the spinal cord," noting its connection to progressive ataxia, sensory loss, and muscle weakness, now recognized as Friedreich ataxia (FRDA). Renewed interest in the disease in the 1970s and 80s by the Quebec Cooperative Group and by Anita Harding led to the development of clinical diagnostic criteria and insights into associated biochemical abnormalities, although the primary defect remained unknown. In 1988, Susan Chamberlain mapped FRDA's location on chromosome 9. In the early 90s, collaborative research, including work by the author's team, identified a gene, later named FXN, containing an expanded GAA repeat-confirming it as the FRDA mutation. This discovery established a diagnostic foundation for FRDA, advancing genetic testing and opening new research avenues. These new areas of study included the characteristics, origin, and pathogenicity of the GAA repeat expansion; the characterization of frataxin, the encoded protein, including its subcellular localization, structure, and function; the identification of cellular pathways disrupted by frataxin deficiency; and the redefinition of FRDA phenotypes based on genetic testing, along with the study of FRDA's natural history. In addition, efforts focused on the search for biomarkers to reflect diagnosis, disease severity, and progression and, most importantly, the identification and development of therapeutic approaches in both preclinical and clinical settings. The creation of cellular and animal models was crucial to this progress, as was the formation of consortia to collaboratively drive basic and clinical research forward. Now, 28 years after the gene discovery, although much remains to be understood about the disease's mechanisms and the development of effective therapies, the progress is undeniable. A thriving community has emerged, uniting researchers, health care providers, industry professionals, individuals with FRDA, their families, and dedicated volunteers. With this collective effort, a cure is within reach.

Mitochondria are essential for cellular function and viability, serving as central hubs of metabolism and signaling. They possess various metabolic and quality control mechanisms crucial for maintaining normal cellular activities. Mitochondrial genetic disorders can arise from a wide range of mutations in either mitochondrial or nuclear DNA, which encode mitochondrial proteins or other contents. These genetic defects can lead to a breakdown of mitochondrial function and metabolism, such as the collapse of oxidative phosphorylation, one of the mitochondria's most critical functions. Mitochondrial diseases, a common group of genetic disorders, are characterized by significant phenotypic and genetic heterogeneity. Clinical symptoms can manifest in various systems and organs throughout the body, with differing degrees and forms of severity. The complexity of the relationship between mitochondria and mitochondrial diseases results in an inadequate understanding of the genotype-phenotype correlation of these diseases, historically making diagnosis and treatment challenging and often leading to unsatisfactory clinical outcomes. However, recent advancements in research and technology have significantly improved our understanding and management of these conditions. Clinical translations of mitochondria-related therapies are actively progressing. This review focuses on the physiological mechanisms of mitochondria, the pathogenesis of mitochondrial diseases, and potential diagnostic and therapeutic applications. Additionally, this review discusses future perspectives on mitochondrial genetic diseases.

Early onset ataxias (EOAs) are a heterogeneous group of rare neurological disorders that not only involve the central and peripheral nervous system but also involve other organs. They are mainly manifested by degeneration or abnormal development of the cerebellum occurring before the age of 25 years and typically the pattern of inheritance is autosomal recessive.The diagnosis of autosomal recessive cerebellar ataxias (ARCAs) is confirmed by the clinical, laboratory, electrophysiological examination, neuroimaging findings, and mutation analysis when the causative gene is detected. Correct diagnosis is crucial for appropriate genetic counseling, estimating the prognosis, and, in some cases, pharmacological intervention. The wide variety of genotypes with a heterogeneous phenotypic manifestation makes the diagnostic work-up challenging, time-consuming, and expensive, not only for the clinician but also for the children and their parents. In this review, we focused on the step-by-step approach in which cerebellar ataxia is a prominent sign. We also outline the most common disorders in ataxias with early-onset manifestations.

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).

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.

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.

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.

