Françoise Piguet, Charline de Montigny, Nadège Vaucamps, Laurence Reutenauer, Aurélie Eisenmann, Hélène Puccio, Molecular Therapy , Volume 0 , Issue 0 , DOI: 10.1016/j.ymthe.2018.05.006
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. Here, we report a new conditional mouse model with complete frataxin deletion in parvalbumin positive cells which recapitulate the sensory ataxia and neuropathy associated to FA, albeit with a more rapid and severe course. Interestingly, proprioceptive neurons can survive for many weeks without frataxin, although fully dysfunctional. Furthermore, we demonstrate that post-symptomatic delivery of frataxin-expressing AAV allows for rapid and complete rescue the sensory neuropathy associated with frataxin deficiency, thus establishing the preclinical proof of concept for the potential of gene therapy in treating FA neuropathy.
Thursday, May 17, 2018
Diabetes mellitus in Friedreich Ataxia: A case series of 19 patients from the German-Austrian diabetes mellitus registry
Angeliki Pappa, Martin G. Häusler, Andreas Veigel, Konstantina Tzamouranis, Martin W. Pfeifer, Andreas Schmidt, Martin Bökamp, Holger Haberland, Siegfried Wagner, Joachim Brückel, Gideon de Sousa, Lukas Hackl, Esther Bollow, Reinhard W Holl, Diabetes Res Clin Pract. 2018 May 12. pii: S0168-8227(17)32029-6 DOI: 10.1016/j.diabres.2018.05.008
Diabetes phenotype in FRDA is intermediate between type 1 and type 2 diabetes with ketoacidosis being frequent at presentation and blood glucose levels similar to T1Dm but higher than in T2Dm (356 ±165 and 384± 203 mg/dl). 63.2% of FRDA patients received insulin monotherapy, 21% insulin plus oral antidiabetics and 15.8% lifestyle change only, applying similar doses of insulin in all three groups.
FRDADm can be controlled by individualized treatment regimen with insulin or oral antidiabetics. Patients with DM in FRDA may show a relevant risk to ketoacidotic complications, which should be avoided.
Diabetes phenotype in FRDA is intermediate between type 1 and type 2 diabetes with ketoacidosis being frequent at presentation and blood glucose levels similar to T1Dm but higher than in T2Dm (356 ±165 and 384± 203 mg/dl). 63.2% of FRDA patients received insulin monotherapy, 21% insulin plus oral antidiabetics and 15.8% lifestyle change only, applying similar doses of insulin in all three groups.
FRDADm can be controlled by individualized treatment regimen with insulin or oral antidiabetics. Patients with DM in FRDA may show a relevant risk to ketoacidotic complications, which should be avoided.
Wednesday, May 16, 2018
The genetic nomenclature of recessive cerebellar ataxias
Rossi, M. , Anheim, M. , Durr, A. , Klein, C. , Koenig, M. , Synofzik, M. , Marras, C. , van de Warrenburg, B. P. and , (2018), Mov Disord.. . doi:10.1002/mds.27415
The recessive cerebellar ataxias are a large group of degenerative and metabolic disorders, the diagnostic management of which is difficult because of the enormous clinical and genetic heterogeneity. Because of several limitations, the current classification systems provide insufficient guidance for clinicians and researchers. Here, we propose a new nomenclature for the genetically confirmed recessive cerebellar ataxias according to the principles and criteria laid down by the International Parkinson and Movement Disorder Society Task Force on Classification and Nomenclature of Genetic Movement Disorders. We apply stringent criteria for considering an association between gene and phenotype to be established. The newly proposed list of recessively inherited cerebellar ataxias includes 62 disorders that were assigned an ATX prefix, followed by the gene name, because these typically present with ataxia as a predominant and/or consistent feature. An additional 30 disorders that often combine ataxia with a predominant or consistent other movement disorder received a double prefix (e.g., ATX/HSP). We also identified a group of 89 entities that usually present with complex nonataxia phenotypes, but may occasionally present with cerebellar ataxia. These are listed separately without the ATX prefix. This new, transparent and adaptable nomenclature of the recessive cerebellar ataxias will facilitate the clinical recognition of recessive ataxias, guide diagnostic testing in ataxia patients, and help in interpreting genetic findings.
The recessive cerebellar ataxias are a large group of degenerative and metabolic disorders, the diagnostic management of which is difficult because of the enormous clinical and genetic heterogeneity. Because of several limitations, the current classification systems provide insufficient guidance for clinicians and researchers. Here, we propose a new nomenclature for the genetically confirmed recessive cerebellar ataxias according to the principles and criteria laid down by the International Parkinson and Movement Disorder Society Task Force on Classification and Nomenclature of Genetic Movement Disorders. We apply stringent criteria for considering an association between gene and phenotype to be established. The newly proposed list of recessively inherited cerebellar ataxias includes 62 disorders that were assigned an ATX prefix, followed by the gene name, because these typically present with ataxia as a predominant and/or consistent feature. An additional 30 disorders that often combine ataxia with a predominant or consistent other movement disorder received a double prefix (e.g., ATX/HSP). We also identified a group of 89 entities that usually present with complex nonataxia phenotypes, but may occasionally present with cerebellar ataxia. These are listed separately without the ATX prefix. This new, transparent and adaptable nomenclature of the recessive cerebellar ataxias will facilitate the clinical recognition of recessive ataxias, guide diagnostic testing in ataxia patients, and help in interpreting genetic findings.
