Luis Bermúdez-Guzmán and Alejandro Leal; Translational Neurodegeneration 20198:14 doi:10.1186/s40035-019-0156-x
Diseases such as Friedreich’s ataxia and MIRAS (caused by POLG mutations) present an extended phenotype, maybe derived from the equal vulnerability that these variants confer to the mitochondria in the whole organism. Even though the clinical difference is evident, still more research is needed to understand the molecular basis of this systemic damage compared with the diseases that tend to present a pathological tropism.
Friday, June 14, 2019
Thursday, June 13, 2019
Prominent Spasticity and Hyperreflexia of the Legs in a Nepalese Patient with Friedreich At
Hiroya Naruse, Yuji Takahashi, Hiroyuki Ishiura, Takashi Matsukawa, Jun Mitsui, Yaeko Ichikawa, Masashi Hamada, Jun Shimizu, Jun Goto, Tatsushi Toda, Shoji Tsuji, axia, Internal Medicine, Article ID 2953-19, [Advance publication] Released June 07, 2019, Online ISSN 1349-7235, Print ISSN 0918-2918, doi:10.2169/internalmedicine.2953-19,
Friedreich ataxia (FRDA) is an autosomal recessive spinocerebellar ataxia caused by mutations of FXN. Hypotonus and hyporeflexia of the lower extremities are observed in most FRDA patients. Patients with hyperreflexia, called Friedreich ataxia with retained reflexes (FARR), have also been identified. We herein report the case of a 16-year-old Nepalese boy presenting with early-onset ataxia with prominent spasticity and hyperreflexia of the legs. Mutational analyses established the diagnosis of FRDA presenting as FARR. A haplotype analysis revealed that expanded alleles of the patient shared a common haplotype with Indian and European FRDA patients, suggesting that the mutation descended from a common founder.
Friedreich ataxia (FRDA) is an autosomal recessive spinocerebellar ataxia caused by mutations of FXN. Hypotonus and hyporeflexia of the lower extremities are observed in most FRDA patients. Patients with hyperreflexia, called Friedreich ataxia with retained reflexes (FARR), have also been identified. We herein report the case of a 16-year-old Nepalese boy presenting with early-onset ataxia with prominent spasticity and hyperreflexia of the legs. Mutational analyses established the diagnosis of FRDA presenting as FARR. A haplotype analysis revealed that expanded alleles of the patient shared a common haplotype with Indian and European FRDA patients, suggesting that the mutation descended from a common founder.
Wednesday, June 12, 2019
Frataxin deficiency induces lipid accumulation and affects thermogenesis in brown adipose tissue
Riccardo Turchi, Flavia Tortolici, Giulio Guidobaldi, Federico Iacovelli, Mattia Falconi, Stefano Rufini, Raffaella Faraonio, Viviana Casagrande, Lorenzo De Angelis, Massimo Federici, Simone Carotti, Maria Francesconi, Maria Zingariello, Sergio Morini, Roberta Bernardini, Maurizio Mattei, Daniele Lettieri-Barbato, Katia Aquilano; bioRxiv 664649; doi:10.1101/664649
Decreased expression of the mitochondrial protein frataxin (FXN) causes Friedreich's ataxia (FRDA). FRDA is a neurodegenerative disease also characterized by systemic metabolic alterations that increase the risk of developing type 2 diabetes thus aggravating FRDA prognosis. Brown adipose tissue (BAT) is a mitochondria-enriched and anti-diabetic tissue that, in addition to its thermoregulatory role, turns excess energy into heat to maintain energy balance. Here we report that the FXN knock-in/knock-out (KIKO) mouse shows reduced energy expenditure and VO2, hyperlipidemia, decreased insulin sensitivity and enhanced circulating levels of leptin, recapitulating diabetes-like signatures. FXN deficiency leads to alteration of mitochondrial structure and oxygen consumption, decreased lipolysis and lipid accumulation in BAT. Transcriptomic data highlighted a blunted thermogenesis response, as several biological processes related to thermogenesis (e.g. response to temperature stimuli, mitochondrial gene transcription, triglyceride metabolism, adipogenesis) resulted affected in BAT of KIKO mice upon cold exposure. Decreased adaptation to cool temperature in association with limited PKA-mediated lipolysis and downregulation of the expression of the genes controlling mitochondrial metabolism and lipid catabolism were observed in KIKO mice. T37i brown adipocytes and primary adipocytes with FXN deficiency showed reduced thermogenesis and adipogenesis markers respectively recapitulating the molecular signatures detected in KIKO mice. Collectively our data point to BAT dysfunction in FRDA and suggest BAT as a promising target to overcome metabolic complications in FRDA.
