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Continuum (Minneapolis, Minn.) Aug 2019This article reviews the symptoms, laboratory and neuroimaging diagnostic tests, genetics, and management of cerebellar ataxia. (Review)
Review
PURPOSE OF REVIEW
This article reviews the symptoms, laboratory and neuroimaging diagnostic tests, genetics, and management of cerebellar ataxia.
RECENT FINDINGS
Recent advances in genetics have led to the identification of novel genetic causes for ataxia and a more comprehensive understanding of the biological pathways critical for normal cerebellar function. When these molecular pathways become dysfunctional, patients develop cerebellar ataxia. In addition, several ongoing clinical trials for Friedreich ataxia and spinocerebellar ataxia will likely result in novel symptomatic and disease-modifying therapies for ataxia. Antisense oligonucleotides for spinocerebellar ataxias associated with CAG repeat expansions might be a promising therapeutic strategy.
SUMMARY
Cerebellar ataxias include heterogeneous disorders affecting cerebellar function, leading to ataxic symptoms. Step-by-step diagnostic workups with genetic investigations are likely to reveal the underlying causes of ataxia. Some disease-specific therapies for ataxia exist, such as vitamin E for ataxia with vitamin E deficiency and thiamine for Wernicke encephalopathy, highlighting the importance of recognizing these forms of ataxia. Finally, genetic diagnosis for patients with ataxia will accelerate clinical trials for disease-modifying therapy and will have prognostic value and implications for family planning for these patients.
Topics: Ataxia; Cerebellar Ataxia; Dopamine Agents; Female; Friedreich Ataxia; Humans; Male; Middle Aged; Physical Therapy Modalities
PubMed: 31356292
DOI: 10.1212/CON.0000000000000753 -
Neurodegenerative Disease Management Oct 2022Friedreich's ataxia (FRDA), a neurodegenerative disease characterized by ataxia and other neurological features, affects 1 in 50,000-100,000 individuals in the USA.... (Review)
Review
Friedreich's ataxia (FRDA), a neurodegenerative disease characterized by ataxia and other neurological features, affects 1 in 50,000-100,000 individuals in the USA. However, FRDA also includes cardiac, orthopedic and endocrine dysfunction, giving rise to many secondary disease characteristics. The multifaceted approach for clinical care has necessitated the development of disease-specific clinical care guidelines. New developments in FRDA include the advancement of clinical drug trials targeting the NRF2 pathway and frataxin restoration. Additionally, a novel understanding of gene silencing in FRDA, reflecting a variegated silencing pattern, will have applications to current and future therapeutic interventions. Finally, new perspectives on the neuroanatomy of FRDA and its developmental features will refine the time course and anatomical targeting of novel approaches.
Topics: Friedreich Ataxia; Humans; NF-E2-Related Factor 2; Neurodegenerative Diseases
PubMed: 35766110
DOI: 10.2217/nmt-2022-0011 -
British Medical Bulletin Dec 2017Friedreich's ataxia is the most common inherited ataxia. (Review)
Review
INTRODUCTION
Friedreich's ataxia is the most common inherited ataxia.
SOURCES OF DATA
Literature search using PubMed with keywords Friedreich's ataxia together with published papers known to the authors.
AREAS OF AGREEMENT
The last decade has seen important advances in our understanding of the pathogenesis of disease. In particular, the genetic and epigenetic mechanisms underlying the disease now offer promising novel therapeutic targets.
AREAS OF CONTROVERSY
The search for effective disease-modifying agents continues. It remains to be determined whether the most effective approach to treatment lies with increasing frataxin protein levels or addressing the metabolic consequences of the disease, for example with antioxidants.
AREAS TIMELY FOR DEVELOPING RESEARCH
Management of Freidreich's ataxia is currently focussed on symptomatic management, delivered by the multidisciplinary team. Phase II clinical trials in agents that address the abberrant silencing of the frataxin gene need to be translated into large placebo-controlled Phase III trials to help establish their therapeutic potential.
Topics: Adaptor Proteins, Signal Transducing; Antioxidants; Cardiomyopathies; Clinical Trials, Phase II as Topic; Disease Progression; Epigenesis, Genetic; Friedreich Ataxia; Gene Expression Regulation; Gene Silencing; Humans; Iron-Binding Proteins; Mitochondria; Molecular Targeted Therapy; Frataxin
PubMed: 29053830
DOI: 10.1093/bmb/ldx034 -
Annals of Neurology Feb 2021Friedreich ataxia (FA) is a progressive genetic neurodegenerative disorder with no approved treatment. Omaveloxolone, an Nrf2 activator, improves mitochondrial function,... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
Friedreich ataxia (FA) is a progressive genetic neurodegenerative disorder with no approved treatment. Omaveloxolone, an Nrf2 activator, improves mitochondrial function, restores redox balance, and reduces inflammation in models of FA. We investigated the safety and efficacy of omaveloxolone in patients with FA.