Friedreich's ataxia (FA) is an autosomal recessive disorder caused by reduced frataxin (FXN) expression in mitochondria, where the lethal component is cardiomyopathy. Using the conditional Fxnflox/null::MCK-Cre knock-out (Fxn-cKO) mouse model, we discovered significant sex differences in the progression towards heart failure, with Fxn-cKO males exhibiting a worse cardiac phenotype, low survival rate, kidney and reproductive organ deficiencies. These differences are likely due to a decline in testosterone in Fxn-cKO males. The decrease in testosterone was related to decreased expression of proteins involved in cholesterol transfer into the mitochondria: StAR and TSPO on the outer mitochondrial membrane, and the cholesterol side-chain cleavage enzyme P450scc and ferredoxin on the inner mitochondrial membrane. Expression of excitation-contraction coupling proteins (L-type calcium channel, RyR2, SERCA2, phospholamban and CaMKIIδ) was decreased significantly more in Fxn-cKO males. This is the first study that extensively investigates the sexual dimorphism in FA mouse model with cardiac calcium signaling impairment.

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).

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.

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.

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.

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.

Machine learning algorithms for rare disorders, such as Friedreich's Ataxia (FRDA), often suffer from a lack of data. Therefore, the ability for continuous optimization of an objective assessment model would be very useful as a clinical decision support system. In this study, we propose a Bayesian Network(BN) system for FRDA severity estimation that incorporates a Bayesian Statistical updating system to continuously improve the predictive ability while providing an easily interpretable graphical model. This can work to improve the understanding of the model by the clinician, thus creating trust in the machine learning process. Furthermore, we demonstrate that by using the updating mechanism, the BN model gives a goodness-of-fit score of 0.95, a root mean square error of 9.35 and a mean absolute error of 6.72, which outperforms other regression approaches as well as improves upon the base BN by 2% in goodness of fit, roughly 1% in RMSE and 6% in MAE.

Friedreich ataxia is a progressive autosomal recessive neurodegenerative disorder characterized by ataxia, dyscoordination, and cardiomyopathy. A subset of patients with Friedreich ataxia have elevated levels of serum cardiac troponin I, but associations with disease outcomes and features of cardiomyopathy remain unclear. In this study, we characterized clinically obtained serum cardiac biomarker levels including troponin I, troponin T, and B-type natriuretic peptide in subjects with Friedreich ataxia and evaluated their association with markers of disease. While unprovoked troponin I levels were elevated in 36% of the cohort, cTnI levels associated with a cardiac event (provoked) were higher than unprovoked levels. In multivariate linear regression models, younger age predicted increased troponin I values, and in logistic regression models younger age, female sex, and marginally longer GAA repeat length predicted abnormal troponin I levels. In subjects with multiple assessments, mean unprovoked troponin I levels decreased slightly over time. The presence of abnormal troponin I values and their levels were predicted by echocardiographic measures of hypertrophy. In addition, troponin I levels predicted long-term markers of clinical cardiac dysfunction over time to a modest degree. Consequently, troponin I values provide a marker of hypertrophy but only a minimally predictive biomarker for later cardiac manifestations of disease such as systolic dysfunction or arrhythmia.

Although a large array of biomarkers have been investigated in Friedreich's ataxia (FRDA) trials, the optimal biomarker for assessing disease progression or therapeutic benefit has yet to be identified. We searched PubMed, MEDLINE, and EMBASE databases up to June 2023 for any original study (with ≥ 5 participants and ≥ 2 months' follow-up) reporting the effect of therapeutic interventions on any clinical, cardiac, biochemical, patient-reported outcome measures, imaging, or neurophysiologic biomarker. We also explored the biomarkers' ability to detect subtle disease progression in untreated patients. The pooled standardized mean difference (SMD) was calculated using a random-effects model. The study's protocol was registered in PROSPERO (CRD42022319196). In total, 43 studies with 1409 FRDA patients were included in the qualitative synthesis. A statistically significant improvement was observed in Friedreich Ataxia Rating Scale scores [combining Friedreich Ataxia Rating Scale (FARS) and modified FARS (mFARS): SMD =  - 0.32 (- 0.62 to - 0.02)] following drugs that augment mitochondrial function in a sensitivity analysis. Left ventricular mass index (LVMI) was improved significantly [SMD =  - 0.34 (- 0.5 to - 0.18)] after 28.5 months of treatment with drugs that augment mitochondrial function. However, LVMI remained stable [SMD = 0.05 (- 0.3 to 0.41)] in untreated patients after 6-month follow-up. None of the remaining biomarkers changed significantly following any treatment intervention nor during the natural disease progression. Nevertheless, clinical implications of these results should be interpreted with caution because of low to very low quality of evidence. Further randomized controlled trials of at least 24 months' duration using a biomarker toolbox rather than a single biomarker are warranted.

