2,801 results match your criteria Friedreich Ataxia


Transcriptional profiling of isogenic Friedreich ataxia neurons and effect of an HDAC inhibitor on disease signatures.

J Biol Chem 2018 Dec 14. Epub 2018 Dec 14.

The Scripps Research Institute, United States.

Friedreich ataxia (FRDA) is a neurodegenerative disorder caused by transcriptional silencing of the FXN gene, resulting in loss of the essential mitochondrial protein frataxin. Based on the knowledge that a GAA•TTC  repeat expansion in the first intron of FXN induces heterochromatin, we previously showed that 2-aminobenzamide-type histone deacetylase inhibitors (HDACi) increase FXN mRNA levels in induced pluripotent stem cell (iPSC)-derived FRDA neurons and in circulating lymphocytes from patients after HDACi oral administration. How the reduced expression of frataxin leads to neurological and other systemic symptoms in FRDA patients remains unclear. Read More

View Article
December 2018

Correction of half the cardiomyocytes fully rescue Friedreich Ataxia mitochondrial cardiomyopathy through cell-autonomous mechanisms.

Hum Mol Genet 2018 Dec 13. Epub 2018 Dec 13.

Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Department of Translational Medicine and Neurogenetics, Illkirch, France.

Friedreich Ataxia (FA) is currently an incurable inherited mitochondrial neurodegenerative disease caused by reduced levels of frataxin. Cardiac failure constitutes the main cause of premature death in FA. While AAV-mediated cardiac gene therapy was shown to fully reverse the cardiac and mitochondrial phenotype in mouse models, this was achieved at high dose of vector resulting in the transduction of almost all cardiomyocytes, a dose and biodistribution that is unlikely to be replicated in clinic. Read More

View Article
December 2018

Large Interruptions of GAA Repeat Expansion Mutations in Friedreich Ataxia Are Very Rare.

Front Cell Neurosci 2018 21;12:443. Epub 2018 Nov 21.

Ataxia Research Group, Division of Biosciences, Department of Life Sciences, College of Health and Life Sciences, Brunel University London, Uxbridge, United Kingdom.

Friedreich ataxia is a multi-system autosomal recessive inherited disorder primarily caused by homozygous GAA repeat expansion mutations within intron 1 of the frataxin gene. The resulting deficiency of frataxin protein leads to progressive mitochondrial dysfunction, oxidative stress, and cell death, with the main affected sites being the large sensory neurons of the dorsal root ganglia and the dentate nucleus of the cerebellum. The GAA repeat expansions may be pure (GAA) in sequence or may be interrupted with regions of non-GAA sequence. Read More

View Article
November 2018
1 Read

Depressive symptoms in Friedreich ataxia.

Int J Clin Health Psychol 2018 Jan-Apr;18(1):18-26. Epub 2017 Dec 8.

Universidad de La Laguna, Spain.

Almost no attention has been paid to depression in Friedreich ataxia (FRDA), a highly disabling cerebellar degenerative disease. Our aim was to study the presence and the profile of depressive symptoms in FRDA and their relationship with demographic-disease variables and cognitive processing speed. The study groups consisted of 57 patients with a diagnosis of FRDA. Read More

View Article
December 2017

Neuroimaging Applications in Chronic Ataxias.

Int Rev Neurobiol 2018 29;143:109-162. Epub 2018 Oct 29.

Nuclear Medicine, "Le Scotte" University Hospital, Siena, Italy.

Magnetic resonance imaging (MRI), single photon emission computed tomography (SPECT) and positron emission tomography (PET) are the main instruments for neuroimaging investigation of patients with chronic ataxia. MRI has a predominant diagnostic role in the single patient, based on the visual detection of three patterns of atrophy, namely, spinal atrophy, cortical cerebellar atrophy and olivopontocerebellar atrophy, which correlate with the aetiologies of inherited or sporadic ataxia. In fact spinal atrophy is observed in Friedreich ataxia, cortical cerebellar atrophy in Ataxia Telangectasia, gluten ataxia and Sporadic Adult Onset Ataxia and olivopontocerebellar atrophy in Multiple System Atrophy cerebellar type. Read More

View Article
October 2018
2 Reads

FAST-1 antisense RNA epigenetically alters FXN expression.

Sci Rep 2018 Nov 21;8(1):17217. Epub 2018 Nov 21.

