Friedreich Ataxia Scientific News: Monthly update: March 8- April 5, 2018

Monthly update: March 8- April 5, 2018 The transcriptional regulator CCCTC-binding factor limits oxidative stress in endothelial cells Suggest a potential mechanism for endothelial dysfunction in FRDA. Read more »

Idebenone: Novel Strategies to Improve Its Systemic and Local Efficacy Liposomes, cyclodextrins and lipid-based nanoparticles could open new perspectives in the therapeutic outcomes of this strong antioxidant agent. Read more »

Impact of Mobility Device Use on Quality of Life in Children With Friedreich Ataxia Mobility device use is associated with significant worsening of all domains of quality of life in children with Friedreich ataxia. Read more »

Management of Pediatric Movement Disorders: Present and Future Treatment such as gene therapy, epigenetic modulation, and stem cell therapy hold promise for improving outcomes in both primary and secondary causes of movement disorders. Read more »

Structure and mechanism of mitochondrial electron transport chain This work provided solid evidence for the existence of megacomplex of human respirasome. This is a great step forward into conquering many severe neurodegenerative diseases, including Alzheimer's syndrome, Parkinson's disease, multiple sclerosis, friedreich's ataxia, Amyotrophic lateral sclerosis, etc. Read more »

Dysfunction in the mitochondrial Fe-S assembly machinery leads to formation of the chemoresistant truncated VDAC1 isoform without HIF-1α activation We show that hypoxia promotes the downregulation of several proteins (ISCU, NFS1, FXN) involved in the early steps of mitochondrial Fe-S cluster biogenesis. Read more »

Rapid exhaustion of auditory neural conduction in a prototypical mitochondrial disease, Friedreich ataxia A large decrease in conduction velocity along auditory neurons occurs within seconds, attributed to fast energetic failure. Read more »

Cell Therapy Instigates Neural Repair In Friedreich’s Ataxia Mice Transplantation of bone marrow cells that express frataxin into the FRDA mice caused the upregulation of frataxin as well as a number of antioxidative proteins, as well as improving movement and coordination in the mice. Read more »

Assistance circulatoire et transplantation d’organes thoraciques chez l’enfant Les maladies neuro-dégénératives (Friedreich, Duchenne) ou certaines maladies mitochondriales, ainsi que des séquelles graves d'accident vasculaire cérébral, sont considérées comme des contre-indications à la greffe. Read more »

Caractéristiques cliniques ; électrophysiologiques et évolutives des formes atypiques de l’ataxie héréditaire de Friedreich : à propos sept cas Devant un tableau d’ataxie atypique avec un début tardif et des réflexes vifs ou conservés l’ataxie de Freidreich doit être évoquée et une étude génétique doit être envisagée. Read more »

L’accumulation intracérébrale de fer, un aspect IRM atypique de l’ataxie de Friedreich L’AF devrait systématiquement être envisagée devant un syndrome cérébelleux lentement progressif même chez les sujets âgés et même en l’absence d’antécédent familial en cas de dépôt de fer au niveau du cervelet ou des noyaux gris centraux à l’IRM. Read more »

L’atteinte du système nerveux périphérique au cours des ataxies cérébelleuses héréditaires autosomiques récessives (ACAR) : étude de 33 cas Read more »

Étude de la population réunionnaise atteinte d’ataxie de Friedreich La Réunion possède un cluster d’ataxie de Friedreich à faible nombre de répétition GAA, dont les caractéristiques peuvent rappeler les formes acadiennes, qui sont également le résultat d’un effet fondateur. Read more »

Mitofusin-Dependent ER Stress Triggers Glial Dysfunction and Nervous System Degeneration in a Drosophila Model of Friedreich’s Ataxia Marf and ER stress represent a hub in the neurodegenerative process of FRDA and uncover both as important elements substantially involved the FRDA pathology. Read more »

Identification of p38 MAPK as a novel therapeutic target for Friedreich’s ataxia The involvement of the p38 MAPK pathway in the pathogenesis of FRDA and the potential use of p38 inhibitors as a treatment for FRDA. Read more »

Mutations in PMPCB Encoding the Catalytic Subunit of the Mitochondrial Presequence Protease Cause Neurodegeneration in Early Childhood Biallelic mutations in PMPCB cause defects in MPP proteolytic activity leading to dysregulation of iron-sulfur cluster biogenesis and triggering a complex neurological phenotype of neurodegeneration in early childhood. Read more »

Iron regulatory protein deficiency compromises mitochondrial function in murine embryonic fibroblasts Overexpression of human ISCU and frataxin in Irp1 or Irp2-null cells was able to rescue the defects in iron-sulfur cluster biogenesis and mitochondrial quality. Read more »

Frataxin overexpression in Müller cells protects retinal ganglion cells in a mouse model of ischemia/reperfusion injury in vivo The aim of this study was to evaluate the effect of frataxin overexpression in Müller cells on neuronal survival after retinal ischemia/reperfusion in the mouse in vivo. Read more »

