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Friedreich ataxia

Michael Dayan, G Olivito, M Molinari, Mara Cercignani, Marco Bozzali, M Leggio
In recent years the cerebellum has been attributed amore important role in higher-level functions than previously believed. We examined a cohort of patients suffering from cerebellar atrophy resulting in ataxia, with two main objectives: first to investigate which regions of the cerebrum were affected by the cerebellar degeneration, and second to assess whether diffusion magnetic resonance imaging (dMRI) metrics within the medial (MCP) and superior cerebellar peduncle (SCP) - namely fractional anisotropy (FA) and radial diffusivity (RD) - could be used as a biomarker in patients with this condition...
October 26, 2016: Functional Neurology
Matthias Groh, Laura Oana Albulescu, Agnese Cristini, Natalia Gromak
R-loops comprise an RNA/DNA hybrid and displaced single-stranded DNA. They play crucial biological functions and are implicated in neurological diseases, including ataxias, amyotrophic lateral sclerosis, nucleotide expansion disorders (Friedreich ataxia, Fragile X syndrome) and cancer. Currently it is unclear which mechanisms cause R-loops structures to become pathogenic. The RNA/DNA helicase Senataxin (SETX) is one of the best characterised R-loop-binding factors in vivo. Mutations in SETX are linked to two neurodegenerative disorders: ataxia with oculomotor apraxia type 2 (AOA2) and amyotrophic lateral sclerosis type 4 (ALS4)...
October 19, 2016: Journal of Molecular Biology
Dana Marcus, Michal Lichtenstein, Natali Cohen, Rita Hadad, Tal Erlich-Hadad, Hagar Greif, Haya Lorberboum-Galski
Mitochondrial Targeting Sequences (MTSs) are responsible for trafficking nuclear-encoded proteins into mitochondria. Once entering the mitochondria, the MTS is recognized and cleaved off. Some MTSs are long and undergo two-step processing, as in the case of the human frataxin (FXN) protein (80aa), implicated in Friedreich's ataxia (FA). Therefore, we chose the FXN protein to examine whether nuclear-encoded mitochondrial proteins can efficiently be targeted via a heterologous MTS (hMTS) and deliver a functional protein into mitochondria...
October 19, 2016: International Journal of Biochemistry & Cell Biology
Claudia Compagnucci, Emanuela Piermarini, Antonella Sferra, Rossella Borghi, Alessia Niceforo, Stefania Petrini, Fiorella Piemonte, Enrico Bertini
Patient-derived induced pluripotent stem cells (iPSCs) provide a novel tool to investigate the pathophysiology of poorly known diseases, in particular those affecting the nervous system, which has been difficult to study for its lack of accessibility. In this emerging and promising field, recent iPSCs studies are mostly used as "proof-of-principle" experiments that are confirmatory of previous findings obtained from animal models and postmortem human studies; its promise as a discovery tool is just beginning to be realized...
October 15, 2016: Molecular and Cellular Neurosciences
Chul-Yong Park, Jin Jea Sung, Sang-Hwi Choi, Dongjin R Lee, In-Hyun Park, Dong-Wook Kim
Genome engineering technology using engineered nucleases has been rapidly developing, enabling the efficient correction of simple mutations. However, the precise correction of structural variations (SVs) such as large inversions remains limited. Here we describe a detailed procedure for the modeling or correction of large chromosomal rearrangements and short nucleotide repeat expansions using engineered nucleases in human induced pluripotent stem cells (hiPSCs) from a healthy donor and patients with SVs. This protocol includes the delivery of engineered nucleases with no donor template to hiPSCs, and genotyping and derivation/characterization of gene-manipulated hiPSC clones...