Cognitive and functional connectivity alterations in Friedreich's ataxia
Sirio Cocozza, Teresa Costabile, Enrico Tedeschi, Filomena Abate, Camilla Russo, Agnese Liguori, Walter Del Vecchio, Francesca Paciello, Mario Quarantelli, Alessandro Filla, Arturo Brunetti, Francesco Saccà; Annals of Clinical and Translational Neurology doi:10.1002/acn3.555
The aim of this study was to perform the first resting‐state functional MRI (RS‐fMRI) analysis in Friedreich's ataxia (FRDA) patients to assess possible brain functional connectivity (FC) differences in these patients, and test their correlations with neuropsychological performances.
The aim of this study was to perform the first resting‐state functional MRI (RS‐fMRI) analysis in Friedreich's ataxia (FRDA) patients to assess possible brain functional connectivity (FC) differences in these patients, and test their correlations with neuropsychological performances.
EU/3/18/1990: Public summary of opinion on orphan designation: Dimethyl fumarate for the treatment of Friedreich's ataxia
European Medicines Agency. On 21 March 2018, orphan designation (EU/3/18/1990) was granted by the European Commission to PharmaBio Consulting, Germany, for dimethyl fumarate for the treatment of Friedreich's ataxia.
Sunday, May 13, 2018
Interactions of iron-bound frataxin with ISCU and ferredoxin on the cysteine desulfurase complex leading to Fe-S cluster assembly
Kai Cai, Ronnie O. Frederick, Marco Tonelli, John L. Markley, Journal of Inorganic Biochemistry, Volume 183, 2018, Pages 107-116,
ISSN 0162-0134, doi: 10.1016/j.jinorgbio.2018.03.007.
Frataxin (FXN) binds one Fe2+; the Fe2+-FXN complex is stabilized by its interaction with the scaffold protein (ISCU) on cysteine desulfurase. Upon the addition of reduced ferredoxin (Red-FDX) and l-cysteine, ferredoxin is oxidized (Ox-FDX), l-cysteine is converted to l-alanine generating sulfur, Fe2+ is oxidized to Fe3+, Fe-S binds to ISCU.
ISSN 0162-0134, doi: 10.1016/j.jinorgbio.2018.03.007.
Frataxin (FXN) binds one Fe2+; the Fe2+-FXN complex is stabilized by its interaction with the scaffold protein (ISCU) on cysteine desulfurase. Upon the addition of reduced ferredoxin (Red-FDX) and l-cysteine, ferredoxin is oxidized (Ox-FDX), l-cysteine is converted to l-alanine generating sulfur, Fe2+ is oxidized to Fe3+, Fe-S binds to ISCU.
Saturday, May 12, 2018
Small molecules capable of activating DNA methylation–repressed genes targeted by the p38 mitogen-activated protein kinase pathway
Xiang Li, Erchang Shang, Qiang Dong, Yingfeng Li, Jing Zhang, Shaohua Xu, Zuodong Zhao, Wei Shao, Cong Lv, Yong Zheng, Hailin Wang, Xiaoguang Lei, Bing Zhu and Zhuqiang Zhang; J. Biol. Chem. 2018 293: 7423-7436. doi: 10.1074/jbc.RA117.000757
DNA methylation changes in certain loci can directly cause certain neurological diseases, including fragile X syndrome, Friedreich’s ataxia and spinal muscular atrophy, which can be caused by DNA hypermethylation on the promoter regions of the FMR1, FXN and SMN genes respectively. Thus, small molecules that can activate genes silenced by DNA methylation are of clinical relevance.
DNA methylation changes in certain loci can directly cause certain neurological diseases, including fragile X syndrome, Friedreich’s ataxia and spinal muscular atrophy, which can be caused by DNA hypermethylation on the promoter regions of the FMR1, FXN and SMN genes respectively. Thus, small molecules that can activate genes silenced by DNA methylation are of clinical relevance.