Genetic Infiltrative Cardiomyopathies Friedreich ataxia: cardiac dysfunction from congestive heart failure or arrhythmia accounts for an estimated 59% of death.  Read more »

Resting-state connectivity in neurodegenerative disorders: Is there potential for an imaging biomarker? For rare neurodegenerative diseases, no clear conclusions can be drawn due to the few published results.  Read more »

Optical coherence tomography in autosomal recessive spastic ataxia of Charlevoix-Saguenay This is a useful tool in identifying cases of autosomal recessive spastic ataxia of Charlevoix-Saguenay from other causes of ataxia. Read more »

Distinct effects of frataxin missence point mutations on mitochondrial localization, protein processing, and cellular metabolism These studies will examine the mechanism by which FRDA-associated missense mutations impair FXN processing and explore the influence they have on cellular metabolism, in addition to exploring the use of fatty acids as a potential therapeutic strategy. Read more »

Interactions of iron-bound frataxin with ISCU and ferredoxin on the cysteine desulfurase complex leading to Fe-S cluster assembly Our results show that FXN tightly binds a single Fe2+ but not Fe3+. While FXN (with or without bound Fe2+) does not bind the scaffold protein ISCU directly. Read more »

Biomarcadores epigenéticos: hacia su implantación en la rutina clínica / Epigenetic biomarkers: towards their incorporation into clinical routine En un futuro cercano, este tipo de tecnologías se incorporarán a los laboratorios clínicos y, por lo tanto, el uso de estos biomarcadores se implementará en la rutina de diagnóstico clínico, contribuyendo así a la aplicación real de la teragnosis y mejorando la medicina de precisión. Read more »

Large-scale computational drug repositioning to find treatments for rare diseases eMatchSite is combined with virtual screening to systematically explore opportunities to reposition known drugs to proteins associated with rare diseases. Read more »

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

Anna R Roy, Abdalla Ahmed, Peter V DiStefano, Lijun Chi, Nadiya Khyzha, Niels Galjart, Michael D Wilson, Jason E Fish and Paul Delgado Olguin; J. Biol. Chem., First Published on April 2, 2018 doi: 10.1074/jbc.M117.814699

Ctcf promotes vascular development, and limits oxidative stress in endothelial cells. These results reveal a function for Ctcf in vascular development, and suggest a potential mechanism for endothelial dysfunction in FRDA.

Idebenone: Novel Strategies to Improve Its Systemic and Local Efficacy

Lucia Montenegro, Rita Turnaturi, Carmela Parenti and Lorella Pasquinucci; Nanomaterials 2018, 8(2), 87; doi:10.3390/nano8020087

Due to IDE poor bioavailability after oral and topical administration, many researchers attempted different strategies to increase IDE efficacy in the treatment of neurodegenerative diseases and skin disorders. IDE chemical modifications mainly focused on increasing IDE activity at cellular or mitochondrial level while nanotechnology approaches aimed at designing novel formulations to improve IDE systemic and local efficacy. The encouraging results obtained loading IDE in different delivery systems such as liposomes, cyclodextrins and lipid-based nanoparticles could open new perspectives in the therapeutic outcomes of this strong antioxidant agent

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

Resham Ejaz, MD, Shiyi Chen, MSc, Charles J. Isaacs, BA, , Amanda Carnevale, MSc, Judith Wilson, RN(EC), MN, NP-Paediatrics, Kristen George, NP-Paediatrics, Martin B. Delatycki, MBBS, FRACP, PhD, Susan L. Perlman, MD, Katherine D. Mathews, MD, George R. Wilmot, MD, PhD, J. Chad Hoyle, MD, Sub H. Subramony, MD, Theresa Zesiewicz, MD, Jennifer M. Farmer, MS, , David R. Lynch, MD, PhD, , , Grace Yoon, MD, FRCPC, Journal of Child Neurology First Published April 2, 2018 doi:10.1177/0883073818764941

Mobility device use is associated with significant worsening of all domains of quality of life in children with Friedreich ataxia.

Management of Pediatric Movement Disorders: Present and Future

Jeffrey B. Russ, Akila M. Nallappan, Amy Robichaux-Viehoever, Seminars in Pediatric Neurology, 2018, ISSN 1071-9091, doi:10.1016/j.spen.2018.02.004.

Management of movement disorders in children is an evolving field. This article outlines the major categories of treatment options for pediatric movement disorders and general guidelines for their use. We review the evidence for existing therapies, which continue to lack large-scale controlled trials to guide treatment decisions. The field continues to rely on extrapolations from adult studies and lower quality evidence such as case reports and case series to guide treatment guidelines and consensus statements. Developments in new pharmaceuticals for rare diseases have begun to provide hope for those cases in which a genetic diagnosis can be made. Advances in surgical therapies such as deep brain stimulation as well as new modes of treatment such as gene therapy, epigenetic modulation, and stem cell therapy hold promise for improving outcomes in both primary and secondary causes of movement disorders. There is a critical need for larger, multicenter, controlled clinical trials to fully evaluate treatments for pediatric movement disorders.

