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Friedreich's ataxia

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https://www.readbyqxmd.com/read/29676235/current-and-promising-therapies-in-autosomal-recessive-ataxias
#1
Vincent Picher-Martel, Nicolas Dupre
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. Many years have passed since the description of Friedreich's ataxia, the most common autosomal recessive ataxia, and mutations in many other genes have now been described...
April 18, 2018: CNS & Neurological Disorders Drug Targets
https://www.readbyqxmd.com/read/29625343/rapid-exhaustion-of-auditory-neural-conduction-in-a-prototypical-mitochondrial-disease-friedreich-ataxia
#2
Fabrice Giraudet, Perrine Charles, Thierry Mom, Odile Boespflug-Tanguy, Alexandra Dürr, Paul Deltenre, Paul Avan
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. ABR recordings were split into four consecutive segments of the total time frame used for data collection, thus allowing the dynamics of ABR averaging to be observed...
March 27, 2018: Clinical Neurophysiology: Official Journal of the International Federation of Clinical Neurophysiology
https://www.readbyqxmd.com/read/29624723/randomized-clinical-trial-of-rt001-early-signals-of-efficacy-in-friedreich-s-ataxia
#3
Theresa Zesiewicz, Frederic Heerinckx, Robert De Jager, Omid Omidvar, Marcus Kilpatrick, Jessica Shaw, Mikhail S Shchepinov
BACKGROUND: RT001 is a deuterated ethyl linoleate that inhibits lipid peroxidation and is hypothesized to reduce cellular damage and recover mitochondrial function in degenerative diseases such as Friedreich's ataxia. OBJECTIVE: To evaluate the safety, pharmacokinetics, and preliminary efficacy of RT001 in Friedreich's ataxia patients. DESIGN/METHODS: We conducted a phase I/II double-blind, comparator-controlled trial with 2 doses of RT001 in Friedreich's ataxia patients (9 subjects each cohort)...
April 6, 2018: Movement Disorders: Official Journal of the Movement Disorder Society
https://www.readbyqxmd.com/read/29623423/clinical-and-genetic-aspects-of-defects-in-the-mitochondrial-iron-sulfur-cluster-synthesis-pathway
#4
REVIEW
A V Vanlander, R Van Coster
Iron-sulfur clusters are evolutionarily conserved biological structures which play an important role as cofactor for multiple enzymes in eukaryotic cells. The biosynthesis pathways of the iron-sulfur clusters are located in the mitochondria and in the cytosol. The mitochondrial iron-sulfur cluster biosynthesis pathway (ISC) can be divided into at least twenty enzymatic steps. Since the description of frataxin deficiency as the cause of Friedreich's ataxia, multiple other deficiencies in ISC biosynthesis pathway have been reported...
April 5, 2018: Journal of Biological Inorganic Chemistry: JBIC
https://www.readbyqxmd.com/read/29610276/the-transcriptional-regulator-ccctc-binding-factor-limits-oxidative-stress-in-endothelial-cells
#5
Anna R Roy, Abdalla Ahmed, Peter V DiStefano, Lijun Chi, Nadiya Khyzha, Niels Galjart, Michael D Wilson, Jason E Fish, Paul Delgado Olguin
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 Ctcf in endothelial progenitors and their descendants affected embryonic growth, and caused lethality at embryonic day 10.5 owing to defective yolk sac and placental vascular development...
April 2, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29607705/impact-of-mobility-device-use-on-quality-of-life-in-children-with-friedreich-ataxia
#6
Resham Ejaz, Shiyi Chen, Charles J Isaacs, Amanda Carnevale, Judith Wilson, Kristen George, Martin B Delatycki, Susan L Perlman, Katherine D Mathews, George R Wilmot, J Chad Hoyle, Sub H Subramony, Theresa Zesiewicz, Jennifer M Farmer, David R Lynch, Grace Yoon
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. RESULTS: Mobility device use was associated with worse mean PedsQL total, physical, emotional, social, and academic subscores, after adjusting for gender, age of disease onset, and Friedreich Ataxia Rating Scale score...
January 1, 2018: Journal of Child Neurology
https://www.readbyqxmd.com/read/29576242/interactions-of-iron-bound-frataxin-with-iscu-and-ferredoxin-on-the-cysteine-desulfurase-complex-leading-to-fe-s-cluster-assembly
#7
Kai Cai, Ronnie O Frederick, Marco Tonelli, John L Markley
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. Our results show that FXN tightly binds a single Fe2+ but not Fe3+ ...
March 15, 2018: Journal of Inorganic Biochemistry
https://www.readbyqxmd.com/read/29568068/identification-of-p38-mapk-as-a-novel-therapeutic-target-for-friedreich-s-ataxia
#8
M Grazia Cotticelli, Shujuan Xia, Avinash Kaur, Daniel Lin, Yongping Wang, Eric Ruff, John W Tobias, Robert B Wilson
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. We now report that gFA11 decreases cytokine secretion in primary FRDA fibroblasts and reverts other changes associated with cell senescence...