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.

Cerebellar ataxias are a wide heterogeneous group of disorders that may present with fine motor deficits as well as gait and balance disturbances that have a significant influence on everyday activities. To review the ocular movements in cerebellar ataxias in order to improve the clinical knowledge of cerebellar ataxias and related subtypes. English papers published from January 1990 to May 2022 were selected by searching PubMed services. The main search keywords were ocular motor, oculomotor, eye movement, eye motility, and ocular motility, along with each ataxia subtype. The eligible papers were analyzed for clinical presentation, involved mutations, the underlying pathology, and ocular movement alterations. Forty-three subtypes of spinocerebellar ataxias and a number of autosomal dominant and autosomal recessive ataxias were discussed in terms of pathology, clinical manifestations, involved mutations, and with a focus on the ocular abnormalities. A flowchart has been made using ocular movement manifestations to differentiate different ataxia subtypes. And underlying pathology of each subtype is reviewed in form of illustrated models to reach a better understanding of each disorder.

Friedreich's ataxia (FRDA) is an autosomal-recessive disorder primarily attributed to biallelic GAA repeat expansions that reduce expression of the mitochondrial protein frataxin (FXN). FRDA is characterized by progressive neurodegeneration, with many patients developing cardiomyopathy that progresses to heart failure and death. The potential to reverse or prevent progression of the cardiac phenotype of FRDA was investigated in a mouse model of FRDA, using an adeno-associated viral vector (AAV8) containing the coding sequence of the FXN gene. The Fxnflox/null::MCK-Cre conditional knockout mouse (FXN-MCK) has an FXN gene ablation that prevents FXN expression in cardiac and skeletal muscle, leading to cardiac insufficiency, weight loss, and morbidity. FXN-MCK mice received a single intravenous injection of an AAV8 vector containing human (hFXN) or mouse (mFXN) FXN genes under the control of a phosphoglycerate kinase promoter. Compared to vehicle-treated FXN-MCK control mice, AAV-treated FXN-MCK mice displayed increases in body weight, reversal of cardiac deficits, and increases in survival without apparent toxicity in the heart or liver for up to 12 weeks postdose. FXN protein expression in heart tissue was detected in a dose-dependent manner, exhibiting wide distribution throughout the heart similar to wild type, but more speckled. These results support an AAV8-based approach to treat FRDA-associated cardiomyopathy.

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.

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.

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.

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.

Friedreich ataxia (FRDA) is a multisystemic, autosomal recessive disorder caused by homozygous GAA expansion mutation in the first intron of frataxin (FXN) gene. FXN is a mitochondrial protein critical for iron-sulfur cluster biosynthesis and deficiency impairs mitochondrial electron transport chain functions and iron homeostasis within the organelle. Currently, there is no effective treatment for FRDA. We have previously demonstrated that single infusion of wild-type hematopoietic stem and progenitor cells (HSPCs) resulted in prevention of neurologic and cardiac complications of FRDA in YG8R mice, and rescue was mediated by FXN transfer from tissue engrafted, HSPC-derived microglia/macrophages to diseased neurons/myocytes. For a future clinical translation, we developed an autologous stem cell transplantation approach using CRISPR/Cas9 for the excision of the GAA repeats in FRDA patients' CD34+ HSPCs; this strategy leading to increased FXN expression and improved mitochondrial functions. The aim of the current study is to validate the efficiency and safety of our gene editing approach in a disease-relevant model. We generated a cohort of FRDA patient-derived iPSCs and isogenic lines that were gene edited with our CRISPR/Cas9 approach. iPSC derived FRDA neurons displayed characteristic apoptotic and mitochondrial phenotype of the disease, such as non-homogenous microtubule staining in neurites, increased caspase-3 expression, mitochondrial superoxide levels, mitochondrial fragmentation, and partial degradation of the cristae compared to healthy controls. These defects were fully prevented in the gene edited neurons. RNASeq analysis of FRDA and gene edited neurons demonstrated striking improvement in gene clusters associated with endoplasmic reticulum (ER) stress in the isogenic lines. Gene edited neurons demonstrated improved ER-calcium release, normalization of ER stress response gene, XBP-1, and significantly increased ER-mitochondrial contacts that are critical for functional homeostasis of both organelles, as compared to FRDA neurons. Ultrastructural analysis for these contact sites displayed severe ER structural damage in FRDA neurons, that was undetected in gene edited neurons. Taken together, these results represent a novel finding for disease pathogenesis showing dramatic ER structural damage in FRDA, validate the efficacy profile of our FXN gene editing approach in a disease relevant model, and support our approach as an effective strategy for therapeutic intervention for Friedreich's ataxia.