Structure and mechanism of mitochondrial electron transport chain

Runyu Guo, Jinke Gu, Shuai Zong, Meng Wu, Maojun Yang, Biomedical Journal, Available online 26 March 2018, ISSN 2319-4170, doi:10.1016/j.bj.2017.12.001.

For the first time, this work provided solid evidence for the existence of megacomplex, observed the possible compartment of Q pool, and connected the organization of respiratory chain more tightly with the shape of cristae. Since this is the first structure of human respirasome, previously reported mitochondrial disease related mutations can all be mapped into our structure. Doubtlessly, this is a great step forward into conquering many severe neurodegenerative diseases, including Alzheimer's syndrome, Parkinson's disease, multiple sclerosis, friedreich's ataxia, Amyotrophic lateral sclerosis, etc.

Dysfunction in the mitochondrial Fe-S assembly machinery leads to formation of the chemoresistant truncated VDAC1 isoform without HIF-1α activation

Ferecatu I, Canal F, Fabbri L, Mazure NM, Bouton C, Golinelli-Cohen M-P (2018). PLoS ONE 13(3): e0194782. doi:10.1371/journal.pone.0194782

We show that hypoxia promotes the downregulation of several proteins (ISCU, NFS1, FXN) involved in the early steps of mitochondrial Fe-S cluster biogenesis.

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

Fabrice Giraudet, Perrine Charles, Thierry Mom, Odile Boespflug-Tanguy, Alexandra Dürr, Paul Deltenre, Paul Avan, Clinical Neurophysiology, Available online 27 March 2018, ISSN 1388-2457, doi:10.1016/j.clinph.2018.03.005.

In FRDA, the assumption of stationarity used for extracting standard auditory brainstem-evoked responsesis invalid. The preservation of early split-ABRs indicates no short-term dyssynchrony of action potentials. A large decrease in conduction velocity along auditory neurons occurs within seconds, attributed to fast energetic failure.

Cell Therapy Instigates Neural Repair In Friedreich’s Ataxia Mice

RELIAWIRE, March 26, 2018; Author: Geoffrey Potjewyd; Regenerative Medicine & Neuroscience PhD student at the University of Manchester.

The group found that transplantation of bone marrow cells that express frataxin into the FRDA mice caused the upregulation of frataxin as well as a number of antioxidative proteins, as well as improving movement and coordination in the mice. The researchers also observed the reversal of FRDA disease pathology, along with integration of transplanted bone marrow cells into damaged nervous system tissue and transplanted cells contributing genetic material to neurons and myelinating Schwann cells.

Assistance circulatoire et transplantation d’organes thoraciques chez l’enfant

Sébastien Hascoet, Angèle Boet, Karine Nubret, Marc Lilot, Séverine Feuillet, Nadir Benbrik, Julien Guihaire, Emmanuel Le Bret, Elie Fadel, Virginie Fouilloux, Pascal Amedro, Lucile Houyel, Bernard Kreitmann, La Presse Médicale, Available online 24 March 2018, ISSN 0755-4982, doi:10.1016/j.lpm.2018.01.014.

L’assistance circulatoire et la transplantation cardiaque et/ou pulmonaire pédiatrique sont les ultimes recours chez l’enfant ayant une défaillance cardiaque et/ou respiratoire terminale avec échec des traitements conventionnels et risque vital engagé à court terme. Actuellement, l’assistance circulatoire est utilisée en attente de récupération ou de transplantation mais pas en stratégie à long terme. Le Berlin Heart Excor est le système d’assistance ventriculaire pneumatique externe de longue durée actuellement disponible du nouveau-né jusqu’à l’âge adulte. Le pronostic à long terme après transplantation cardiaque et/ou pulmonaire pédiatrique est conditionné par la survenue d’une défaillance du greffon, par la maladie coronaire du greffon cardiaque, par les infections virales et la bronchiolite oblitérante du greffon pulmonaire, dont les incidences augmentent avec le temps. La pénurie de greffons et le risque de rejet aigu de greffon par défaut de compliance au traitement immunosuppresseur imposent un choix par les équipes spécialisées des candidats à la greffe en fonction de critères psychosociaux et biologiques. Les prochains développements attendus concernent surtout les assistances ventriculaires de longue durée avec des systèmes permettant d’envisager une plus grande autonomie et un retour à domicile de l’enfant.

Les maladies neuro-dégénératives (Friedreich, Duchenne) ou certaines maladies mitochondriales, ainsi que des séquelles graves d'accident vasculaire cérébral, sont considérées comme des contre-indications à la greffe.