Division of Biosciences, Department of Life Sciences, College of Health & Life Sciences, and Synthetic Biology Theme, Institute of Environment, Health & Societies, Brunel University London, Uxbridge, United Kingdom.

Friedreich ataxia (FRDA) is a multisystem genetic disorder caused by GAA repeat expansion mutations within the FXN gene, resulting in heterochromatin formation and deficiency of frataxin protein. Elevated levels of the FXN antisense transcript (FAST-1) have previously been detected in FRDA. To investigate the effects of FAST-1 on the FXN gene expression, we first stably overexpressed FAST-1 in non-FRDA cell lines and then we knocked down FAST-1 in FRDA fibroblast cells. Read More

View Article
November 2018

Cardiac Phenotypes in Hereditary Muscle Disorders: JACC State-of-the-Art Review.

J Am Coll Cardiol 2018 Nov;72(20):2485-2506

Centre for Inherited Cardiovascular Diseases, IRCCS Foundation, University Hospital Policlinico San Matteo, Pavia, Italy.

Hereditary muscular diseases commonly involve the heart. Cardiac manifestations encompass a spectrum of phenotypes, including both cardiomyopathies and rhythm disorders. Common biomarkers suggesting cardiomuscular diseases include increased circulating creatine kinase and/or lactic acid levels or disease-specific metabolic indicators. Read More

View Article
November 2018
4 Reads

The impact of histone post-translational modifications in neurodegenerative diseases.

Biochim Biophys Acta Mol Basis Dis 2018 Oct 20. Epub 2018 Oct 20.

Chemistry Department of Brooklyn College, Brooklyn, New York 11210, United States; Ph.D. Programs in Chemistry, Biochemistry, and Biology, The Graduate Center of the City University of New York, New York 10016, United States. Electronic address:

Every year, neurodegenerative disorders take more than 5000 lives in the US alone. Cures have not yet been found for many of the multitude of neuropathies. The majority of amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and Parkinson's disease (PD) cases have no known genetic basis. Read More

View Article
October 2018
1 Read

Developmental and neurodegenerative damage in Friedreich's ataxia.

Eur J Neurol 2018 Oct 16. Epub 2018 Oct 16.

Department of Neurology and Neuroimaging Laboratory, School of Medical Sciences, University of Campinas (UNICAMP), Campinas.

Background And Purpose: Friedreich's ataxia (FRDA) is the most common autosomal-recessive ataxia worldwide. It is characterized by early onset, sensory abnormalities and slowly progressive ataxia. All magnetic resonance imaging (MRI)-based studies have focused on the evaluation of adult patients. Read More

View Article
October 2018
15 Reads

Injuries to amateur participants in traditional bullfighting festivals.

Cir Esp 2018 Oct 12. Epub 2018 Oct 12.

Sección de Cirugía, Hospital Reina Sofía, Tudela, Navarra, España.

Introduction: To identify the different types of injuries occurred during activities for the general public involving bulls. We analyze the conditions in which these injuries occurred, radiological examinations performed, treatment and complications.

Method: We present a 10-year retrospective study examining 107 patients who came to the Emergency Department of our hospital with pathologies associated with bulls or bull calves over a period of 10years. Read More

View Article
October 2018
12 Reads

Automated functional upper limb evaluation of patients with Friedreich ataxia using serious games rehabilitation exercises.

J Neuroeng Rehabil 2018 Oct 4;15(1):87. Epub 2018 Oct 4.

Department of Neurology, Erasme Hospital, Brussels, Belgium.

Background: Friedreich ataxia (FRDA) is a disease with neurological and systemic involvement. Clinical assessment tools commonly used for FRDA become less effective in evaluating decay in patients with advanced FRDA, particularly when they are in a wheelchair. Further motor worsening mainly impairs upper limb function. Read More

View Article
October 2018
1 Read

Functional and Structural Brain Damage in Friedreich's Ataxia.

Front Neurol 2018 6;9:747. Epub 2018 Sep 6.

Severe Developmental Disabilities Unit, Scientific Institute, IRCCS "Eugenio Medea", Conegliano, Italy.