Cerebellar ataxias are a wide heterogeneous group of movement disorders. Within this broad umbrella of diseases, there are both genetics and sporadic forms. The clinical presentation of these conditions can exhibit a diverse range of symptoms across different age groups, spanning from pure cerebellar manifestations to sensory ataxia and multisystemic diseases. Over the last few decades, advancements in our understanding of genetics and molecular pathophysiology related to both dominant and recessive ataxias have propelled the field forward, paving the way for innovative therapeutic strategies aimed at preventing and arresting the progression of these diseases. Nevertheless, the rarity of certain forms of ataxia continues to pose challenges, leading to limited insights into the etiology of the disease and the identification of target pathways. Additionally, the lack of suitable models hampers efforts to comprehensively understand the molecular foundations of disease's pathophysiology and test novel therapeutic interventions. In the following review, we describe the epidemiology, symptomatology, and pathological progression of hereditary ataxia, including both the prevalent and less common forms of these diseases. Furthermore, we illustrate the diverse molecular pathways and therapeutic approaches currently undergoing investigation in both pre-clinical studies and clinical trials. Finally, we address the existing and anticipated challenges within this field, encompassing both basic research and clinical endeavors.

Autosomal recessive cerebellar ataxias (ARCAs) are a heterogeneous group of neurodegenerative disorders affecting primarily the cerebellum and/or its afferent tracts, often accompanied by damage of other neurological or extra-neurological systems. Due to the overlap of clinical presentation among ARCAs and the variety of hereditary, acquired, and reversible etiologies that can determine cerebellar dysfunction, the differential diagnosis is challenging, but also urgent considering the ongoing development of promising target therapies. The examination of afferent and efferent visual system may provide neurophysiological and structural information related to cerebellar dysfunction and neurodegeneration thus allowing a possible diagnostic classification approach according to ocular features. While optic coherence tomography (OCT) is applied for the parametrization of the optic nerve and macular area, the eye movements analysis relies on a wide range of eye-tracker devices and the application of machine-learning techniques. We discuss the results of clinical and eye-tracking oculomotor examination, the OCT findings and some advancing of computer science in ARCAs thus providing evidence sustaining the identification of robust eye parameters as possible markers of ARCAs.

Friedreich's ataxia (FA) is a debilitating, multisystemic disease caused by the depletion of frataxin (FXN), a mitochondrial iron-sulfur (Fe-S) cluster biogenesis factor. To understand the cellular pathogenesis of FA, we performed quantitative proteomics in FXN-deficient human cells. Nearly every annotated Fe-S cluster-containing protein was depleted, indicating that as a rule, cluster binding confers stability to Fe-S proteins. We also observed depletion of a small mitoribosomal assembly factor METTL17 and evidence of impaired mitochondrial translation. Using comparative sequence analysis, mutagenesis, biochemistry, and cryoelectron microscopy, we show that METTL17 binds to the mitoribosomal small subunit during late assembly and harbors a previously unrecognized [Fe4S4]2+ cluster required for its stability. METTL17 overexpression rescued the mitochondrial translation and bioenergetic defects, but not the cellular growth, of FXN-depleted cells. These findings suggest that METTL17 acts as an Fe-S cluster checkpoint, promoting translation of Fe-S cluster-rich oxidative phosphorylation (OXPHOS) proteins only when Fe-S cofactors are replete.

Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, Huntington's disease, and Friedrich ataxia are all incurable neurodegenerative diseases defined by the continuous progressive loss of distinct neuronal subtypes. Despite their rising prevalence among the world's ageing population, fewer advances have been made in the concurrent massive efforts to develop newer drugs. Recently, there has been a shift in research focus towards the discovery of new therapeutic agents for neurodegenerative diseases. In this review, we have summarized the recently developed therapies and their status in the management of neurodegenerative diseases.