March 22, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29563863/mitofusin-dependent-er-stress-triggers-glial-dysfunction-and-nervous-system-degeneration-in-a-drosophila-model-of-friedreich-s-ataxia
#9
Oliver Edenharter, Stephan Schneuwly, Juan A Navarro
Friedreich's ataxia (FRDA) is the most important recessive ataxia in the Caucasian population. It is caused by a deficit of the mitochondrial protein frataxin. Despite its pivotal effect on biosynthesis of iron-sulfur clusters and mitochondrial energy production, little is known about the influence of frataxin depletion on homeostasis of the cellular mitochondrial network. We have carried out a forward genetic screen to analyze genetic interactions between genes controlling mitochondrial homeostasis and Drosophila frataxin...
2018: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/29538656/optical-coherence-tomography-in-autosomal-recessive-spastic-ataxia-of-charlevoix-saguenay
#10
Michael H Parkinson, Ana P Bartmann, Lisa M S Clayton, Suran Nethisinghe, Rolph Pfundt, J Paul Chapple, Mary M Reilly, Hadi Manji, Nicholas J Wood, Fion Bremner, Paola Giunti
Autosomal recessive spastic ataxia of Charlevoix-Saguenay is a rare neurodegenerative disorder caused by mutations in the SACS gene. Thickened retinal nerve fibres visible on fundoscopy have previously been described in these patients; however, thickening of the retinal nerve fibre layer as demonstrated by optical coherence tomography appears to be a more sensitive and specific feature. To test this observation, we assessed 292 individuals (191 patients with ataxia and 101 control subjects) by peripapillary time-domain optical coherence tomography...
March 12, 2018: Brain: a Journal of Neurology
https://www.readbyqxmd.com/read/29534309/bone-marrow-transplantation-stimulates-neural-repair-in-friedreich-s-ataxia-mice
#11
Kevin C Kemp, Kelly Hares, Juliana Redondo, Amelia J Cook, Harry R Haynes, Bronwen R Burton, Mark A Pook, Claire M Rice, Neil J Scolding, Alastair Wilkins
OBJECTIVES: Friedreich's ataxia is an incurable inherited neurological disease caused by frataxin deficiency. Here we report the neuro-reparative effects of myeloablative allogeneic bone marrow transplantation in a humanised murine model of the disease. METHODS: Mice received a transplant of fluorescently-tagged sex mis-matched bone marrow cells expressing wild-type frataxin and were assessed at monthly intervals using a range of behavioural motor performance tests...
March 13, 2018: Annals of Neurology
https://www.readbyqxmd.com/read/29530802/pitfalls-in-molecular-diagnosis-of-friedreich-ataxia
#12
Giulia Barcia, Myriam Rachid, Maryse Magen, Zahra Assouline, Michel Koenig, Benoit Funalot, Christine Barnerias, Agnès Rötig, Arnold Munnich, Jean-Paul Bonnefont, Julie Steffann
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. Molecular screening for FXN expansion is therefore focused on (GAA)n expansion analysis, commonly performed by triplet repeat primed PCR (PT-PCR). We report on an initial pitfall in the molecular characterization of a 15 year-old girl with Freidreich ataxia (FRDA) who carried a rare deletion in intron 1 of the FXN gene...
March 9, 2018: European Journal of Medical Genetics
https://www.readbyqxmd.com/read/29529236/gaa%C3%A2-ttc-repeat-expansion-in-human-cells-is-mediated-by-mismatch-repair-complex-mutl%C3%AE-and-depends-upon-the-endonuclease-domain-in-mlh3-isoform-one
#13
Anasheh Halabi, Kayla T B Fuselier, Ed Grabczyk
DNA repeat expansion underlies dozens of progressive neurodegenerative disorders. While the mechanisms driving repeat expansion are not fully understood, increasing evidence suggests a central role for DNA mismatch repair. The mismatch repair recognition complex MutSβ (MSH2-MSH3) that binds mismatched bases and/or insertion/deletion loops has previously been implicated in GAA•TTC, CAG•CTG and CGG•CCG repeat expansion, suggesting a shared mechanism. MutSβ has been studied in a number of models, but the contribution of subsequent steps mediated by the MutL endonuclease in this pathway is less clear...
February 26, 2018: Nucleic Acids Research
https://www.readbyqxmd.com/read/29517052/molecular-genetic-testing-for-hereditary-ataxia-what-every-neurologist-should-know
#14
REVIEW
Stephanie E Wallace, Thomas D Bird
Purpose of review: Because of extensive clinical overlap among many forms of hereditary ataxia, molecular genetic testing is often required to establish a diagnosis. Interrogation of multiple genes has become a popular diagnostic approach as the cost of sequence analysis has decreased and the number of genes associated with overlapping phenotypes has increased. We describe the benefits and limitations of molecular genetic tests commonly used to determine the etiology of hereditary ataxia...