Friedreich's ataxia (FRDA) is a rare hereditary neurodegenerative disorder caused by a GAA repeat expansion in the gene. There is still no cure or quantitative biomarkers reliaby correlating with the progression rate and disease severity. Investigation of functional and structural alterations characterizing white (WM) and gray matter (GM) in FRDA are needed prerequisite to monitor progression and response to treatment. Read More

View Article
September 2018
13 Reads

Iron in Friedreich Ataxia: A Central Role in the Pathophysiology or an Epiphenomenon?

Pharmaceuticals (Basel) 2018 Sep 19;11(3). Epub 2018 Sep 19.

Departament de Ciències Mèdiques Bàsiques, IRBLleida, Universitat de Lleida, 25198 Lleida, Spain.

Friedreich ataxia is a neurodegenerative disease with an autosomal recessive inheritance. In most patients, the disease is caused by the presence of trinucleotide GAA expansions in the first intron of the frataxin gene. These expansions cause the decreased expression of this mitochondrial protein. Read More

View Article
September 2018
3 Reads

Sudomotor dysfunction is frequent and correlates with disability in Friedreich ataxia.

Clin Neurophysiol 2018 Nov 31;129(11):2290-2295. Epub 2018 Aug 31.

Departments of Neurology, School of Medical Sciences, University of Campinas - UNICAMP, Campinas, SP, Brazil. Electronic address:

Objectives: To evaluate autonomic symptoms and function in Friedreich's Ataxia (FRDA).

Methods: Twenty-eight FRDA patients and 24 controls underwent clinical/electrophysiological testing. We employed the Friedreich's Ataxia Rating Scale (FARS) and the Scales for Outcomes in Parkinson's Disease: Autonomic Questionnaire-SCOPA-AUT to estimate the intensity of ataxia and autonomic complaints, respectively. Read More

View Article
November 2018
1 Read

Increased Frataxin Expression Induced in Friedreich Ataxia Cells by Platinum TALE-VP64s or Platinum TALE-SunTag.

Mol Ther Nucleic Acids 2018 Sep 27;12:19-32. Epub 2018 Apr 27.

Centre de Recherche du CHU, Québec-Université Laval, Québec, QC, Canada; Département de Médecine Moléculaire, l'Université Laval Québec, Québec, QC, Canada. Electronic address:

Frataxin gene (FXN) expression is reduced in Friedreich's ataxia patients due to an increase in the number of GAA trinucleotides in intron 1. The frataxin protein, encoded by that gene, plays an important role in mitochondria's iron metabolism. Platinum TALE (plTALE) proteins targeting the regulatory region of the FXN gene, fused with a transcriptional activator (TA) such as VP64 or P300, were used to increase the expression of that gene. Read More

View Article
September 2018
2 Reads

Child Neurology: Friedreich ataxia with upper motor neuron findings: A case study.

Neurology 2018 Aug;91(9):426-428

From the University of Kentucky College of Medicine, Lexington.

A 16-year-old boy with hypertrophic cardiomyopathy, gait abnormalities, and balance problems was found to have Friedreich ataxia. Though Friedreich ataxia typically renders patients areflexic, this child had upper motor neuron findings of spasticity in both lower extremities, with crossed adductors, and 4+ deep tendon reflexes at the patella and Achilles bilaterally. This unusual presentation of an uncommon genetic disorder led to uncertainty of the patient's true diagnosis until genetic testing confirmed that he had 2 alleles with the Friedreich ataxia mutation. Read More

View Article
August 2018
8 Reads

Test-retest reliability of an instrumented electronic walkway system (GAITRite) for the measurement of spatio-temporal gait parameters in young patients with Friedreich's ataxia.

Gait Posture 2018 Oct 20;66:45-50. Epub 2018 Aug 20.

AP-HP, Robert Debré University Hospital, Physical Rehabilitation Department, France; INSERM UMR-S 1141, Robert Debré University Hospital, France.

Background: Friedreich ataxia (FRDA) affects the spatio-temporal parameters (STP) of gait. To our knowledge, proper tools to measure the variability of ataxic gait have not been validated yet. The aims of the present study were: (1) to measure the reproducibility of STP and gait scores in young patients with FRDA and (2) to describe the characteristics of gait parameters in this population. Read More

View Article
October 2018

Nonataxia symptoms in Friedreich Ataxia: Report from the Registry of the European Friedreich's Ataxia Consortium for Translational Studies (EFACTS).

