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Friedreich ataxia

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https://www.readbyqxmd.com/read/28936086/diabetes-mellitus-as-the-presenting-feature-of-friedreich-s-ataxia
#1
Meenal Garg, Shilpa D Kulkarni, Krishnakumar N Shah, Anaita Udwadia Hegde
Patients with Friedreich's ataxia (FA) are at an increased risk of developing diabetes mellitus and glucose intolerance. Diabetes usually develops many years after the initial presentation. We report an 8-year-old girl who initially presented with diabetic ketoacidosis and was treated as a case of insulin-dependent diabetes mellitus. Around a year later, she developed gait problems and ataxia. Cardiac involvement was detected on echocardiography. Genetic testing confirmed the diagnosis of FA. FA should be a diagnostic consideration in children presenting with diabetes and neurological issues, even with early presentation of the former...
August 2017: Journal of Neurosciences in Rural Practice
https://www.readbyqxmd.com/read/28935570/molecular-alterations-in-a-mouse-cardiac-model-of-friedreich-s-ataxia-an-impaired-nrf2-response-mediated-via-up-regulation-of-keap1-and-activation-of-the-gsk3%C3%AE-axis
#2
Amy Anzovino, Shannon Chiang, Bronwyn E Brown, Clare L Hawkins, Des R Richardson, Michael L-H Huang
Nuclear factor-erythroid 2-related factor-2 (Nrf2) is a master regulator of the anti-oxidant response. However, studies in models of Friedreich's ataxia (FA), a neuro- and cardio-degenerative disease associated with oxidative stress, reported decreased Nrf2 expression due to unknown mechanisms. Using a mouse conditional frataxin knockout (KO) model in the heart and skeletal muscle, we examined the Nrf2 pathway in these tissues. Frataxin KO results in fatal cardiomyopathy, while skeletal muscle was asymptomatic...
September 18, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28930516/new-targeted-therapies-and-diagnostic-methods-for-iron-overload-diseases
#3
Annita Kolnagou, Christina N Kontoghiorghe, George John Kontoghiorghes
Millions of people worldwide suffer from iron overload toxicity diseases such as transfusional iron overload in thalassaemia and hereditary haemochromatosis. The accumulation and presence of toxic focal iron deposits causing tissue damage can also be identified in Friedreich's ataxia, Alzheimer's, Parkinson's, renal and other diseases. Different diagnostic criteria of toxicity and therapeutic interventions apply to each disease of excess or misplaced iron. Magnetic resonance imaging relaxation times T2 and T2* for monitoring iron deposits in organs and iron biomarkers such as serum ferritin and transferrin iron saturation have contributed in the elucidation of iron toxicity mechanisms and pathways, and also the evaluation of the efficacy and mode of action of chelating drugs in the treatment of diseases related to iron overload, toxicity and metabolism...
January 1, 2018: Frontiers in Bioscience (Scholar Edition)
https://www.readbyqxmd.com/read/28927904/lipophilic-methylene-violet-analogues-as-modulators-of-mitochondrial-function-and-dysfunction
#4
Sandipan Roy Chowdhury, Omar M Khdour, Indrajit Bandyopadhyay, Sidney M Hecht
In an effort to identify methylene blue analogues having improved antioxidant activity, a series of new methylene violet analogues have been designed and synthesized. The analogues were prepared following a synthetic route that is more efficient than the previously reported methods, both in terms of yield and purity of the final products. The route involves the Smiles rearrangement as one of the crucial steps. Smiles rearrangement of suitably substituted diphenyl sulfide intermediates afforded the corresponding phenothiazine analogues in high yields, which were subsequently converted to the final products...
August 18, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28918000/nitric-oxide-prevents-aft1-activation-and-metabolic-remodeling-in-frataxin-deficient-yeast
#5
David Alsina, Joaquim Ros, Jordi Tamarit
Yeast frataxin homolog (Yfh1) is the orthologue of human frataxin, a mitochondrial protein whose deficiency causes Friedreich Ataxia. Yfh1 deficiency activates Aft1, a transcription factor governing iron homeostasis in yeast cells. Although the mechanisms causing this activation are not completely understood, it is assumed that it may be caused by iron-sulfur deficiency. However, several evidences indicate that activation of Aft1 occurs in the absence of iron-sulfur deficiency. Besides, Yfh1 deficiency also leads to metabolic remodeling (mainly consisting in a shift from respiratory to fermentative metabolism) and to induction of Yhb1, a nitric oxide (NO) detoxifying enzyme...