METHODS
We conducted an international, double-blind, randomized, placebo-controlled, parallel-group, registrational phase 2 trial at 11 institutions in the United States, Europe, and Australia (NCT02255435, EudraCT2015-002762-23). Eligible patients, 16 to 40 years of age with genetically confirmed FA and baseline modified Friedreich's Ataxia Rating Scale (mFARS) scores between 20 and 80, were randomized 1:1 to placebo or 150mg per day of omaveloxolone. The primary outcome was change from baseline in the mFARS score in those treated with omaveloxolone compared with those on placebo at 48 weeks.
RESULTS
One hundred fifty-five patients were screened, and 103 were randomly assigned to receive omaveloxolone (n = 51) or placebo (n = 52), with 40 omaveloxolone patients and 42 placebo patients analyzed in the full analysis set. Changes from baseline in mFARS scores in omaveloxolone (-1.55 ± 0.69) and placebo (0.85 ± 0.64) patients showed a difference between treatment groups of -2.40 ± 0.96 (p = 0.014). Transient reversible increases in aminotransferase levels were observed with omaveloxolone without increases in total bilirubin or other signs of liver injury. Headache, nausea, and fatigue were also more common among patients receiving omaveloxolone.
INTERPRETATION
In the MOXIe trial, omaveloxolone significantly improved neurological function compared to placebo and was generally safe and well tolerated. It represents a potential therapeutic agent in FA. ANN NEUROL 2021;89:212-225.
Topics: Accidental Falls; Activities of Daily Living; Adolescent; Adult; Antioxidants; Double-Blind Method; Exercise Test; Female; Friedreich Ataxia; Humans; Male; Mitochondria; NF-E2-Related Factor 2; Oxidative Stress; Signal Transduction; Treatment Outcome; Triterpenes; Young Adult
PubMed: 33068037
DOI: 10.1002/ana.25934 -
Expert Review of Neurotherapeutics Dec 2020Friedreich's ataxia (FRDA) is a progressive, neurodegenerative disease that results in gait and limb ataxia, diabetes, cardiac hypertrophy, and scoliosis. At the... (Review)
Review
INTRODUCTION
Friedreich's ataxia (FRDA) is a progressive, neurodegenerative disease that results in gait and limb ataxia, diabetes, cardiac hypertrophy, and scoliosis. At the cellular level, FRDA results in the deficiency of frataxin, a mitochondrial protein that plays a vital role in iron homeostasis and amelioration of oxidative stress. No cure currently exists for FRDA, but exciting therapeutic developments which target different parts of the pathological cascade are on the horizon.
AREAS COVERED
Areas covered include past and emerging therapies for FRDA, including antioxidants and mitochondrial-related agents, nuclear factor erythroid-derived 2-related factor 2 (Nrf2) activators, deuterated polyunsaturated fatty acids, iron chelators, histone deacetylase (HDAC) inhibitors, trans-activator of transcription (TAT)-frataxin, interferon gamma (IFNγ), erythropoietin, resveratrol, gene therapy, and anti-sense oligonucleotides (ASOs), among others.
EXPERT OPINION
While drug discovery has been challenging, new and exciting prospective treatments for FRDA are currently on the horizon, including pharmaceutical agents and gene therapy. Agents that enhance mitochondrial function, such as Nrf2 activators, dPUFAs and catalytic antioxidants, as well as novel methods of frataxin augmentation and genetic modulation will hopefully provide treatment for this devastating disease.