Neurology 2018 Sep 10;91(10):e917-e930. Epub 2018 Aug 10.

From the Department of Neurology (K.R., I.D., C.H., C.D., J.B.S.), RWTH Aachen University; JARA-BRAIN Institute Molecular Neuroscience and Neuroimaging (K.R., I.D., C.H., C.D., J.B.S.), Forschungszentrum Jülich GmbH and RWTH Aachen University, Germany; Department of Molecular Neuroscience (P.G.), Ataxia Center, UCL Institute of Neurology, London, UK; Unit of Genetics of Neurodegenerative and Metabolic Diseases (C.M.), Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy; ICM (Brain and Spine Institute) Sorbonne Universités (A.D.), UPMC Univ Paris 06 UMR S 1127, and INSERM U 1127, CNRS UMR 7225 and APHP, Pitié-Salpêtrière University Hospital, Genetic Department, Paris, France; Department of Neurology (S.B.), Medical University Innsbruck, Austria; Department of Neurology (T.K.), Friedrich Baur Institute, University Hospital of the Ludwig-Maximilians-Universität München; German Center for Neurodegenerative Diseases (DZNE) (T.K.), Munich; Munich Cluster for Systems Neurology (SyNergy) (T.K.), Munich, Germany; Reference Unit of Hereditary Ataxias and Paraplegias (F.J.R.d.R.G.), Department of Neurology, IdiPAZ, Hospital Universitario La Paz, Madrid, Spain; Department of Neurodegenerative Diseases (L.S.), Hertie-Institute for Clinical Brain Research, University of Tübingen; Department of Neurology (I.G.), University Hospital of Bonn; German Center for Neurodegenerative Diseases (DZNE) (I.G.), Bonn; Department of Neurology (K.B.), Philipps University of Marburg, Germany; and Laboratory of Experimental Neurology (M.P.), Université Libre de Bruxelles, Brussels, Belgium.

Objective: To provide a systematic evaluation of the broad clinical variability in Friedreich ataxia (FRDA), a multisystem disorder presenting mainly with afferent ataxia but also a complex phenotype of nonataxia symptoms.

Methods: From the large database of the European Friedreich's Ataxia Consortium for Translational Studies, 650 patients with genetically confirmed FRDA were included. Detailed data of medical history documentation, questionnaires, and reports on clinical features were analyzed to provide in-depth description of the clinical profile and frequency rates of phenotypical features with a focus on differences between typical-onset and late-onset FRDA. Read More

View Article
September 2018
8 Reads

Activating frataxin expression by single-stranded siRNAs targeting the GAA repeat expansion.

Bioorg Med Chem Lett 2018 Sep 21;28(17):2850-2855. Epub 2018 Jul 21.

Department of Pharmacology, UT Southwestern Medical Center at Dallas, Dallas, TX 75390, United States; Department of Biochemistry, UT Southwestern Medical Center at Dallas, Dallas, TX 75390, United States. Electronic address:

Friedreich's ataxia (FRDA) is an incurable neurodegenerative disorder caused by reduced expression of the mitochondrial protein frataxin (FXN). The genetic cause of the disease is an expanded GAA repeat within the FXN gene. Agents that increase expression of FXN protein are a potential approach to therapy. Read More

View Article
September 2018
3 Reads

Longitudinal analysis of contrast acuity in Friedreich ataxia.

Neurol Genet 2018 Aug 23;4(4):e250. Epub 2018 Jul 23.

Department of Neurology (A.G.H., D.R.L.), University of Pennsylvania; Divisions of Neurology and Pediatrics (L.A.H., D.R.L.), Children's Hospital of Philadelphia, PA; Department of Neurology (S.P.), University of California at Los Angeles; Departments of Neurology and Pediatrics (K.M.), University of Iowa; Department of Neurology (G.R.W.), Emory University, Atlanta, GA; Department of Neurology (T.Z.), University of South Florida, Tampa Bay; Department of Neurology (S.H.S.), University of Florida, Gainesville; Department of Neurology (T.A.), Houston Methodist Hospital, TX; Murdoch Children's Research Institute (M.B.D.), Melbourne, Victoria, Australia; and Department of Neurology (A.B.), University of Rochester, NY.

Objective: To determine the natural history of contrast acuity in Friedreich ataxia.

