Friedreich's ataxia

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Friedreich ataxia (FA) is an inherited autosomal recessive neurodegenerative disease (NDD) characterized primarily by progressive sensory and spinocerebellar ataxia associated with hypertrophic cardiomyopathy. FA is due to an intronic GAA repeat expansion within the frataxin gene (FXN) leading to reduced levels of frataxin (FXN) which causes mitochondrial dysfunction, production of reactive oxygen species (ROS), and altered iron metabolism. To date there is no resolutive cure for FA; however, the FDA has recently approved omaveloxolone - a potent activator of nuclear factor erythroid 2-related factor 2 (NRF2) - as the first treatment for FA...

INTRODUCTION: Omavaloxolone, an NRF2 activator, recently became the first drug approved specifically for the treatment of Friedreich ataxia (FRDA). This landmark achievement provides a background for a review of the detailed data leading to the approval. AREAS COVERED: The authors review the data from the 4 major articles on FRDA in the context of the authors' considerable (>1000 patients) experience in treating individuals with FRDA. The data is presented in the context not only of its scientific meaning but also in the practical context of therapy in FRDA...

BACKGROUND: Optical coherence tomography (OCT) biomarkers are increasingly used by neurologists, psychiatrists, and ophthalmologists for the diagnosis, prognosis, and follow-up of neurodegenerative diseases. Long-term data on OCT biomarkers of selected primary and secondary neurodegenerative diseases of the central nervous system (CNS), such as multiple sclerosis (MS) or Parkinson's disease, are already available in part. In addition, there are rare neurodegenerative diseases with early disease onset that may show OCT abnormalities...

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...

An important part of the central nervous system (CNS), the cerebellum is involved in motor control, learning, reflex adaptation, and cognition. Diminished cerebellar function results in the motor and cognitive impairment observed in patients with neurodegenerative disorders such as Alzheimer's disease (AD), vascular dementia (VD), Parkinson's disease (PD), Huntington's disease (HD), spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS), Friedreich's ataxia (FRDA), and multiple sclerosis (MS), and even during the normal aging process...

Friedreich's ataxia is a degenerative and progressive multisystem disorder caused by mutations in the highly conserved frataxin (FXN) gene that results in FXN protein deficiency and mitochondrial dysfunction. While gene therapy approaches are promising, consistent induction of therapeutic FXN protein expression that is sub-toxic has proven challenging, and numerous therapeutic approaches are being tested in animal models. FXN (hFXN in humans, mFXN in mice) is proteolytically modified in mitochondria to produce mature FXN...

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...

BACKGROUND: Hereditary spastic paraplegia (HSP) is a rare neurodegenerative disease that lacks specific and validated patient-centered outcome measures (PCOMs). We aimed to develop and validate a health-related quality of life (HRQoL) questionnaire specific to HSP ("TreatHSP-QoL") that could be used as a PCOM. RESULTS: The pilot-items of the TreatHSP-QoL (45 five-level Likert scale items, with values per item between 0 and 4) were developed based on a qualitative data analysis of 54 semi-structured interviews, conducted in person with 36 HSP patients and 18 caregivers...

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...

INTRODUCTION: Hereditary ataxias (HAs) encompass a diverse and genetically intricate group of rare neurodegenerative disorders, presenting diagnostic challenges. Whole-exome sequencing (WES) has significantly improved diagnostic success. This study aimed to elucidate genetic causes of cerebellar ataxia within a diverse Brazilian cohort. METHODS: Biological samples were collected from individuals with sporadic or familial cerebellar ataxia, spanning various ages and phenotypes, excluding common SCAs and Friedreich ataxia...

Friedreich's ataxia (FRDA) is a rare neurodegenerativedisorder caused by over expansion of GAA repeats in thefirstintron ofFXN gene. Here, we generated two iPSC lines from FRDA patients with biallelic expansion of GAA repeats in the first intron ofFXNgene.IGIBi014-A and IGIBi015-Aboth iPSC lines demonstrated characteristics of pluripotency, normal karyotypes (46, XY),the capacity to differentiate into all three germ layers, and the ability to sustain the GAA repeat expansion with decreased FXN mRNA expression...

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...

Mitochondria play a key role in cellular functions, including energy production and oxidative stress regulation. For this reason, maintaining mitochondrial homeostasis and proteostasis (homeostasis of the proteome) is essential for cellular health. Therefore, there are different mitochondrial quality control mechanisms, such as mitochondrial biogenesis, mitochondrial dynamics, mitochondrial-derived vesicles (MDVs), mitophagy, or mitochondrial unfolded protein response (mtUPR). The last item is a stress response that occurs when stress is present within mitochondria and, especially, when the accumulation of unfolded and misfolded proteins in the mitochondrial matrix surpasses the folding capacity of the mitochondrion...

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 FXNI151F mouse model, frataxin deficiency resulted in lower activity and levels of the electron transport complexes, mainly complexes I and II...

Iron is an essential transition metal for all eukaryotic cells, and its trafficking throughout the cell is highly regulated. However, the overall cellular mechanism of regulation is poorly understood despite knowing many of the molecular players involved. Here, an ordinary-differential-equations (ODE) based kinetic model of iron trafficking within a growing yeast cell was developed that included autoregulation. The 9-reaction 8-component in-silico cell model was solved under both steady-state and time-dependent dynamical conditions...

Skeletal myopathies and ataxias with secondary cardiac involvement are complex, progressive and debilitating conditions. As life expectancy increases across these conditions, cardiac involvement often becomes more prominent. This highlights the need for targeted therapies that address these evolving cardiac pathologies. Musculopathies by and large lack cures that directly target the genetic basis of the diseases; however, as our understanding of the genetic causes of these conditions has evolved, it has become tractable to develop targeted therapies using biologics, to design precision approaches to target the primary genetic causes of these varied diseases...

BACKGROUND: Cognitive deficits were related to Spinocerebellar Ataxia type 3/Machado-Joseph Disease (SCA3/MJD), but the Cerebellar Cognitive Affective Syndrome (CCAS) needs further investigation in this disorder. We aimed to characterize cognitive-affective deficits in manifest and premanifest SCA3/MJD carriers. METHODS: Subjects at 50% risk, manifest carriers and unrelated controls were evaluated in-person or in virtual settings with CCAS Scale (CCAS-S), Stroop Color-Word Test (SCWT), Trail-Making Test (TMT), and Reading the Mind in the Eyes Test (RMET)...

Friedreich Ataxia (FRDA) is an inherited disorder that affects the cerebellum and other regions of the human nervous system. It causes impaired movement that affects quality and reduces lifespan. Clinical assessment of movement is a key part of diagnosis and assessment of severity. Recent studies have examined instrumented measurement of movement to support clinical assessments. This paper presents a frequency domain approach based on Average Band Power (ABP) estimation for clinical assessment using Inertial Measurement Unit (IMU) signals...

Friedreich ataxia (FRDA) requires an objective measure of severity to overcome the shortcoming of clinical scales when applied to trials for treatments. This is hindered due to the rarity of the disease resulting in small datasets. Further, the published quantitative measures for ataxia do not incorporate or underutilise expert knowledge. Bayesian Networks (BNs) provide a structure to adopt both subjective and objective measures to give a severity value while addressing these issues. The BN presented in this paper uses a hybrid learning approach, which utilises both subjective clinical assessments as well as instrumented measurements of disordered upper body movement of individuals with FRDA...