Topics: Antioxidants; Friedreich Ataxia; Humans; Iron-Binding Proteins; Mitochondria; NF-E2-Related Factor 2; Frataxin
PubMed: 32909841
DOI: 10.1080/14737175.2020.1821654 -
Neurobiology of Disease Dec 2019Friedreich ataxia is the most common of the hereditary ataxias. It is due to homozygous/compound heterozygous mutations in FXN. This gene encodes frataxin, a protein... (Review)
Review
Friedreich ataxia is the most common of the hereditary ataxias. It is due to homozygous/compound heterozygous mutations in FXN. This gene encodes frataxin, a protein largely localized to mitochondria. In about 96% of affected individuals there is homozygosity for a GAA repeat expansion in intron 1 of the FXN gene. Studies of people with Friedreich ataxia and of animal and cell models, have provided much insight into the pathogenesis of this disorder. The expanded GAA repeat leads to transcriptional deficiency of the FXN gene. The consequent deficiency of frataxin protein leads to reduced iron-sulfur cluster biogenesis and mitochondrial ATP production, elevated mitochondrial iron, and oxidative stress. More recently, a role for inflammation has emerged as being important in the pathogenesis of Friedreich ataxia. These findings have led to a number of potential therapies that have been subjected to clinical trials or are being developed toward human studies. Therapies that have been proposed include pharmaceuticals that increase frataxin levels, protein and gene replacement therapies, antioxidants, iron chelators and modulators of inflammation. Whilst no therapies have yet been approved for Friedreich ataxia, there is much optimism that the advances in the understanding of the pathogenesis of this disorder since the discovery its genetic basis, will result in approved disease modifying therapies in the near future.
Topics: Animals; Friedreich Ataxia; Humans
PubMed: 31494282
DOI: 10.1016/j.nbd.2019.104606 -
Journal of Neurology Jan 2023This narrative review aims at providing an update on the management of inherited cerebellar ataxias (ICAs), describing main clinical entities, genetic analysis... (Review)
Review
This narrative review aims at providing an update on the management of inherited cerebellar ataxias (ICAs), describing main clinical entities, genetic analysis strategies and recent therapeutic developments. Initial approach facing a patient with cerebellar ataxia requires family medical history, physical examination, exclusions of acquired causes and genetic analysis, including Next-Generation Sequencing (NGS). To guide diagnosis, several algorithms and a new genetic nomenclature for recessive cerebellar ataxias have been proposed. The challenge of NGS analysis is the identification of causative variant, trio analysis being usually the most appropriate option. Public genomic databases as well as pathogenicity prediction software facilitate the interpretation of NGS results. We also report on key clinical points for the diagnosis of the main ICAs, including Friedreich ataxia, CANVAS, polyglutamine spinocerebellar ataxias, Fragile X-associated tremor/ataxia syndrome. Rarer forms should not be neglected because of diagnostic biomarkers availability, disease-modifying treatments, or associated susceptibility to malignancy. Diagnostic difficulties arise from allelic and phenotypic heterogeneity as well as from the possibility for one gene to be associated with both dominant and recessive inheritance. To complicate the phenotype, cerebellar cognitive affective syndrome can be associated with some subtypes of cerebellar ataxia. Lastly, we describe new therapeutic leads: antisense oligonucleotides approach in polyglutamine SCAs and viral gene therapy in Friedreich ataxia. This review provides support for diagnosis, genetic counseling and therapeutic management of ICAs in clinical practice.
Topics: Humans; Cerebellar Ataxia; Friedreich Ataxia; Mutation; Ataxia; Spinocerebellar Ataxias
PubMed: 36152050
DOI: 10.1007/s00415-022-11383-6 -
The New England Journal of Medicine Jan 2023The late-onset cerebellar ataxias (LOCAs) have largely resisted molecular diagnosis.
BACKGROUND
The late-onset cerebellar ataxias (LOCAs) have largely resisted molecular diagnosis.
METHODS
We sequenced the genomes of six persons with autosomal dominant LOCA who were members of three French Canadian families and identified a candidate pathogenic repeat expansion. We then tested for association between the repeat expansion and disease in two independent case-control series - one French Canadian (66 patients and 209 controls) and the other German (228 patients and 199 controls). We also genotyped the repeat in 20 Australian and 31 Indian index patients. We assayed gene and protein expression in two postmortem cerebellum specimens and two induced pluripotent stem-cell (iPSC)-derived motor-neuron cell lines.
RESULTS
In the six French Canadian patients, we identified a GAA repeat expansion deep in the first intron of , which encodes fibroblast growth factor 14. Cosegregation of the repeat expansion with disease in the families supported a pathogenic threshold of at least 250 GAA repeats ([GAA]). There was significant association between (GAA) expansions and LOCA in the French Canadian series (odds ratio, 105.60; 95% confidence interval [CI], 31.09 to 334.20; P<0.001) and in the German series (odds ratio, 8.76; 95% CI, 3.45 to 20.84; P<0.001). The repeat expansion was present in 61%, 18%, 15%, and 10% of French Canadian, German, Australian, and Indian index patients, respectively. In total, we identified 128 patients with LOCA who carried an (GAA) expansion. Postmortem cerebellum specimens and iPSC-derived motor neurons from patients showed reduced expression of RNA and protein.
CONCLUSIONS
A dominantly inherited deep intronic GAA repeat expansion in was found to be associated with LOCA. (Funded by Fondation Groupe Monaco and others.).