Methods: In the Friedreich Ataxia-Clinical Outcome Measures Study, participants (n = 764) underwent binocular high- and low-contrast visual acuity testing at annual study visits. Mixed-effects linear regression was used to model visual acuity as a function of time, with random intercepts and slopes to account for intraindividual correlation of repeated measurements. Read More

View Article

Double-blind, randomized and controlled trial of EPI-743 in Friedreich's ataxia.

Neurodegener Dis Manag 2018 Aug 27;8(4):233-242. Epub 2018 Jul 27.

Bioelectron Technology Corporation, Mountain View, CA, 94043 USA.

Aim: To evaluate the safety and clinical effects of EPI-743 in Friedreich's ataxia patients. EPI-743 is a compound that targets oxidoreductase enzymes essential for redox control of metabolism.

Methods: We conducted a multicenter trial that evaluated EPI-743 during a 6-month placebo-controlled phase, followed by an 18-month open-label phase. Read More

View Article

Zinc(II) binding on human wild-type ISCU and Met140 variants modulates NFS1 desulfurase activity.

Biochimie 2018 Sep 20;152:211-218. Epub 2018 Jul 20.

Structural Genomics Consortium, Nuffield Department of Clinical Medicine, University of Oxford, OX3 7DQ, UK. Electronic address:

Human de novo iron-sulfur (Fe-S) assembly complex consists of cysteine desulfurase NFS1, accessory protein ISD11, acyl carrier protein ACP, scaffold protein ISCU, and allosteric activator frataxin (FXN). FXN binds the NFS1-ISD11-ACP-ISCU complex (SDAU), to activate the desulfurase activity and Fe-S cluster biosynthesis. In the absence of FXN, the NFS1-ISD11-ACP (SDA) complex was reportedly inhibited by binding of recombinant ISCU. Read More

View Article
September 2018
14 Reads

Impact of Models in the Study and Treatment of Friedreich's Ataxia.

Int J Mol Sci 2018 Jul 7;19(7). Epub 2018 Jul 7.

Lehrstuhl für Entwicklungsbiologie, Universität Regensburg, 93040 Regensburg, Germany.

has been for over a century the model of choice of several neurobiologists to decipher the formation and development of the nervous system as well as to mirror the pathophysiological conditions of many human neurodegenerative diseases. The rare disease Friedreich’s ataxia (FRDA) is not an exception. Since the isolation of the responsible gene more than two decades ago, the analysis of the fly orthologue has proven to be an excellent avenue to understand the development and progression of the disease, to unravel pivotal mechanisms underpinning the pathology and to identify genes and molecules that might well be either disease biomarkers or promising targets for therapeutic interventions. Read More

View Article
July 2018
1 Read

The Etiologies of Chronic Progressive Cerebellar Ataxia in a Korean Population.

J Clin Neurol 2018 Jul;14(3):374-380

Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

Background And Purpose: The etiologies and frequencies of cerebellar ataxias vary between countries. Our primary aim was to determine the frequency of each diagnostic group of cerebellar ataxia patients in a Korean population.

Methods: We reviewed the medical records of patients who were being followed up between November 1994 and February 2016. Read More

View Article

Autonomic function testing in Friedreich's ataxia.

J Neurol 2018 Sep 27;265(9):2015-2022. Epub 2018 Jun 27.

Department of Neurology, Innsbruck Medical University, Anichstrasse 35, 6020, Innsbruck, Austria.

Background: Friedreich ataxia (FRDA) is an inherited movement disorder which manifests with progressive gait instability, sensory loss and cardiomyopathy. Peripheral neuropathy is an established feature of FRDA. At neuropathological examination, a depletion of large, myelinated axons is evident, but also unmyelinated fibers are affected which may result in a variety of sensory and autonomic signs and symptoms. Read More

View Article
September 2018
13 Reads
3.380 Impact Factor

Friedreich Ataxia: Diagnostic Yield and Minimal Frequency in South Brazil.

Cerebellum 2018 Jun 25. Epub 2018 Jun 25.

Programa de Pós-Graduação em Saúde da Criança e do Adolescente, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2400, sala 220, Porto Alegre, 90035-003, Brazil.