The Scale for Assessment and Rating of Ataxia (SARA) is widely used in different types of ataxias and has been chosen as the primary outcome measure in the European natural history study for Friedreich ataxia (FA).

To assess distribution and longitudinal changes of SARA scores and its single items, we analyzed SARA scores of 502 patients with typical-onset FA (<25 years) participating in the 4-year prospective European FA Consortium for Translational Studies (EFACTS). Pattern of disease progression was determined using linear mixed-effects regression models. The chosen statistical model was re-fitted in order to estimate parameters and predict disease progression. Median time-to-change and rate of score progression were estimated using the Kaplan-Meier method and weighted linear regression models, respectively.

SARA score at study enrollment and age at onset were the major predictive factors of total score progression during the 4-year follow-up. To a less extent, age at evaluation also influenced the speed of SARA progression, while disease duration did not improve the prediction of the statistical model. Temporal dynamics of total SARA and items showed a great variability in the speed of score increase during disease progression. Gait item had the highest annual progression rate, with median time for one-point score increase of 1 to 2 years.

Analyses of statistical properties of SARA suggest a variable sensitivity of the scale at different disease stages, and provide important information for population selection and result interpretation in future clinical trials.

Friedreich ataxia (FA) neuropathology affects dorsal root ganglia, posterior columns in the spinal cord, the spinocerebellar tracts, and cerebellar dentate nuclei. The impact of the somatosensory system on ataxic symptoms remains debated. This study aims to better evaluate the contribution of somatosensory processing to ataxia clinical severity by simultaneously investigating passive movement and tactile pneumatic stimulation in individuals with FA.

Twenty patients with FA and 20 healthy participants were included. All subjects underwent two 6 min block-design functional magnetic resonance imaging (fMRI) paradigms consisting of twelve 30 s alternating blocks (10 brain volumes per block, 120 brain volumes per paradigm) of a tactile oddball paradigm and a passive movement paradigm. Spearman rank correlation tests were used for correlations between BOLD levels and ataxia severity.

The passive movement paradigm led to the lower activation of primary (cSI) and secondary somatosensory cortices (cSII) in FA compared with healthy subjects (respectively 1.1 ± 0.78 vs. 0.61 ± 1.02, p = 0.04, and 0.69 ± 0.5 vs. 0.3 ± 0.41, p = 0.005). In the tactile paradigm, there was no significant difference between cSI and cSII activation levels in healthy controls and FA (respectively 0.88 ± 0.73 vs. 1.14 ± 0.99, p = 0.33, and 0.54 ± 0.37 vs. 0.55 ± 0.54, p = 0.93). Correlation analysis showed a significant correlation between cSI activation levels in the tactile paradigm and the clinical severity (R = 0.481, p = 0.032).

Our study captured the difference between tactile and proprioceptive impairments in FA using somatosensory fMRI paradigms. The lack of correlation between the proprioceptive paradigm and ataxia clinical parameters supports a low contribution of afferent ataxia to FA clinical severity.

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.

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.

The primary endpoint will be a change in FXN gene expression level after 12 weeks of treatment. Secondary endpoints will be frataxin protein level, cardiopulmonary exercise test outputs, echocardiographic measures, Nrf2 pathway and mitochondrial biogenesis gene expression, safety, clinical scales, and quality of life scales.

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.

Neurodegenerative disorders often acquire due to genetic predispositions and genomic alterations after exposure to multiple risk factors. The most commonly found pathologies are variations of dementia, such as frontotemporal dementia and Lewy body dementia, as well as rare subtypes of cerebral and cerebellar atrophy-based syndromes. In an emerging era of biomedical advances, molecular-cellular studies offer an essential avenue for a thorough recognition of the underlying mechanisms and their possible implications in the patient's symptomatology. This comprehensive review is focused on deciphering molecular mechanisms and the implications regarding those pathologies' clinical advancement and provides an analytical overview of genetic mutations in the case of neurodegenerative disorders. With the help of well-developed modern genetic investigations, these clinically complex disturbances are highly understood nowadays, being an important step in establishing molecularly targeted therapies and implementing those approaches in the physician's practice.

Myocardial ischemia/reperfusion (I/R) injury is characterized by cell death via various cellular mechanisms upon reperfusion. As a new type of cell death, ferroptosis provides new opportunities to reduce myocardial cell death. Ferroptosis is known to be more active during reperfusion than ischemia. However, the mechanisms regulating ferroptosis during ischemia and reperfusion remain largely unknown.

