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Friedreich's ataxia

Katrin Bürk, Deborah A Sival
Clinical scales represent an important tool not only for the initial grading/scoring of disease and assessment of progression, but also for the quantification of therapeutic effects in clinical trials. There are several scales available for the clinical evaluation of cerebellar symptoms. While some scales have been developed and evaluated for specific cerebellar disorders such as Friedreich ataxia, others reliably capture cerebellar symptoms with no respect to the underlying etiology. Each scale has its strengths and weaknesses...
2018: Handbook of Clinical Neurology
Arnulf H Koeppen
This chapter summarizes the neuropathologic features of nonneoplastic disorders of the adult cerebellum. Gait ataxia and extremity dysmetria are clinical manifestations of diseases that interrupt the complex cerebellar circuitry between the neurons of the cerebellar cortex, the cerebellar nuclei (especially the dentate nuclei), and the inferior olivary nuclei. The cerebellum is a prominent target of several sporadic and hereditary neurodegenerative diseases, including multiple system atrophy, spinocerebellar ataxia, and Friedreich ataxia...
2018: Handbook of Clinical Neurology
Amandine Palandri, Elodie Martin, Maria Russi, Michael Rera, Hervé Tricoire, Véronique Monnier
Friedreich's ataxia (FA) is caused by reduced levels of frataxin, a highly conserved mitochondrial protein. There is currently no effective treatment for this disease, characterized by progressive neurodegeneration and cardiomyopathy, the latter being the most common cause of death in patients. We previously developed a Drosophila melanogaster cardiac model of FA, in which the fly frataxin is inactivated specifically in the heart, leading to heart dilatation and impaired systolic function. Methylene Blue (MB) was highly efficient to prevent these cardiac dysfunctions...
June 13, 2018: Disease Models & Mechanisms
Matthis Synofzik, Andrea H Németh
Recessive ataxias (spinocerebellar ataxias, recessive or SCARs) are a heterogeneous group of rare, mostly neurodegenerative genetic disorders which usually start in childhood or early adult life. They can be subdivided into two major groups: predominant sensory or afferent ataxias, which are disorders mainly of the peripheral input to the cerebellum, and predominant cerebellar ataxias, in which the cerebellum is primarily affected. Next-generation sequencing technology has enabled the identification of >100 novel SCAR genes in the last 5 years, although most of them are ultrarare...
2018: Handbook of Clinical Neurology
Mario Manto, Christiane S Hampe
Hormonal disorders are a source of cerebellar ataxia in both children and adults. Normal development of the cerebellum is critically dependent on thyroid hormone, which crosses both the blood-brain barrier and the blood-cerebrospinal fluid barrier thanks to specific transporters, including monocarboxylate transporter 8 and the organic anion-transporting polypeptide 1C1. In particular, growth and dendritic arborization of Purkinje neurons, synaptogenesis, and myelination are dependent on thyroid hormone. Disturbances of thyroid hormone may also impact on cerebellar ataxias of other origin, decompensating or aggravating the pre-existing ataxia manifesting with motor ataxia, oculomotor ataxia, and/or Schmahmann syndrome...
2018: Handbook of Clinical Neurology
Mercedes Serrano
Epigenetics is a growing field of knowledge that is changing our understanding of pathologic processes. For many cerebellar disorders, recent discoveries of epigenetic mechanisms help us to understand their pathophysiology. In this chapter, a short explanation of each epigenetic mechanism (including methylation, histone modification, and miRNA) is followed by references to those cerebellar disorders in which relevant epigenetic advances have been made. The importance of normal timing and distribution of methylation during neurodevelopment is explained...
2018: Handbook of Clinical Neurology
Olena Bereznyakova, Nicolas Dupré
The presence of spasticity and pyramidal features is a hallmark of some of hereditary ataxias, such as autosomal-recessive spastic ataxia of Charlevoix-Saguenay, other primary spastic ataxias, Friedreich ataxia, or ataxia with isolated vitamin E deficiency. Certain spastic paraplegias, such as spastic paraplegia 7, may present as an ataxic phenotype and often share common pathophysiologic pathways with cerebellar ataxias. Because of the rarity and genetic heterogeneity of these conditions, their molecular diagnosis remains challenging and time consuming...