Decreased expression of the mitochondrial protein frataxin (FXN) causes Friedreich's ataxia (FRDA). FRDA is a neurodegenerative disease also characterized by systemic metabolic alterations that increase the risk of developing type 2 diabetes thus aggravating FRDA prognosis. Brown adipose tissue (BAT) is a mitochondria-enriched and anti-diabetic tissue that, in addition to its thermoregulatory role, turns excess energy into heat to maintain energy balance. Here we report that the FXN knock-in/knock-out (KIKO) mouse shows reduced energy expenditure and VO2, hyperlipidemia, decreased insulin sensitivity and enhanced circulating levels of leptin, recapitulating diabetes-like signatures. FXN deficiency leads to alteration of mitochondrial structure and oxygen consumption, decreased lipolysis and lipid accumulation in BAT. Transcriptomic data highlighted a blunted thermogenesis response, as several biological processes related to thermogenesis (e.g. response to temperature stimuli, mitochondrial gene transcription, triglyceride metabolism, adipogenesis) resulted affected in BAT of KIKO mice upon cold exposure. Decreased adaptation to cool temperature in association with limited PKA-mediated lipolysis and downregulation of the expression of the genes controlling mitochondrial metabolism and lipid catabolism were observed in KIKO mice. T37i brown adipocytes and primary adipocytes with FXN deficiency showed reduced thermogenesis and adipogenesis markers respectively recapitulating the molecular signatures detected in KIKO mice. Collectively our data point to BAT dysfunction in FRDA and suggest BAT as a promising target to overcome metabolic complications in FRDA.
Tuesday, June 11, 2019
Pharmacokinetics and pharmacodynamics of the novel Nrf2 activator omaveloxolone in primates
Reisman SA, Gahir SS, Lee CY, Proksch JW, Sakamoto M, Ward KW (Reata Pharmaceuticals, Inc., Irving, TX 75063, USA); Drug Des Devel Ther. 2019; 13: 1259–1270.Published online 2019 Apr 17. doi: 10.2147/DDDT.S193889
Overall, the monkey data demonstrate a well-characterized and dose-proportional PK and tissue distribution profile after oral administration of omaveloxolone, which was associated with Nrf2 activation. Further, systemic exposures to omaveloxolone that produce Nrf2 activation in monkeys were readily achievable in Friedreich's ataxia patients after oral administration.
Overall, the monkey data demonstrate a well-characterized and dose-proportional PK and tissue distribution profile after oral administration of omaveloxolone, which was associated with Nrf2 activation. Further, systemic exposures to omaveloxolone that produce Nrf2 activation in monkeys were readily achievable in Friedreich's ataxia patients after oral administration.
Is left ventricular longitudinal strain a good prognostic factor in Friedreich ataxia?
C. Heuze, L. Legrand, A. Diallo, M.L. Monin, C. Ewenczyk, R. Isnard, E. Vicaut, A. Durr, F. Pousset, Archives of Cardiovascular Diseases Supplements, Volume 11, Issue 3, 2019, Page e321, doi:10.1016/j.acvdsp.2019.04.036.
GLS is a predictor of morbimortality but is not superior to LVEF in FRDA patients.
GLS is a predictor of morbimortality but is not superior to LVEF in FRDA patients.
Friday, June 7, 2019
Microvascular pathology in Friedreich cardiomyopathy
Arnulf H. Koeppen, Jiang Qian, Alicia M. Travis, Alyssa B. Sossei, Paul J. Feustel and Joseph E. Mazurkiewicz; Histol Histopathol. 2019 Jun 5:18132. doi: 10.14670/HH-18-132. [Epub ahead of print]
Heart disease is an integral part of Friedreich ataxia (FA). In addition to cardiomyocyte hypertrophy, fiber necrosis, and inflammatory infiltration, sections show fibrosis and disorganized capillaries. We examined the left ventricular wall (LVW) of 41 homozygous and 2 compound heterozygous FA patients aged 10-87 and 21 controls aged 2-69.