The contribution of ferroptosis in ischemic and reperfused myocardium were detected by administered of Fer-1, a ferroptosis inhibitor to C57BL/6 mice, followed by left anterior descending (LAD) ligation surgery. Ferroptosis was evaluated by measurement of cell viability, ptgs2 mRNA level, iron production, malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) levels. H9C2 cells were exposed to hypoxia/reoxygenation to mimic in vivo I/R. We used LC-MS/MS to identify potential E3 ligases that interacted with frataxin in heart tissue. Cardiac-specific overexpression of frataxin in whole heart was achieved by intracardiac injection of frataxin, carried by adeno-associated virus serotype 9 (AAV9) containing cardiac troponin T (cTnT) promoter.

We showed that regulators of iron metabolism, especially iron regulatory protein activity, were increased in the ischemic myocardium or hypoxia cardiomyocytes. In addition, we found that frataxin, which is involved in iron metabolism, is differentially expressed in the ischemic and reperfused myocardium and involved in the regulation of cardiomyocytes ferroptosis. Furthermore, we identified an E3 ligase, NHL repeat-containing 1 (NHLRC1), that mediates frataxin ubiquitination degradation. Cardiac-specific overexpression of frataxin ameliorated myocardial I/R injury through ferroptosis inhibition.

Through a multi-level study from molecule to animal model, these findings uncover the key role of frataxin in inhibiting cardiomyocyte ferroptosis and provide new strategies and perspectives for the treatment of myocardial I/R injury.

Friedreich's ataxia (FA) is a devastating, multi-systemic neurodegenerative disease affecting thousands of people worldwide. We previously reported that oxygen is a key environmental variable that can modify FA pathogenesis. In particular, we showed that chronic, continuous normobaric hypoxia (11% FIO2) prevents ataxia and neurological disease in a murine model of FA, although it did not improve cardiovascular pathology or lifespan. Here, we report the pre-clinical evaluation of seven 'hypoxia-inspired' regimens in the shFxn mouse model of FA, with the long-term goal of designing a safe, practical and effective regimen for clinical translation. We report three chief results. First, a daily, intermittent hypoxia regimen (16 h 11% O2/8 h 21% O2) conferred no benefit and was in fact harmful, resulting in elevated cardiac stress and accelerated mortality. The detrimental effect of this regimen is likely owing to transient tissue hyperoxia that results when daily exposure to 21% O2 combines with chronic polycythemia, as we could blunt this toxicity by pharmacologically inhibiting polycythemia. Second, we report that more mild regimens of chronic hypoxia (17% O2) confer a modest benefit by delaying the onset of ataxia. Third, excitingly, we show that initiating chronic, continuous 11% O2 breathing once advanced neurological disease has already started can rapidly reverse ataxia. Our studies showcase both the promise and limitations of candidate hypoxia-inspired regimens for FA and underscore the need for additional pre-clinical optimization before future translation into humans.

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).

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.

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.

ClinicalTrials.gov Registry (NCT05943002); Pre-results.

Optic neuropathy is a near ubiquitous feature of Friedreich's ataxia (FRDA). Previous studies have examined varying aspects of the anterior and posterior visual pathways but none so far have comprehensively evaluated the heterogeneity of degeneration across different areas of the retina, changes to the macula layers and combined these with volumetric MRI studies of the visual cortex and frataxin level.

We investigated 62 genetically confirmed FRDA patients using an integrated approach as part of an observational cohort study. We included measurement of frataxin protein levels, clinical evaluation of visual and neurological function, optical coherence tomography to determine retinal nerve fibre layer thickness and macular layer volume and volumetric brain MRI.

We demonstrate that frataxin level correlates with peripapillary retinal nerve fibre layer thickness and that retinal sectors differ in their degree of degeneration. We also shown that retinal nerve fibre layer is thinner in FRDA patients than controls and that this thinning is influenced by the AAO and GAA1. Furthermore we show that the ganglion cell and inner plexiform layers are affected in FRDA. Our MRI data indicate that there are borderline correlations between retinal layers and areas of the cortex involved in visual processing.