2018: Handbook of Clinical Neurology
Aristotelis V Kalyvas, Evangelos Drosos, Stefanos Korfias, Stylianos Gatzonis, Marios Themistocleous, Damianos E Sakas
Friedreich's ataxia (FA) is the most frequent hereditary ataxia syndrome, while painful muscle spasms and spasticity have been reported in 11-15% of FA patients. This report describes the successful management of painful spasms in a 65-year-old woman with FA via intrathecal baclofen (ITB) therapy following unsuccessful medical treatments. To our knowledge, this is the third reported case in the literature. Unfortunately, the pathophysiological characteristics of muscle spasms in FA are not well explored and understood while the therapeutic mechanisms of the different treatments are rather vague...
June 8, 2018: Stereotactic and Functional Neurosurgery
P Calap-Quintana, J A Navarro, J González-Fernández, M J Martínez-Sebastián, M D Moltó, J V Llorens
Friedreich's ataxia (FRDA) is a rare inherited recessive disorder affecting the central and peripheral nervous systems and other extraneural organs such as the heart and pancreas. This incapacitating condition usually manifests in childhood or adolescence, exhibits an irreversible progression that confines the patient to a wheelchair, and leads to early death. FRDA is caused by a reduced level of the nuclear-encoded mitochondrial protein frataxin due to an abnormal GAA triplet repeat expansion in the first intron of the human FXN gene...
2018: BioMed Research International
Bianca Simone Zeigelboim, Hélio A G Teive, Michèlli Rodrigues da Rosa, Jéssica Spricigo Malisky, Vinicius Ribas Fonseca, Jair Mendes Marques, Paulo Breno Liberalesso
Objective To assess central auditory function in Friedreich's ataxia. Methods A cross-sectional, retrospective study was carried out. Thirty patients underwent the anamnesis, otorhinolaryngology examination, pure tone audiometry, acoustic immittance measures and brainstem auditory evoked potential (BAEP) assessments. Results The observed alterations were: 43.3% in the pure tone audiometry, bilateral in 36.7%; 56.6% in the BAEP test, bilateral in 50%; and 46.6% in the acoustic immittance test. There was a significant difference (p < 0...
March 2018: Arquivos de Neuro-psiquiatria
Tommaso Vannocci, Roberto Notario Manzano, Ombretta Beccalli, Barbara Bettegazzi, Fabio Grohovaz, Gianfelice Cinque, Antonio de Riso, Luca Quaroni, Franca Codazzi, Annalisa Pastore
The neurodegenerative disease Friedreich's ataxia is caused by lower than normal levels of frataxin, an important protein involved in iron sulphur cluster biogenesis. An important step in designing strategies to treat this disease is to understand whether increasing the frataxin levels by gene therapy would be tout-court beneficial or detrimental since previous studies, mostly based on animal models, have reported conflicting results. Here, we have exploited an inducible model, which we developed using the CRISPR/Cas9 methodology, to study the effects of frataxin overexpression in human cells and follow how the system recovers after overexpression...
May 24, 2018: Disease Models & Mechanisms
Daniel Nachun, Fuying Gao, Charles Isaacs, Cassandra Strawser, Zhongan Yang, Deepika Dokuru, Victoria Van Berlo, Renee Sears, Jennifer Farmer, Susan Perlman, David R Lynch, Giovanni Coppola
Transcriptional changes in Friedreich's ataxia (FRDA), a rare and debilitating recessive Mendelian neurodegenerative disorder, have been studied in affected but inaccessible tissues - such as dorsal root ganglia, sensory neurons, and cerebellum - in animal models or small patient series. However, transcriptional changes induced by FRDA in peripheral blood, a readily accessible tissue, have not been characterized in a large sample. We used differential expression, association with disability stage, network analysis, and enrichment analysis to characterize the peripheral blood transcriptome and identify genes that were differentially expressed in FRDA patients (n = 418) compared to both heterozygous expansion carriers (n = 228) and controls (n = 93, 739 individuals in total), or were associated with disease progression, resulting in a disease signature for FRDA...