November 2016: Nature Protocols
Rubens Paulo A Salomão, Maria Thereza Drumond Gama, Flávio Moura Rezende Filho, Fernanda Maggi, José Luiz Pedroso, Orlando G P Barsottini
Herein, we report a patient that presented with late-onset progressive steppage gait, neuropathy and pes cavus, suggesting Charcot-Marie-Tooth (CMT) disease. Subsequent genetic investigation confirmed Friedreich's ataxia (FRDA). We demonstrate that late-onset Friedreich's ataxia (LOFA) may be a CMT mimicker. This case reinforces that other genetic conditions may clinically resemble CMT. The clinical similarities between CMT and FRDA include a symmetrical neuropathy (axonal in FRDA), steppage gait, and eventually scoliosis...
September 29, 2016: Cerebellum
G Tai, L A Corben, E M Yiu, M B Delatycki
OBJECTIVES: The Medical Outcomes Study 36 item Short-Form Health Survey (SF-36) is one of the most commonly used patient reported outcome measure. This study aimed to examine the relationship between SF-36 version 2 (SF-36V2) summary scores and Friedreich ataxia (FRDA) clinical characteristics, and to investigate the responsiveness of the scale, in comparison with the Friedreich Ataxia Rating Scale (FARS), over 1, 2 and 3 years. MATERIALS AND METHODS: Descriptive statistics were used to examine the characteristics of the cohort at baseline and years 1, 2 and 3...
September 28, 2016: Acta Neurologica Scandinavica
Semiha Kurt, Betul Cevik, Durdane Aksoy, E Irmak Sahbaz, Aslı Gundogdu Eken, A Nazli Basak
Here, we describe the clinical features of several members of the same family diagnosed with Friedreich ataxia (FRDA) and cerebral lesions, demyelinating neuropathy, and late-age onset without a significant cardiac involvement and presenting with similar symptoms, although genetic testing was negative for the GAA repeat expansion in one patient of the family. The GAA repeat expansion in the frataxin gene was shown in all of the family members except in a young female patient. MRI revealed arachnoid cysts in two patients; MRI was consistent with both cavum septum pellucidum-cavum vergae and nodular signal intensity increase in one patient...
2016: Case Reports in Neurological Medicine
Maya Patel, Charles J Isaacs, Lauren Seyer, Karlla Brigatti, Sarah Gelbard, Cassandra Strawser, Debbie Foerster, Julianna Shinnick, Kimberly Schadt, Eppie M Yiu, Martin B Delatycki, Susan Perlman, George R Wilmot, Theresa Zesiewicz, Katherine Mathews, Christopher M Gomez, Grace Yoon, Sub H Subramony, Alicia Brocht, Jennifer Farmer, David R Lynch
OBJECTIVE: Friedreich ataxia (FRDA) is a progressive neurodegenerative disorder of adults and children. This study analyzed neurological outcomes and changes to identify predictors of progression and generate power calculations for clinical trials. METHODS: Eight hundred and twelve subjects in a natural history study were evaluated annually across 12 sites using the Friedreich Ataxia Rating Scale (FARS), 9-Hole Peg Test, Timed 25-Foot Walk, visual acuity tests, self-reported surveys and disability scales...
September 2016: Annals of Clinical and Translational Neurology
Cong Lu, Yi-Cen Zheng, Yi Dong, Hong-Fu Li
BACKGROUND: Autosomal recessive cerebellar ataxias (ARCA) are a group of neurodegenerative disorders characterized by early onset of gait impairment, disturbed limb coordination, dysarthria, and eye movement abnormalities, most likely due to the degeneration of cerebellum, brainstem, and spinal cord. Despite of the rarity, ARCA are both clinically and genetically heterogeneous. To date, more than 30 culprit genes have been identified in ARCA. Unraveling the specific causative mutation in cases with ARCA remains challenging so far...