Friedreich ataxia (FRDA) is an autosomal recessive disorder due to mutations in the FXN gene. FRDA is characterized by the classical triad of ataxia, absent reflexes, and Babinski sign, but atypical presentations might also occur. Our aims were to describe the proportion of FRDA diagnoses in suspected families living in Rio Grande do Sul, South Brazil, and to estimate a minimum frequency of symptomatic subjects. Read More

View Article

Scales for the clinical evaluation of cerebellar disorders.

Handb Clin Neurol 2018 ;154:329-339

Beatrix Kinderziekenhuis, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

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. Read More

View Article
September 2018

The neuropathology of the adult cerebellum.

Authors:
Arnulf H Koeppen

Handb Clin Neurol 2018 ;154:129-149

Research, Neurology, and Pathology Services, Veterans Affairs Medical Center and Departments of Neurology and Pathology, Albany Medical College, Albany, NY, United States. Electronic address:

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. Read More

View Article
September 2018
4 Reads

Identification of cardioprotective drugs by medium-scale pharmacological screening on a cardiac model of Friedreich's ataxia.

Dis Model Mech 2018 07 20;11(7). Epub 2018 Jul 20.

Université Paris Diderot, Sorbonne Paris Cité, Unité de Biologie Fonctionnelle et Adaptative (BFA) UMR8251 CNRS, 75205, Paris Cedex 13, France

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, which is characterized by progressive neurodegeneration and cardiomyopathy, the latter being the most common cause of death in patients. We previously developed a cardiac model of FA, in which the fly frataxin is inactivated specifically in the heart, leading to heart dilatation and impaired systolic function. Read More

View Article
July 2018
1 Read

Recessive ataxias.

Handb Clin Neurol 2018 ;155:73-89

Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom; Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Trust, Oxford, United Kingdom.

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. Read More

View Article
October 2018
2 Reads

Endocrine disorders and the cerebellum: from neurodevelopmental injury to late-onset ataxia.

Handb Clin Neurol 2018 ;155:353-368

Department of Medicine, University of Washington, Seattle, United States.

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. Read More

View Article
October 2018
1 Read

Epigenetic cerebellar diseases.

Authors:
Mercedes Serrano

Handb Clin Neurol 2018 ;155:227-244

Pediatric Neurology Department and Pediatric Institute for Genetic Medicine and Rare Diseases, Hospital Sant Joan de Déu; and Centre for Biomedical Research on Rare Diseases, Instituto de Salud Carlos III, Barcelona, Spain. Electronic address:

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. Read More

View Article
October 2018

Spastic ataxias.

Handb Clin Neurol 2018 ;155:191-203

Neuroscience Axis, CHU de Québec-Laval University, Quebec, QC, Canada; Neuromuscular and Neurogenetic Disease Clinic, CHU de Québec-Laval University, Quebec, QC, Canada. Electronic address:

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. Read More

View Article
October 2018
2 Reads

Rapid and Complete Reversal of Sensory Ataxia by Gene Therapy in a Novel Model of Friedreich Ataxia.

Mol Ther 2018 Aug 28;26(8):1940-1952. Epub 2018 May 28.

Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), 67404 Illkirch, France; Institut National de la Santé et de la Recherche Médicale, U1258, 67404 Illkirch, France; Centre National de la Recherche Scientifique, UMR7104, 67404 Illkirch, France; Université de Strasbourg, 67000 Strasbourg, France. Electronic address:

Friedreich ataxia (FA) is a rare mitochondrial disease characterized by sensory and spinocerebellar ataxia, hypertrophic cardiomyopathy, and diabetes, for which there is no treatment. FA is caused by reduced levels of frataxin (FXN), an essential mitochondrial protein involved in the biosynthesis of iron-sulfur (Fe-S) clusters. Despite significant progress in recent years, to date, there are no good models to explore and test therapeutic approaches to stop or reverse the ganglionopathy and the sensory neuropathy associated to frataxin deficiency. Read More

View Article
August 2018
1 Read

Models of Friedreich's Ataxia.

Biomed Res Int 2018 5;2018:5065190. Epub 2018 Apr 5.

Department of Genetics, University of Valencia, Campus of Burjassot, Valencia, Spain.

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 gene. Read More

View Article
October 2018

The importance of central auditory evaluation in Friedreich's ataxia.

Arq Neuropsiquiatr 2018 Mar;76(3):170-176

Departament of Neurology, Hospital Pequeno Príncipe, Curitiba, Paraná State, Brasil.