May 22, 2018: Human Molecular Genetics
Wing-Hang Tong, Nunziata Maio, De-Liang Zhang, Erika M Palmieri, Hayden Ollivierre, Manik C Ghosh, Daniel W McVicar, Tracey A Rouault
Given the essential roles of iron-sulfur (Fe-S) cofactors in mediating electron transfer in the mitochondrial respiratory chain and supporting heme biosynthesis, mitochondrial dysfunction is a common feature in a growing list of human Fe-S cluster biogenesis disorders, including Friedreich ataxia and GLRX5-related sideroblastic anemia. Here, our studies showed that restriction of Fe-S cluster biogenesis not only compromised mitochondrial oxidative metabolism but also resulted in decreased overall histone acetylation and increased H3K9me3 levels in the nucleus and increased acetylation of α-tubulin in the cytosol by decreasing the lipoylation of the pyruvate dehydrogenase complex, decreasing levels of succinate dehydrogenase and the histone acetyltransferase ELP3, and increasing levels of the tubulin acetyltransferase MEC17...
May 22, 2018: Blood Advances
Omar M Khdour, Indrajit Bandyopadhyay, Sandipan Roy Chowdhury, Nishant P Visavadiya, Sidney M Hecht
Friedreich's ataxia (FRDA) is an autosomal recessive neurodegenerative disorder resulting from reduced expression of the protein frataxin (FXN). Although its function is not fully understood, frataxin appears to help assemble iron sulfur clusters; these are critical for the function of many proteins, including those needed for mitochondrial energy production. Finding ways to increase FXN levels has been a major therapeutic strategy for this disease. Previously, we described a novel series of methylene violet analogues and their structural optimization as potential therapeutic agents for neurodegenerative and mitochondrial disorders...
May 4, 2018: Bioorganic & Medicinal Chemistry
Angeliki Pappa, Martin G Häusler, Andreas Veigel, Konstantina Tzamouranis, Martin W Pfeifer, Andreas Schmidt, Martin Bökamp, Holger Haberland, Siegfried Wagner, Joachim Brückel, Gideon de Sousa, Lukas Hackl, Esther Bollow, Reinhard W Holl
Friedreich ataxia (FRDA) is a multisystem autosomal recessive disease with progressive clinical course involving the neuromuscular and endocrine system. Diabetes mellitus (DM) is one typical non-neurological manifestation, caused by beta cell failure and insulin resistance. Because of its rarity, knowledge on DM in FRDA is limited. Based on data from 200 301 patients with DM of the German-Austrian diabetes registry (DPV) and two exemplary patient reports, characteristics of patients with DM and FRDA are compared with classical type 1 or type 2 diabetes...
May 12, 2018: Diabetes Research and Clinical Practice
Belinda J Boehm, Charles Whidborne, Alexander L Button, Tara L Pukala, David M Huang
Molecular dynamics simulations are used to elucidate the structure and thermodynamics of DNA triplexes associated with the neurodegenerative disease Friedreich's ataxia (FRDA), as well as complexes of these triplexes with the small molecule netropsin, which is known to destabilise triplexes. The ability of molecular simulations in explicit solvent to accurately capture triplex thermodynamics is verified for the first time, with the free energy to dissociate a 15-base antiparallel purine triplex-forming oligomer (TFO) from the duplex found to be slightly higher than reported experimentally...
May 10, 2018: Physical Chemistry Chemical Physics: PCCP
Yannis Dionyssiotis, Athina Kapsokoulou, Anna Danopoulou, Maria Kokolaki, Athina Vadalouka
Introduction: Friedreich's ataxia (FDRA) is the most common autosomal recessive, early-onset ataxia. FDRA is a progressive neurodegenerative disease that mainly affects the posterior (dorsal) columns of the spinal cord resulting in sensory ataxia. It manifests in initial symptoms of poor coordination and gait disturbance. Case presentation: We present two cases, a brother (54 years old) and sister (56 years old), with FDRA that are chronically institutionalized for incomplete quadriplegia without spasticity...
2018: Spinal Cord Series and Cases
David R Lynch, Ashley McCormick, Kimberly Schadt, Elizabeth Kichula
Evaluation of a pediatric patient presenting with ataxia can be expensive and time consuming. Acute causes tend to have a clear developmental paradigm, but chronic presentations are more likely to be secondary to a genetic disorder, either one that primarily causes ataxia or that presents ataxia as one of a multitude of symptoms. Evaluation should focus on a quick diagnosis for those that have treatment options and for those that require other systemic monitoring. Friedreich ataxia is the most common, and genetic testing can easily confirm the suspicion...
April 2018: Seminars in Pediatric Neurology
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[This corrects the article DOI: 10.1371/journal.pone.0190495.].
2018: PloS One
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