2016: BMC Neurology
Amanda Tabib, Sailaja Vishwanathan, Andrei Seleznev, Peter C McKeown, Tim Downing, Craig Dent, Eduardo Sanchez-Bermejo, Luana Colling, Charles Spillane, Sureshkumar Balasubramanian
Triplet repeat expansions underlie several human genetic diseases such as Huntington's disease and Friedreich's ataxia. Although such mutations are primarily known from humans, a triplet expansion associated genetic defect has also been reported at the IIL1 locus in the Bur-0 accession of the model plant Arabidopsis thaliana. The IIL1 triplet expansion is an example of cryptic genetic variation as its phenotypic effects are seen only under genetic or environmental perturbation, with high temperatures resulting in a growth defect...
2016: Frontiers in Plant Science
Volkan Coskun, Dawn M Lombardo
The cardiovascular and nervous systems are deeply connected during development, health, and disease. Both systems affect and regulate the development of each other during embryogenesis and the early postnatal period. Specialized neural crest cells contribute to cardiac structures, and a number of growth factors released from the cardiac tissue (e.g., glial cell line-derived neurotrophic factor, neurturin, nerve growth factor, Neurotrophin-3) ensure proper maturation of the incoming parasympathetic and sympathetic neurons...
December 2016: Journal of Neuroscience Research
Michela Guaraldo, Paolo Santambrogio, Elisabetta Rovelli, Augusta Di Savino, Giuseppe Saglio, Davide Cittaro, Antonella Roetto, Sonia Levi
Mitochondrial ferritin (FtMt) is an iron storage protein belonging to the ferritin family but, unlike the cytosolic ferritin, it has an iron-unrelated restricted tissue expression. FtMt appears to be preferentially expressed in cell types characterized by high metabolic activity and oxygen consumption, suggesting a role in protecting mitochondria from iron-dependent oxidative damage. The human gene (FTMT) is intronless and its promoter region has not been described yet. To analyze the regulatory mechanisms controlling FTMT expression, we characterized the 5' flanking region upstream the transcriptional starting site of FTMT by in silico enquiry of sequences conservation, DNA deletion analysis, and ChIP assay...
2016: Scientific Reports
Urszula Polak, Yanjie Li, Jill Sergesketter Butler, Marek Napierala
Friedreich's ataxia (FRDA) is the most common autosomal recessive ataxia. This severe neurodegenerative disease is caused by an expansion of guanine-adenine-adenine (GAA) repeats located in the first intron of the frataxin (FXN) gene, which represses its transcription. Although transcriptional silencing is associated with heterochromatin-like changes in the vicinity of the expanded GAAs, the exact mechanism and pathways involved in transcriptional inhibition are largely unknown. As major remodeling of the epigenome is associated with somatic cell reprogramming, modulating chromatin modification pathways during the cellular transition from a somatic to a pluripotent state is likely to generate permanent changes to the epigenetic landscape...
October 17, 2016: Stem Cells and Development
Imis Dogan, Eugenie Tinnemann, Sandro Romanzetti, Shahram Mirzazade, Ana S Costa, Cornelius J Werner, Stefan Heim, Kathrin Fedosov, Stefanie Schulz, Dagmar Timmann, Ilaria A Giordano, Thomas Klockgether, Jörg B Schulz, Kathrin Reetz
OBJECTIVE: Friedreich's ataxia (FRDA) is a spinocerebellar degenerative disorder, in which cognitive deficits are sparsely explored. In this behavioral and multimodal magnetic resonance imaging (MRI) study, we investigated the neurocognitive profile and cortico-cerebellar dysfunctions underlying executive functioning in individuals with FRDA. METHODS: 22 FRDA patients and 22 controls were clinically and neuropsychologically examined. Fifteen of each underwent structural and functional MRI using a verbal-fluency task with phonemic and semantic conditions...