September 6, 2017: Redox Biology
https://www.readbyqxmd.com/read/28912677/reversible-axonal-dystrophy-by-calcium-modulation-in-frataxin-deficient-sensory-neurons-of-yg8r-mice
#6
Belén Mollá, Diana C Muñoz-Lasso, Fátima Riveiro, Arantxa Bolinches-Amorós, Federico V Pallardó, Angel Fernandez-Vilata, María de la Iglesia-Vaya, Francesc Palau, Pilar Gonzalez-Cabo
Friedreich's ataxia (FRDA) is a peripheral neuropathy involving a loss of proprioceptive sensory neurons. Studies of biopsies from patients suggest that axonal dysfunction precedes the death of proprioceptive neurons in a dying-back process. We observed that the deficiency of frataxin in sensory neurons of dorsal root ganglia (DRG) of the YG8R mouse model causes the formation of axonal spheroids which retain dysfunctional mitochondria, shows alterations in the cytoskeleton and it produces impairment of axonal transport and autophagic flux...
2017: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/28904984/impact-of-diabetes-in-the-friedreich-ataxia-clinical-outcome-measures-study
#7
Ashley McCormick, Jennifer Farmer, Susan Perlman, Martin Delatycki, George Wilmot, Katherine Matthews, Grace Yoon, Chad Hoyle, Sub H Subramony, Theresa Zesiewicz, David R Lynch, Shana E McCormack
OBJECTIVE: Friedreich ataxia (FA) is a progressive neuromuscular disorder caused by GAA triplet repeat expansions or point mutations in the FXN gene. FA is associated with increased risk of diabetes mellitus (DM). This study assessed the age-specific prevalence of FA-associated DM and its impact on neurologic outcomes. RESEARCH DESIGN AND METHODS: Participants were 811 individuals with FA from 12 international sites in a prospective natural history study (FA Clinical Outcome Measures Study, FACOMS)...
September 2017: Annals of Clinical and Translational Neurology
https://www.readbyqxmd.com/read/28887402/detection-of-long-repeat-expansions-from-pcr-free-whole-genome-sequence-data
#8
Egor Dolzhenko, Joke J F A van Vugt, Richard J Shaw, Mitchell A Bekritsky, Marka van Blitterswijk, Giuseppe Narzisi, Subramanian S Ajay, Vani Rajan, Bryan Lajoie, Nathan H Johnson, Zoya Kingsbury, Sean J Humphray, Raymond D Schellevis, William J Brands, Matt Baker, Rosa Rademakers, Maarten Kooyman, Gijs H P Tazelaar, Michael A van Es, Russell McLaughlin, William Sproviero, Aleksey Shatunov, Ashley Jones, Ahmad Al Khleifat, Alan Pittman, Sarah Morgan, Orla Hardiman, Ammar Al-Chalabi, Chris Shaw, Bradley Smith, Edmund J Neo, Karren Morrison, Pam Shaw, Catherine Reeves, Lara Winterkorn, Nancy S Wexler, David E Housman, Christopher W Ng, Alina L Li, Ryan J Taft, Leonard H van den Berg, David R Bentley, Jan H Veldink, Michael A Eberle
Identifying large expansions of short tandem repeats (STRs) such as those that cause amyotrophic lateral sclerosis (ALS) and fragile X syndrome is challenging for short-read whole-genome sequencing (WGS) data. A solution to this problem is an important step towards integrating WGS into precision medicine. We have developed a software tool called ExpansionHunter that, using PCR-free WGS short-read data, can genotype repeats at the locus of interest, even if the expanded repeat is larger than the read length...
September 8, 2017: Genome Research
https://www.readbyqxmd.com/read/28877480/a-defective-mrna-cleavage-and-polyadenylation-complex-facilitates-expansions-of-transcribed-gaa-n-repeats-associated-with-friedreich-s-ataxia
#9
Ryan J McGinty, Franco Puleo, Anna Y Aksenova, Julia A Hisey, Alexander A Shishkin, Erika L Pearson, Eric T Wang, David E Housman, Claire Moore, Sergei M Mirkin
Expansions of microsatellite repeats are responsible for numerous hereditary diseases in humans, including myotonic dystrophy and Friedreich's ataxia. Whereas the length of an expandable repeat is the main factor determining disease inheritance, recent data point to genomic trans modifiers that can impact the likelihood of expansions and disease progression. Detection of these modifiers may lead to understanding and treating repeat expansion diseases. Here, we describe a method for the rapid, genome-wide identification of trans modifiers for repeat expansion in a yeast experimental system...