Our study demonstrates the uneven distribution of the axonopathy in the retinal nerve fibre layer and highlight the relative sparing of the papillomacular bundle and temporal sectors. We show that thinning of the retinal nerve fibre layer is associated with frataxin levels, supporting the use the two biomarkers in future clinical trials design. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Degenerative ataxias and hereditary spastic paraplegias (HSPs) form a continuous, often overlapping disease spectrum sharing not only phenotypic features and underlying genes, but also cellular pathways and disease mechanisms. Mitochondrial metabolism presents a major molecular theme underlying both multiple ataxias and HSPs, thus indicating a heightened vulnerability of Purkinje cells, spinocerebellar tracts, and motor neurons to mitochondrial dysfunction, which is of particular interest for translational approaches. Mitochondrial dysfunction might be the primary (upstream) or secondary (downstream) result of a genetic defect, with underlying genetic defects in nuclear-encoded genes being much more frequent than in mtDNA genes in both, ataxias and HSPs. Here, we outline the substantial number of ataxias, spastic ataxias and HSPs caused by mutated genes implicated in (primary or secondary) mitochondrial dysfunction, highlighting several key "mitochondrial" ataxias and HSPs which are of particular interest for their frequency, pathogenesis and translational opportunities. We then showcase prototypic mitochondrial mechanisms by which disruption of these ataxia and HSP genes contributes to Purkinje cells or corticospinal neuron dysfunction, thus elucidating hypotheses on Purkinje cells and corticospinal neuron vulnerability to mitochondrial dysfunction.

MOXIe was a two-part study evaluating the safety and efficacy of omaveloxolone in patients with Friedreich's ataxia, a rare, progressive neurological disease with no proven therapy. MOXIe part 2, a randomized double-blind placebo-controlled trial, showed omaveloxolone significantly improved modified Friedreich's Ataxia Rating Scale (mFARS) scores relative to placebo. Patients who completed part 1 or 2 were eligible to receive omaveloxolone in an open-label extension study.

The delayed-start study compared mFARS scores at the end of MOXIe part 2 with those at 72 weeks in the open-label extension period (up to 144 weeks) for patients initially randomized to omaveloxolone versus those initially randomized to placebo.

We performed a noninferiority test to compare the difference between treatment groups (placebo to omaveloxolone versus omaveloxolone to omaveloxolone) using a single mixed model repeated measures (MMRM) model. In addition, slopes of the change in mFARS scores were compared between both groups in the open-label extension.

The noninferiority testing demonstrated that the difference in mFARS between omaveloxolone and placebo observed at the end of placebo-controlled MOXIe part 2 (-2.17 ± 1.09 points) was preserved after 72 weeks in the extension (-2.91 ± 1.44 points). In addition, patients previously randomized to omaveloxolone in MOXIe part 2 continued to show no worsening in mFARS relative to their extension baseline through 144 weeks.

These results support the positive results of MOXIe part 2 and indicate a persistent benefit of omaveloxolone treatment on disease course in Friedreich's ataxia. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Friedreich's ataxia (FRDA) is an inherited recessive neurodegenerative disorder caused by a homozygous guanine-adenine-adenine (GAA) repeat expansion within intron 1 of the FXN gene, which encodes the essential mitochondrial protein frataxin. There is still no effective therapy for FRDA, therefore the development of optimal cell and animal models of the disease is one of the priorities for preclinical therapeutic testing.

We obtained the latest FRDA humanized mouse model that was generated on the basis of our previous YG8sR, by Jackson laboratory [YG8JR, Fxn ^null:YG8s(GAA) > 800]. We characterized the behavioral, cellular, molecular and epigenetics properties of the YG8JR model, which has the largest GAA repeat sizes compared to all the current FRDA mouse models.

We found statistically significant behavioral deficits, together with reduced levels of frataxin mRNA and protein, and aconitase activity in YG8JR mice compared with control Y47JR mice. YG8JR mice exhibit intergenerational GAA repeat instability by the analysis of parent and offspring tissue samples. Somatic GAA repeat instability was also detected in individual brain and cerebellum tissue samples. In addition, increased DNA methylation of CpG U13 was identified in FXN GAA repeat region in the brain, cerebellum, and heart tissues. Furthermore, we show decreased histone H3K9 acetylation and increased H3K9 methylation of YG8JR cerebellum tissues within the FXN gene, upstream and downstream of the GAA repeat region compared to Y47JR controls.