Heart disease is an integral part of Friedreich ataxia (FA). In addition to cardiomyocyte hypertrophy, fiber necrosis, and inflammatory infiltration, sections show fibrosis and disorganized capillaries. We examined the left ventricular wall (LVW) of 41 homozygous and 2 compound heterozygous FA patients aged 10-87 and 21 controls aged 2-69.
Wednesday, June 5, 2019
Minoryx inicia el primer tratamiento de un paciente con Ataxia de Friedreich en el Hospital La Paz
Mataró (Barcelona)-Charleroi (Bélgica), 4 de mayo de 2019. Minoryx Therapeutics, compañía biotecnológica especializada en el desarrollo de nuevos medicamentos para enfermedades huérfanas, anuncia hoy que ha dosificado con el fármaco leriglitazona (MIN-102) al primer paciente en el ensayo clínico FRAMES de Fase II para el tratamiento de la Ataxia de Friedreich (FRDA).
Minoryx Therapeutics enrôle le premier patient de son essai clinique de phase II dans l’ataxie de Friedreich
Mataró, Barcelone, Espagne et Charleroi, Belgique, le 4 juin 2019 - Minoryx Therapeutics, une société spécialisée dans le développement de nouveaux médicaments contre des maladies orphelines, annonce aujourd'hui qu’un premier dosage de patient a été réalisé dans l’essai clinique FRAMES de phase II sur l’ataxie de Friedreich avec son candidat médicament leriglitazone (MIN-102).
Minoryx Therapeutics announces first patient dosed in the FRAMES phase 2 trial in Friedreich’s Ataxia
Minoryx Therapeutics, a company specializing in the development of new drugs for orphan diseases, today announces that the first patient has been dosed with its lead candidate, leriglitazone (MIN-102), in the phase 2 FRAMES clinical trial in Friedreich’s Ataxia.
Tuesday, June 4, 2019
Dimethyl fumarate dosing in humans increases frataxin expression: A potential therapy for Friedreich’s Ataxia
Mittal Jasoliya , Francesco Sacca , Sunil Sahdeo, Frederic Chedin, Chiara Pane, Vincenzo Brescia Morra, Alessandro Filla, Mark Pook, Gino Cortopassi. PLoS ONE 14(6): e0217776. doi:10.1371/journal.pone.0217776
Friedreich’s Ataxia (FA) is an inherited neurodegenerative disorder resulting from decreased expression of the mitochondrial protein frataxin, for which there is no approved therapy. High throughput screening of clinically used drugs identified Dimethyl fumarate (DMF) as protective in FA patient cells. Here we demonstrate that DMF significantly increases frataxin gene (FXN) expression in FA cell model, FA mouse model and in DMF treated humans. DMF also rescues mitochondrial biogenesis deficiency in FA-patient derived cell model. We further examined the mechanism of DMF's frataxin induction in FA patient cells. It has been shown that transcription-inhibitory R-loops form at GAA expansion mutations, thus decreasing FXN expression. In FA patient cells, we demonstrate that DMF significantly increases transcription initiation. As a potential consequence, we observe significant reduction in both R-loop formation and transcriptional pausing thereby significantly increasing FXN expression. Lastly, DMF dosed Multiple Sclerosis (MS) patients showed significant increase in FXN expression by ~85%. Since inherited deficiency in FXN is the primary cause of FA, and DMF is demonstrated to increase FXN expression in humans, DMF could be considered for Friedreich's therapy.
Friedreich’s Ataxia (FA) is an inherited neurodegenerative disorder resulting from decreased expression of the mitochondrial protein frataxin, for which there is no approved therapy. High throughput screening of clinically used drugs identified Dimethyl fumarate (DMF) as protective in FA patient cells. Here we demonstrate that DMF significantly increases frataxin gene (FXN) expression in FA cell model, FA mouse model and in DMF treated humans. DMF also rescues mitochondrial biogenesis deficiency in FA-patient derived cell model. We further examined the mechanism of DMF's frataxin induction in FA patient cells. It has been shown that transcription-inhibitory R-loops form at GAA expansion mutations, thus decreasing FXN expression. In FA patient cells, we demonstrate that DMF significantly increases transcription initiation. As a potential consequence, we observe significant reduction in both R-loop formation and transcriptional pausing thereby significantly increasing FXN expression. Lastly, DMF dosed Multiple Sclerosis (MS) patients showed significant increase in FXN expression by ~85%. Since inherited deficiency in FXN is the primary cause of FA, and DMF is demonstrated to increase FXN expression in humans, DMF could be considered for Friedreich's therapy.
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