September 5, 2017: Cell Reports
https://www.readbyqxmd.com/read/28852135/peptide-ss-31-upregulates-frataxin-expression-and-improves-the-quality-of-mitochondria-implications-in-the-treatment-of-friedreich-ataxia
#10
Hongting Zhao, Huihui Li, Shuangying Hao, Jiping Chen, Jing Wu, Chuanhui Song, Meng Zhang, Tong Qiao, Kuanyu Li
Friedreich ataxia is a progressive neurodegenerative disease caused by the expansion of GAA trinucleotide repeats within the first intron of the FXN gene, which encodes frataxin. The pathophysiology of the disease is thought to be derived from the decrease of Fe-S cluster biogenesis due to frataxin deficiency. There is currently no effective treatment for the disease. In our study, we demonstrated that treatment with the mitochondrion-targeted peptide SS-31 reduced frataxin deficiency-induced oxidative stress in lymphoblasts and fibroblasts derived from patients...
August 29, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28838288/overexpression-of-drosophila-frataxin-triggers-cell-death-in-an-iron-dependent-manner
#11
Oliver Edenharter, Janik Clement, Stephan Schneuwly, Juan A Navarro
Friedreich ataxia (FRDA) is the most important autosomal recessive ataxia in the Caucasian population. FRDA patients display severe neurological and cardiac symptoms that reflect a strong cellular and axonal degeneration. FRDA is caused by a loss of function of the mitochondrial protein frataxin which impairs the biosynthesis of iron-sulfur clusters and in turn the catalytic activity of several enzymes in the Krebs cycle and the respiratory chain leading to a diminished energy production. Although FRDA is due to frataxin depletion, overexpression might also be very helpful to better understand cellular functions of frataxin...
August 24, 2017: Journal of Neurogenetics
https://www.readbyqxmd.com/read/28819075/-advances-in-neurological-therapeutics-for-friedreich-ataxia-and-machado-joseph-disease
#12
Ichiro Yabe, Hidenao Sasaki
We reviewed advances in therapeutics for both Friedreich ataxia and Machado-Joseph disease. Various clinical trials have been carried out, mainly for Friedreich ataxia; however, the therapeutic reports from these trials have not provided much evidence for success. Some interesting clinical trials have been reported, and further developments are expected. Regenerative therapy using umbilical cord mesenchymal stem cells and a therapeutic study investigating a new pathomechanism in animal and/or cell culture studies were reported...
August 2017: Brain and Nerve, Shinkei Kenkyū No Shinpo
https://www.readbyqxmd.com/read/28812047/selected-missense-mutations-impair-frataxin-processing-in-friedreich-ataxia
#13
Elisia Clark, Jill S Butler, Charles J Isaacs, Marek Napierala, David R Lynch
OBJECTIVE: Frataxin (FXN) is a highly conserved mitochondrial protein. Reduced FXN levels cause Friedreich ataxia, a recessive neurodegenerative disease. Typical patients carry GAA repeat expansions on both alleles, while a subgroup of patients carry a missense mutation on one allele and a GAA repeat expansion on the other. Here, we report that selected disease-related FXN missense mutations impair FXN localization, interaction with mitochondria processing peptidase, and processing. METHODS: Immunocytochemical studies and subcellular fractionation were performed to study FXN import into the mitochondria and examine the mechanism by which mutations impair FXN processing...
August 2017: Annals of Clinical and Translational Neurology
https://www.readbyqxmd.com/read/28803513/mechanisms-of-unexpected-death-and-autopsy-findings-in-friedreich-ataxia
#14
Roger W Byard, John D Gilbert
A 36-year-old woman with a clinical history of Friedreich ataxia and hypertrophic cardiomyopathy was found unexpectedly dead at her home. The heart showed asymmetric left ventricular hypertrophy, with an interventricular septal thickness of 20-25 mm (the remainder of the left ventricular wall measured 15 mm). Histologically, both ventricles had irregular areas of marked myocyte hypertrophy with associated interstitial fibrosis and focal myofibre disarray. There was neuronal loss within the dentate nucleus of the cerebellum, with vacuolation and axonal loss in the dorsal columns and spinocerebellar tracts of the upper cervical spinal cord...
January 1, 2017: Medicine, Science, and the Law
https://www.readbyqxmd.com/read/28782591/mitochondrial-dysfunction-in-the-neuro-degenerative-and-cardio-degenerative-disease-friedreich-s-ataxia
#15
Shannon Chiang, Danuta S Kalinowski, Patric J Jansson, Des R Richardson, Michael L-H Huang
Mitochondrial homeostasis is essential for maintaining healthy cellular function and survival. The detrimental involvement of mitochondrial dysfunction in neuro-degenerative diseases has recently been highlighted in human conditions, such as Parkinson's, Alzheimer's and Huntington's disease. Friedreich's ataxia (FA) is another neuro-degenerative, but also cardio-degenerative condition, where mitochondrial dysfunction plays a crucial role in disease progression. Deficient expression of the mitochondrial protein, frataxin, is the primary cause of FA, which leads to adverse alterations in whole cell and mitochondrial iron metabolism...