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. Read More

View Article

Adding a temporal dimension to the study of Friedreich's ataxia: the effect of frataxin overexpression in a human cell model.

Dis Model Mech 2018 06 25;11(6). Epub 2018 Jun 25.

Basic and Clinical Neuroscience, Maurice Wohl Institute, King's College London, 5 Cutcombe Road, London SE5 9RT, UK

The neurodegenerative disease Friedreich's ataxia is caused by lower than normal levels of frataxin, an important protein involved in iron-sulfur (Fe-S) cluster biogenesis. An important step in designing strategies to treat this disease is to understand whether increasing the frataxin levels by gene therapy would simply be beneficial or detrimental, because 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 monitor how the system recovers after overexpression. Read More

View Article

TLR-activated repression of Fe-S cluster biogenesis drives a metabolic shift and alters histone and tubulin acetylation.

Blood Adv 2018 May;2(10):1146-1156

Metals Biology and Molecular Medicine Group, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD; and.

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. Previous studies have shown that the metabolic shift in Toll-like receptor (TLR)-activated myeloid cells involves rapid activation of glycolysis and subsequent mitochondrial respiratory failure due to nitric oxide (NO)-mediated damage to Fe-S proteins. Read More

View Article
May 2018
3 Reads

Lipophilic methylene blue analogues enhance mitochondrial function and increase frataxin levels in a cellular model of Friedreich's ataxia.

Bioorg Med Chem 2018 07 4;26(12):3359-3369. Epub 2018 May 4.

Biodesign Center for BioEnergetics, and School of Molecular Sciences, Arizona State University, Tempe, AZ 85287, USA.

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. Read More

View Article
July 2018
3 Reads

Diabetes mellitus in Friedreich Ataxia: A case series of 19 patients from the German-Austrian diabetes mellitus registry.

Diabetes Res Clin Pract 2018 Jul 26;141:229-236. Epub 2018 May 26.

Institute for Epidemiology and medical Biometry, ZIBMT, University of Ulm, Germany; German Center for Diabetes-Research (DZD), Munich-Neuherberg, Germany.

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. Read More

View Article
July 2018
5 Reads

Pediatric Ataxia: Focus on Chronic Disorders.

Semin Pediatr Neurol 2018 04 5;25:54-64. Epub 2018 Jan 5.

Departments of Pediatrics and Neurology, The Children's Hospital of Philadelphia, Philadelphia, PA; Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.

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. Read More

View Article
April 2018
2 Reads

Cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) with chronic cough and preserved muscle stretch reflexes: evidence for selective sparing of afferent Ia fibres.

J Neurol 2018 Jun 25;265(6):1454-1462. Epub 2018 Apr 25.

Service of Neurology, University Hospital "Marqués de Valdecilla (IDIVAL)", University of Cantabria, and "Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED)", Santander, Spain.

The aim of this study was to describe five patients with cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) with chronic cough and preserved limb muscle stretch reflexes. All five patients were in the seventh decade of age, their gait imbalance having been initiated in the fifth decade. In four patients cough antedated gait imbalance between 15 and 29 years; cough was spasmodic and triggered by variable factors. Read More

View Article
June 2018
13 Reads

Current and Promising Therapies in Autosomal Recessive Ataxias.

CNS Neurol Disord Drug Targets 2018 ;17(3):161-171

Department of Medicine, Faculty of Medicine, Laval University and CHU de Quebec-Laval University, Axe Neurosciences, 1401, 18th Street, Quebec, QC, Canada.

Background & Objective: Ataxia is clinically characterized by unsteady gait and imbalance. Cerebellar disorders may arise from many causes such as metabolic diseases, stroke or genetic mutations. The genetic causes are classified by mode of inheritance and include autosomal dominant, X-linked and autosomal recessive ataxias. Read More

View Article
January 2018
4 Reads

Rapid exhaustion of auditory neural conduction in a prototypical mitochondrial disease, Friedreich ataxia.

Clin Neurophysiol 2018 Jun 27;129(6):1121-1129. Epub 2018 Mar 27.