Topics: Humans; Australia; Canada; Cerebellar Ataxia; Friedreich Ataxia; Introns; DNA Repeat Expansion
PubMed: 36516086
DOI: 10.1056/NEJMoa2207406 -
Annals of Clinical and Translational... Jan 2019Previous studies have demonstrated that suppression of Nrf2 in Friedreich ataxia tissues contributes to excess oxidative stress, mitochondrial dysfunction, and reduced... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
Previous studies have demonstrated that suppression of Nrf2 in Friedreich ataxia tissues contributes to excess oxidative stress, mitochondrial dysfunction, and reduced ATP production. Omaveloxolone, an Nrf2 activator and NF-kB suppressor, targets dysfunctional inflammatory, metabolic, and bioenergetic pathways. The dose-ranging portion of this Phase 2 study assessed the safety, pharmacodynamics, and potential benefit of omaveloxolone in Friedreich ataxia patients (NCT02255435).
METHODS
Sixty-nine Friedreich ataxia patients were randomized 3:1 to either omaveloxolone or placebo administered once daily for 12 weeks. Patients were randomized in cohorts of eight patients, at dose levels of 2.5-300 mg/day.
RESULTS
Omaveloxolone was well tolerated, and adverse events were generally mild. Optimal pharmacodynamic changes (noted by changes in ferritin and GGT) were observed at doses of 80 and 160 mg/day. No significant changes were observed in the primary outcome, peak work load in maximal exercise testing (0.9 ± 2.9 W, placebo corrected). At the 160 mg/day dose, omaveloxolone improved the secondary outcome of the mFARS by 3.8 points versus baseline (=0.0001) and by 2.3 points versus placebo (=0.06). Omaveloxolone produced greater improvements in mFARS in patients that did not have musculoskeletal foot deformity (pes cavus). In patients without this foot deformity, omaveloxolone improved mFARS by 6.0 points from baseline (<0.0001) and by 4.4 points versus placebo (=0.01) at the 160 mg/day.
INTERPRETATION
Treatment of Friedreich ataxia patients with omaveloxolone at the optimal dose level of 160 mg/day appears to improve neurological function. Therefore, omaveloxolone treatment is being examined in greater detail at 150 mg/day for Friedreich ataxia.
Topics: Adolescent; Adult; Dose-Response Relationship, Drug; Female; Friedreich Ataxia; Humans; Male; NF-E2-Related Factor 2; NF-kappa B; Treatment Outcome; Triterpenes; Young Adult
PubMed: 30656180
DOI: 10.1002/acn3.660 -
The Journal of Clinical Investigation Jun 2021The dynamic regulation of endothelial pathophenotypes in pulmonary hypertension (PH) remains undefined. Cellular senescence is linked to PH with intracardiac shunts;...
The dynamic regulation of endothelial pathophenotypes in pulmonary hypertension (PH) remains undefined. Cellular senescence is linked to PH with intracardiac shunts; however, its regulation across PH subtypes is unknown. Since endothelial deficiency of iron-sulfur (Fe-S) clusters is pathogenic in PH, we hypothesized that a Fe-S biogenesis protein, frataxin (FXN), controls endothelial senescence. An endothelial subpopulation in rodent and patient lungs across PH subtypes exhibited reduced FXN and elevated senescence. In vitro, hypoxic and inflammatory FXN deficiency abrogated activity of endothelial Fe-S-containing polymerases, promoting replication stress, DNA damage response, and senescence. This was also observed in stem cell-derived endothelial cells from Friedreich's ataxia (FRDA), a genetic disease of FXN deficiency, ataxia, and cardiomyopathy, often with PH. In vivo, FXN deficiency-dependent senescence drove vessel inflammation, remodeling, and PH, whereas pharmacologic removal of senescent cells in Fxn-deficient rodents ameliorated PH. These data offer a model of endothelial biology in PH, where FXN deficiency generates a senescent endothelial subpopulation, promoting vascular inflammatory and proliferative signals in other cells to drive disease. These findings also establish an endothelial etiology for PH in FRDA and left heart disease and support therapeutic development of senolytic drugs, reversing effects of Fe-S deficiency across PH subtypes.
Topics: Animals; Cellular Senescence; Endothelial Progenitor Cells; Endothelium, Vascular; Female; Friedreich Ataxia; Humans; Hypertension, Pulmonary; Iron-Binding Proteins; Male; Mice; Mice, Knockout; Vascular Remodeling; Frataxin
PubMed: 33905372
DOI: 10.1172/JCI136459