February 2018: Neurology. Clinical Practice
https://www.readbyqxmd.com/read/29511832/iron-sulfur-clusters-from-metals-through-mitochondria-biogenesis-to-disease
#15
REVIEW
Mauricio Cardenas-Rodriguez, Afroditi Chatzi, Kostas Tokatlidis
Iron-sulfur clusters are ubiquitous inorganic co-factors that contribute to a wide range of cell pathways including the maintenance of DNA integrity, regulation of gene expression and protein translation, energy production, and antiviral response. Specifically, the iron-sulfur cluster biogenesis pathways include several proteins dedicated to the maturation of apoproteins in different cell compartments. Given the complexity of the biogenesis process itself, the iron-sulfur research area constitutes a very challenging and interesting field with still many unaddressed questions...
March 6, 2018: Journal of Biological Inorganic Chemistry: JBIC
https://www.readbyqxmd.com/read/29511616/biophysical-characterisation-of-the-recombinant-human-frataxin-precursor
#16
Ignacio Hugo Castro, Alejandro Ferrari, María Georgina Herrera, Martín Ezequiel Noguera, Lorenzo Maso, Monica Benini, Alessandra Rufini, Roberto Testi, Paola Costantini, Javier Santos
Friedreich's ataxia is a disease caused by a decrease in the levels of expression or loss of functionality of the mitochondrial protein frataxin (FXN). The development of an active and stable recombinant variant of FXN is important for protein replacement therapy. Although valuable data about the mature form FXN81-210 has been collected, not enough information is available about the conformation of the frataxin precursor (FXN1-210). We investigated the conformation, stability and function of a recombinant precursor variant (His6-TAT-FXN1-210), which includes a TAT peptide in the N-terminal region to assist with transport across cell membranes...
March 2018: FEBS Open Bio
https://www.readbyqxmd.com/read/29509186/small-rna-seq-analysis-of-circulating-mirnas-to-identify-phenotypic-variability-in-friedreich-s-ataxia-patients
#17
Marta Seco-Cervera, Dayme González-Rodríguez, José Santiago Ibáñez-Cabellos, Lorena Peiró-Chova, Federico V Pallardó, José Luis García-Giménez
Friedreich's ataxia (FRDA; OMIM 229300), an autosomal recessive neurodegenerative mitochondrial disease, is the most prevalent hereditary ataxia. In addition, FRDA patients have shown additional non-neurological features such as scoliosis, diabetes, and cardiac complications. Hypertrophic cardiomyopathy, which is found in two thirds of patients at the time of diagnosis, is the primary cause of death in these patients. Here, we used small RNA-seq of microRNAs (miRNAs) purified from plasma samples of FRDA patients and controls...
March 6, 2018: Scientific Data
https://www.readbyqxmd.com/read/29499876/progress-in-the-treatment-of-friedreich-ataxia
#18
REVIEW
Geneieve Tai, Louise A Corben, Eppie M Yiu, Sarah C Milne, Martin B Delatycki
Friedreich ataxia (FRDA) is a progressive neurological disorder affecting approximately 1 in 29,000 individuals of European descent. At present, there is no approved pharmacological treatment for this condition however research into treatment of FRDA has advanced considerably over the last two decades since the genetic cause was identified. Current proposed treatment strategies include decreasing oxidative stress, increasing cellular frataxin, improving mitochondrial function as well as modulating frataxin controlled metabolic pathways...
February 19, 2018: Neurologia i Neurochirurgia Polska
https://www.readbyqxmd.com/read/29490390/-hereditary-optic-neuropathies
#19
Klaus Rüther
Hereditary optic nerve disorders are rare. For ophthalmologists, Leber's hereditary optic neuropathy (LHON) and autosomal dominant optic atrophy (ADOA) are of particular relevance. LHON and ADOA are diseases of the retinal ganglion cells and are caused by mitchochondrial dysfunction. LHON is based on mutations of the mitochondrial, ADOA of the nuclear DNA. LHON is a disease that usually leads to severe visual impairment (visual acuity < 0.1). Since there is an approved therapy for LHON (Idebenone [Raxone]), the diagnosis has to be confirmed immediately by means of molecular genetic diagnostics...
February 28, 2018: Klinische Monatsblätter Für Augenheilkunde
https://www.readbyqxmd.com/read/29447396/rna-dna-hybrids-promote-the-expansion-of-friedreich-s-ataxia-gaa-n-repeats-via-break-induced-replication
#20
Alexander J Neil, Miranda U Liang, Alexandra N Khristich, Kartik A Shah, Sergei M Mirkin
Expansion of simple DNA repeats is responsible for numerous hereditary diseases in humans. The role of DNA replication, repair and transcription in the expansion process has been well documented. Here we analyzed, in a yeast experimental system, the role of RNA-DNA hybrids in genetic instability of long (GAA)n repeats, which cause Friedreich's ataxia. Knocking out both yeast RNase H enzymes, which counteract the formation of RNA-DNA hybrids, increased (GAA)n repeat expansion and contraction rates when the repetitive sequence was transcribed...
February 13, 2018: Nucleic Acids Research
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