Laboratory of Neurosensory Biophysics, UMR INSERM 1107, University Clermont Auvergne, Clermont-Ferrand, France; Centre Jean Perrin, Clermont-Ferrand, France. Electronic address:

Objectives: In patients with Friedreich ataxia (FRDA), mitochondrial failure leads to impaired cellular energetics. Since many FRDA patients have impaired hearing in noise, we investigated the objective consequences on standard auditory brainstem-evoked responses (ABRs).

Methods: In 37 FRDA patients, among whom 34 with abnormal standard ABRs, hearing sensitivity, speech-in-noise intelligibility and otoacoustic emissions were controlled. Read More

View Article
June 2018
5 Reads

The transcriptional regulator CCCTC-binding factor limits oxidative stress in endothelial cells.

J Biol Chem 2018 Jun 2;293(22):8449-8461. Epub 2018 Apr 2.

From the Translational Medicine Research Program, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada,

The CCCTC-binding factor (CTCF) is a versatile transcriptional regulator required for embryogenesis, but its function in vascular development or in diseases with a vascular component is poorly understood. Here, we found that endothelial Ctcf is essential for mouse vascular development and limits accumulation of reactive oxygen species (ROS). Conditional knockout of in endothelial progenitors and their descendants affected embryonic growth, and caused lethality at embryonic day 10. Read More

View Article
June 2018
9 Reads
1 Citation
4.573 Impact Factor

Impact of Mobility Device Use on Quality of Life in Children With Friedreich Ataxia.

J Child Neurol 2018 May 2;33(6):397-404. Epub 2018 Apr 2.

1 Division of Clinical and Metabolic Genetics, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.

Objective: To determine how mobility device use impacts quality of life in children with Friedreich ataxia.

Study Design: Data from 111 pediatric patients with genetically confirmed Friedreich ataxia were collected from a prospective natural history study utilizing standardized clinical evaluations, including health-related quality of life using the Pediatric Quality of Life Inventory (PedsQL) 4.0 Generic Core Module. Read More

View Article
May 2018
7 Reads

Interactions of iron-bound frataxin with ISCU and ferredoxin on the cysteine desulfurase complex leading to Fe-S cluster assembly.

J Inorg Biochem 2018 Jun 15;183:107-116. Epub 2018 Mar 15.

National Magnetic Resonance Facility at Madison and Biochemistry Department, University of Wisconsin-Madison, 433 Babcock Drive, Madison, WI 53706, United States. Electronic address:

Frataxin (FXN) is involved in mitochondrial iron‑sulfur (Fe-S) cluster biogenesis and serves to accelerate Fe-S cluster formation. FXN deficiency is associated with Friedreich ataxia, a neurodegenerative disease. We have used a combination of isothermal titration calorimetry and multinuclear NMR spectroscopy to investigate interactions among the components of the biological machine that carries out the assembly of iron‑sulfur clusters in human mitochondria. Read More

View Article
June 2018
4 Reads

Identification of p38 MAPK as a novel therapeutic target for Friedreich's ataxia.

Sci Rep 2018 Mar 22;8(1):5007. Epub 2018 Mar 22.

Department of Pathology and Laboratory Medicine, Children's Hospital Philadelphia, Philadelphia, PA, USA.

Friedreich ataxia (FRDA) is an autosomal recessive neuro- and cardio-degenerative disorder caused by decreased expression of frataxin, a protein that localizes to mitochondria and is critical for iron-sulfur-cluster (ISC) assembly. There are no proven effective treatments for FRDA. We previously screened a random shRNA library and identified a synthetic shRNA (gFA11) that reverses the growth defect of FRDA cells in culture. Read More

View Article
March 2018
2 Reads

Pitfalls in molecular diagnosis of Friedreich ataxia.

Eur J Med Genet 2018 Mar 9. Epub 2018 Mar 9.

Université Paris Descartes - Sorbonne Paris Cité, Institut Imagine, INSERM UMR1163, Laboratoire des Maladies Mitochondriales, Paris, France; Service de Génétique, Groupe hospitalier Necker Enfants Malades, Assistance Publique -Hôpitaux de Paris, Paris, France. Electronic address:

Freidreich ataxia (FRDA) is the most common hereditary ataxia, nearly 98% of patients harbouring homozygous GAA expansions in intron 1 of the FXN gene (NM_000144.4). The remaining patients are compound heterozygous for an expansion and a point mutation or an exonic deletion. Read More

View Article
March 2018
9 Reads