August 4, 2017: Neurochemistry International
https://www.readbyqxmd.com/read/28770399/triphenylphosphonium-desferrioxamine-as-a-candidate-mitochondrial-iron-chelator
#16
Roxana Y P Alta, Hector A Vitorino, Dibakar Goswami, M Terêsa Machini, Breno P Espósito
Cell-impermeant iron chelator desferrioxamine (DFO) can have access to organelles if appended to suitable vectors. Mitochondria are important targets for the treatment of iron overload-related neurodegenerative diseases. Triphenylphosphonium (TPP) is a delocalized lipophilic cation used to ferry molecules to mitochondria. Here we report the synthesis and characterization of the conjugate TPP-DFO as a mitochondrial iron chelator. TPP-DFO maintained both a high affinity for iron and the antioxidant activity when compared to parent DFO...
August 2, 2017: Biometals: An International Journal on the Role of Metal Ions in Biology, Biochemistry, and Medicine
https://www.readbyqxmd.com/read/28724806/nicotinamide-mononucleotide-requires-sirt3-to-improve-cardiac-function-and-bioenergetics-in-a-friedreich-s-ataxia-cardiomyopathy-model
#17
Angelical S Martin, Dennis M Abraham, Kathleen A Hershberger, Dhaval P Bhatt, Lan Mao, Huaxia Cui, Juan Liu, Xiaojing Liu, Michael J Muehlbauer, Paul A Grimsrud, Jason W Locasale, R Mark Payne, Matthew D Hirschey
Increasing NAD+ levels by supplementing with the precursor nicotinamide mononucleotide (NMN) improves cardiac function in multiple mouse models of disease. While NMN influences several aspects of mitochondrial metabolism, the molecular mechanisms by which increased NAD+ enhances cardiac function are poorly understood. A putative mechanism of NAD+ therapeutic action exists via activation of the mitochondrial NAD+-dependent protein deacetylase sirtuin 3 (SIRT3). We assessed the therapeutic efficacy of NMN and the role of SIRT3 in the Friedreich's ataxia cardiomyopathy mouse model (FXN-KO)...
July 20, 2017: JCI Insight
https://www.readbyqxmd.com/read/28724340/pharmacological-therapeutics-in-friedreich-ataxia-the-present-state
#18
Cassandra Strawser, Kimberly Schadt, Lauren Hauser, Ashley McCormick, McKenzie Wells, Jane Larkindale, Hong Lin, David R Lynch
Friedreich ataxia (FRDA) is a progressive, inherited, neurodegenerative disease for which there is currently no cure or approved treatment. FRDA is caused by deficits in the production and expression of frataxin, a protein found in the mitochondria that is most likely responsible for regulating iron-sulfur cluster enzymes within the cell. A decrease in frataxin causes dysfunction of adenosine triphosphate synthesis, accumulation of mitochondrial iron, and other events leading to downstream cellular dysfunction...
July 26, 2017: Expert Review of Neurotherapeutics
https://www.readbyqxmd.com/read/28716278/single-step-blood-direct-pcr-a-robust-and-rapid-method-to-diagnose-triplet-repeat-disorders
#19
Inder Singh, Vishnu Swarup, Sunil Shakya, Vinay Goyal, Mohammed Faruq, Achal Kumar Srivastava
OBJECTIVE: DNA extraction prior to polymerase chain reaction (PCR) amplification in genetic diagnoses of triplet repeat disorders (TRDs) is tedious and labour-intensive and has the limitations of sample contamination with foreign DNA, including that from preceding samples. Therefore, we aimed to develop a rapid, robust, and cost-effective method for expeditious genetic investigation of TRDs from whole blood as a DNA template. METHODS: Peripheral blood samples were collected from 70 clinically suspected patients of progressive ataxia...
August 15, 2017: Journal of the Neurological Sciences
https://www.readbyqxmd.com/read/28701783/circulating-mir-323-3p-is-a-biomarker-for-cardiomyopathy-and-an-indicator-of-phenotypic-variability-in-friedreich-s-ataxia-patients
#20
M Seco-Cervera, D González-Rodríguez, J S Ibáñez-Cabellos, L Peiró-Chova, P González-Cabo, E García-López, J J Vílchez, I Sanz-Gallego, F V Pallardó, J L García-Giménez
MicroRNAs (miRNAs) are noncoding RNAs that contribute to gene expression modulation by regulating important cellular pathways. In this study, we used small RNA sequencing to identify a series of circulating miRNAs in blood samples taken from Friedreich's ataxia patients. We were thus able to develop a miRNA biomarker signature to differentiate Friedreich's ataxia (FRDA) patients from healthy people. Most research on FDRA has focused on understanding the role of frataxin in the mitochondria, and a whole molecular view of pathological pathways underlying FRDA therefore remains to be elucidated...
July 12, 2017: Scientific Reports
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