These studies provide a detailed characterization of the GAA repeat expansion-based YG8JR transgenic mouse models that will help investigations of FRDA disease mechanisms and therapy.

Auditory neuropathy spectrum disorder (ANSD) refers to a range of hearing impairments characterized by an impaired transmission of sound from the cochlea to the brain. This defect can be due to a lesion or defect in the inner hair cell (IHC), IHC ribbon synapse (e.g., pre-synaptic release of glutamate), postsynaptic terminals of the spiral ganglion neurons, or demyelination and axonal loss within the auditory nerve. To date, the only clinical treatment options for ANSD are hearing aids and cochlear implantation. However, despite the advances in hearing-aid and cochlear-implant technologies, the quality of perceived sound still cannot match that of the normal ear. Recent advanced genetic diagnostics and clinical audiology made it possible to identify the precise site of a lesion and to characterize the specific disease mechanisms of ANSD, thus bringing renewed hope to the treatment or prevention of auditory neurodegeneration. Moreover, genetic routes involving the replacement or corrective editing of mutant sequences or defected genes to repair damaged cells for the future restoration of hearing in deaf people are showing promise. In this review, we provide an update on recent discoveries in the molecular pathophysiology of genetic lesions, auditory synaptopathy and neuropathy, and gene-therapy research towards hearing restoration in rodent models and in clinical trials.

The spinal cord is a conduit within the central nervous system (CNS) that provides ongoing communication between the brain and the rest of the body, conveying complex sensory and motor information necessary for safety, movement, reflexes, and optimization of autonomic function. After a traumatic spinal cord injury (SCI), supraspinal influences on the peripheral nervous system and autonomic nervous system (ANS) are disrupted, leading to spastic paralysis, sympathetic blunting, and parasympathetic dominance, resulting in cardiac dysrhythmias, systemic hypotension, bronchoconstriction, copious respiratory secretions, and uncontrolled bowel, bladder, and sexual dysfunction. This article outlines the pathophysiology of the less reported nontraumatic SCI (NTSCI), its classification, its influence on sensory/motor function, and introduces the probable comorbidities associated with SCI that will be discussed in more detail in the accompanying manuscripts of this special issue. Finally, management strategies for NTSCI will be provided.

The aim of this paper is to carry out a historical overview of the evolution of the knowledge on degenerative cerebellar disorders and hereditary spastic paraplegias, over the last century and a half. Original descriptions of the main pathological subtypes, including Friedreich's ataxia, hereditary spastic paraplegia, olivopontocerebellar atrophy and cortical cerebellar atrophy, are revised. Special attention is given to the first accurate description of striatonigral degeneration by Hans Joachim Scherer, his personal and scientific trajectory being clarified. Pathological classifications of ataxia are critically analysed. The current clinical-genetic classification of ataxia is updated by taking into account recent molecular discoveries. We conclude that there has been an enormous progress in the knowledge of the nosology of hereditary ataxias and paraplegias, currently encompassing around 200 genetic subtypes.

Friedreich ataxia is a rare autosomal recessive, neuromuscular degenerative disease caused by an expansion of a trinucleotide [guanine-adenine-adenine (GAA)] repeat in intron 1 of the FXN gene. It is common in the White population, characterized by progressive gait and limb ataxia, lack of tendon reflexes in the legs, loss of position sense, and hypertrophic cardiomyopathy. Detection and genotyping of the trinucleotide repeat length is important for the diagnosis and prognosis of the disease. A two-tier genotyping assay with an improved triple-repeat primed PCR (TR-PCR) for alleles <200 GAA repeats (±1 to 5 repeats) and an agarose gel-based, long-range PCR (LR-PCR) assay to genotype expanded alleles >200 GAA repeats (±50 repeats) is described. Of the 1236 DNA samples tested using TR-PCR, 31 were identified to have expanded alleles >200 repeats and were reflexed to the LR-PCR procedure for confirmation and quantification. The TR-PCR assay described herein is a diagnostic genotyping assay that reduces the need for further testing. The LR-PCR component is a confirmatory test for true homozygous and heterozygous samples with normal and expanded alleles, as indicated by the TR-PCR assay. The use of this two-tier method offers a comprehensive evaluation to detect and genotype the smallest and largest number of GAA repeats, improving the classification of FXN alleles as normal, mutable normal, borderline, and expanded alleles.