August 2016: Annals of Clinical and Translational Neurology
Gessica Vasco, Simone Gazzellini, Maurizio Petrarca, Maria Luisa Lispi, Alessandra Pisano, Marco Zazza, Gessica Della Bella, Enrico Castelli, Enrico Bertini
Friedreich's ataxia is the most common autosomal recessive form of neurodegenerative ataxia. We present a longitudinal study on the gait pattern of children and adolescents affected by Friedreich's ataxia using Gait Analysis and the Scale for the Assessment and Rating of Ataxia (SARA). We assessed the spectrum of changes over 12 months of the gait characteristics and the relationship between clinical and instrumental evaluations. We enrolled 11 genetically confirmed patients affected by Friedreich's ataxia in this study together with 13 normally developing age-matched subjects...
2016: PloS One
Franca Codazzi, Amelié Hu, Myriam Rai, Floramarida Salerno Scarzella, Elisabeth Mangiameli, Ilaria Pelizzoni, Fabio Grohovaz, Massimo Pandolfo
We employed induced pluripotent stem cell (iPSC)-derived neurons obtained from Friedreich ataxia (FRDA) patients and healthy subjects, FRDA neurons and CT neurons, respectively, to unveil phenotypic alterations related to frataxin (FXN) deficiency and investigate if they can be reversed by treatments that upregulate FXN. FRDA and control iPSCs were equally capable of differentiating into a neuronal or astrocytic phenotype. FRDA neurons showed lower levels of iron-sulfur and lipoic acid-containing proteins, higher labile iron pool (LIP), higher expression of mitochondrial superoxide dismutase (SOD2), increased reactive oxygen species (ROS) and lower reduced glutathione (GSH) levels, and enhanced sensitivity to oxidants compared to CT neurons, indicating deficient iron-sulfur cluster biogenesis, altered iron metabolism, and oxidative stress...
September 4, 2016: Human Molecular Genetics
Marissa Z McMackin, Chelsea K Henderson, Gino A Cortopassi
Friedreich's Ataxia (FA) is a pediatric neurodegenerative disease whose clinical presentation includes ataxia, muscle weakness, and peripheral sensory neuropathy. The KIKO mouse is an animal model of FA with frataxin deficiency first described in 2002, but neurobehavioral deficits have never been described in this model. The identification of robust neurobehavioral deficits in KIKO mice could support the testing of drugs for FA, which currently has no approved therapy. We tested 13 neurobehavioral tasks to identify a robust KIKO phenotype: Open Field, Grip Strength Test(s), Cylinder, Skilled Forelimb Grasp Task(s), Treadmill Endurance, Locotronic Motor Coordination, Inverted Screen, Treadscan, and Von Frey...
January 1, 2017: Behavioural Brain Research
Mary Kearney, Richard W Orrell, Michael Fahey, Ruth Brassington, Massimo Pandolfo
BACKGROUND: Friedreich ataxia is a rare inherited autosomal recessive neurological disorder, characterised initially by unsteadiness in standing and walking, slowly progressing to wheelchair dependency usually in the late teens or early twenties. It is associated with slurred speech, scoliosis, and pes cavus. Heart abnormalities cause premature death in 60% of people with the disorder. There is no easily defined clinical or biochemical marker and no known treatment. This is the second update of a review first published in 2009 and previously updated in 2012...
2016: Cochrane Database of Systematic Reviews
Nishaki Mehta, Paul Chacko, James Jin, Tam Tran, Thomas W Prior, Xin He, Gunjan Agarwal, Subha V Raman
Patients with Friedreich ataxia typically die of cardiomyopathy, marked by myocardial fibrosis and abnormal left ventricular (LV) geometry. We measured procollagen I carboxyterminal propeptide (PICP), a serum biomarker of collagen production, and characterized genotypes, phenotypes, and outcomes in these patients. Twenty-nine patients with Friedreich ataxia (mean age, 34.2 ± 2.2 yr) and 29 healthy subjects (mean age, 32.5 ± 1.1 yr) underwent serum PICP measurements. Patients underwent cardiac magnetic resonance imaging and outcome evaluations at baseline and 12 months...
August 2016: Texas Heart Institute Journal
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