Tuesday, May 8, 2018
Monthly update: April 6-Mai 6, 2018
Monthly
update: April 6-Mai 6, 2018
Emergence of breath testing as a new
non-invasive diagnostic modality for neurodegenerative diseases
Sunday,
April 22, 2018
Sunday, May 6, 2018
Low-level mitochondrial heteroplasmy modulates DNA replication, glucose metabolism and lifespan in mice
Misa Hirose, Paul Schilf, Yask Gupta, Kim Zarse, Axel Künstner, Anke Fähnrich, Hauke Busch, Junping Yin, Marvin N. Wright, Andreas Ziegler, Marie Vallier, Meriem Belheouane, John F Baines, Diethard Tautz, Kornelia Johann, Rebecca Oelkrug, Jens Mittag, Hendrik Lehnert, Alaa Othman, Olaf Jöhren, Markus Schwaninger, Cornelia Prehn, Jerzy Adamski, Kensuke Shima, Jan Rupp, Robert Häsler, Georg Fuellen, Rüdiger Köhling, Michael Ristow & Saleh M. Ibrahim; Scientific Reports volume 8, Article number: 5872 (2018) doi:10.1038/s41598-018-24290-6
One example of such disorders is Friedreich Ataxia (FA), which is resulted by the impaired expression of the nuclear genome encoded frataxin protein that affect OXPHOS function by mediating mitochondrial iron-sulphur-cluster biosynthesis. FA patients develop diabetes and exhibited decreased lifespan, and experimental evidence using different models showed that a frataxin knock-out cause diabetes in mice, and knocking down of the frataxin gene resulted in shorter lifespan in worms.
One example of such disorders is Friedreich Ataxia (FA), which is resulted by the impaired expression of the nuclear genome encoded frataxin protein that affect OXPHOS function by mediating mitochondrial iron-sulphur-cluster biosynthesis. FA patients develop diabetes and exhibited decreased lifespan, and experimental evidence using different models showed that a frataxin knock-out cause diabetes in mice, and knocking down of the frataxin gene resulted in shorter lifespan in worms.
Advances in Biomarker-Guided Therapy for Pediatric- and Adult-Onset Neuroinflammatory Disorders: Targeting Chemokines/Cytokines
Michael R. Pranzatelli, Front Immunol. 2018; 9: 557. Published online 2018 Apr 4. doi:10.3389/fimmu.2018.00557
The concept and recognized components of “neuroinflammation” are expanding at the intersection of neurobiology and immunobiology. Chemokines (CKs), no longer merely necessary for immune cell trafficking and positioning, have multiple physiologic, developmental, and modulatory functionalities in the central nervous system (CNS) through neuron–glia interactions and other mechanisms affecting neurotransmission. They issue the “help me” cry of neurons and astrocytes in response to CNS injury, engaging invading lymphoid cells (T cells and B cells) and myeloid cells (dendritic cells, monocytes, and neutrophils) (adaptive immunity), as well as microglia and macrophages (innate immunity), in a cascade of events, some beneficial (reparative), others destructive (excitotoxic).
Filling in knowledge gaps between pediatric- and adult-onset neuroinflammation by systematic collection of CSF data on CKs/cytokines in temporal and clinical contexts and incorporating immunobiomarkers in clinical trials is a challenge hereby set forth for clinicians and researchers.
Interferon-gamma, the sole type 2 IFN, binds to the IFN-γ-R1 and IFN-γ-R2 receptors (also denoted IFNGR1 and R2). IFN-γ-1b is FDA-approved for chronic granulomatous diseases and osteopetrosis. A phase III study (NCT024155127) of IFN-γ-1b for the treatment of Friedreich ataxia has been completed recently, but without study results yet, based on positive results from as phase II study. Treatment with IFN-γ exacerbated MS.
In preclinical studies, administration of G-CSF in a murine model of Friedreich ataxia resulted in clinical improvement and reduction in inflammation and gliosis. IL-10 is such a powerful counteractant of pro-inflammatory cytokines, one would hope there is more progress in this area.
The concept and recognized components of “neuroinflammation” are expanding at the intersection of neurobiology and immunobiology. Chemokines (CKs), no longer merely necessary for immune cell trafficking and positioning, have multiple physiologic, developmental, and modulatory functionalities in the central nervous system (CNS) through neuron–glia interactions and other mechanisms affecting neurotransmission. They issue the “help me” cry of neurons and astrocytes in response to CNS injury, engaging invading lymphoid cells (T cells and B cells) and myeloid cells (dendritic cells, monocytes, and neutrophils) (adaptive immunity), as well as microglia and macrophages (innate immunity), in a cascade of events, some beneficial (reparative), others destructive (excitotoxic).
Filling in knowledge gaps between pediatric- and adult-onset neuroinflammation by systematic collection of CSF data on CKs/cytokines in temporal and clinical contexts and incorporating immunobiomarkers in clinical trials is a challenge hereby set forth for clinicians and researchers.
Interferon-gamma, the sole type 2 IFN, binds to the IFN-γ-R1 and IFN-γ-R2 receptors (also denoted IFNGR1 and R2). IFN-γ-1b is FDA-approved for chronic granulomatous diseases and osteopetrosis. A phase III study (NCT024155127) of IFN-γ-1b for the treatment of Friedreich ataxia has been completed recently, but without study results yet, based on positive results from as phase II study. Treatment with IFN-γ exacerbated MS.
In preclinical studies, administration of G-CSF in a murine model of Friedreich ataxia resulted in clinical improvement and reduction in inflammation and gliosis. IL-10 is such a powerful counteractant of pro-inflammatory cytokines, one would hope there is more progress in this area.
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