Jeffrey B. Russ, Akila M. Nallappan, Amy Robichaux-Viehoever, Seminars in Pediatric Neurology, 2018, ISSN 1071-9091, doi:10.1016/j.spen.2018.02.004.
Management of movement disorders in children is an evolving field. This article outlines the major categories of treatment options for pediatric movement disorders and general guidelines for their use. We review the evidence for existing therapies, which continue to lack large-scale controlled trials to guide treatment decisions. The field continues to rely on extrapolations from adult studies and lower quality evidence such as case reports and case series to guide treatment guidelines and consensus statements. Developments in new pharmaceuticals for rare diseases have begun to provide hope for those cases in which a genetic diagnosis can be made. Advances in surgical therapies such as deep brain stimulation as well as new modes of treatment such as gene therapy, epigenetic modulation, and stem cell therapy hold promise for improving outcomes in both primary and secondary causes of movement disorders. There is a critical need for larger, multicenter, controlled clinical trials to fully evaluate treatments for pediatric movement disorders.
Saturday, March 31, 2018
Structure and mechanism of mitochondrial electron transport chain
Runyu Guo, Jinke Gu, Shuai Zong, Meng Wu, Maojun Yang, Biomedical Journal, Available online 26 March 2018, ISSN 2319-4170, doi:10.1016/j.bj.2017.12.001.
For the first time, this work provided solid evidence for the existence of megacomplex, observed the possible compartment of Q pool, and connected the organization of respiratory chain more tightly with the shape of cristae. Since this is the first structure of human respirasome, previously reported mitochondrial disease related mutations can all be mapped into our structure. Doubtlessly, this is a great step forward into conquering many severe neurodegenerative diseases, including Alzheimer's syndrome, Parkinson's disease, multiple sclerosis, friedreich's ataxia, Amyotrophic lateral sclerosis, etc.
For the first time, this work provided solid evidence for the existence of megacomplex, observed the possible compartment of Q pool, and connected the organization of respiratory chain more tightly with the shape of cristae. Since this is the first structure of human respirasome, previously reported mitochondrial disease related mutations can all be mapped into our structure. Doubtlessly, this is a great step forward into conquering many severe neurodegenerative diseases, including Alzheimer's syndrome, Parkinson's disease, multiple sclerosis, friedreich's ataxia, Amyotrophic lateral sclerosis, etc.
Dysfunction in the mitochondrial Fe-S assembly machinery leads to formation of the chemoresistant truncated VDAC1 isoform without HIF-1α activation
Ferecatu I, Canal F, Fabbri L, Mazure NM, Bouton C, Golinelli-Cohen M-P (2018). PLoS ONE 13(3): e0194782. doi:10.1371/journal.pone.0194782
We show that hypoxia promotes the downregulation of several proteins (ISCU, NFS1, FXN) involved in the early steps of mitochondrial Fe-S cluster biogenesis.
We show that hypoxia promotes the downregulation of several proteins (ISCU, NFS1, FXN) involved in the early steps of mitochondrial Fe-S cluster biogenesis.
Rapid exhaustion of auditory neural conduction in a prototypical mitochondrial disease, Friedreich ataxia
Fabrice Giraudet, Perrine Charles, Thierry Mom, Odile Boespflug-Tanguy, Alexandra Dürr, Paul Deltenre, Paul Avan, Clinical Neurophysiology, Available online 27 March 2018, ISSN 1388-2457, doi:10.1016/j.clinph.2018.03.005.
In FRDA, the assumption of stationarity used for extracting standard auditory brainstem-evoked responsesis invalid. The preservation of early split-ABRs indicates no short-term dyssynchrony of action potentials. A large decrease in conduction velocity along auditory neurons occurs within seconds, attributed to fast energetic failure.
In FRDA, the assumption of stationarity used for extracting standard auditory brainstem-evoked responsesis invalid. The preservation of early split-ABRs indicates no short-term dyssynchrony of action potentials. A large decrease in conduction velocity along auditory neurons occurs within seconds, attributed to fast energetic failure.
Tuesday, March 27, 2018
Cell Therapy Instigates Neural Repair In Friedreich’s Ataxia Mice
RELIAWIRE, March 26, 2018; Author: Geoffrey Potjewyd; Regenerative Medicine & Neuroscience PhD student at the University of Manchester.
The group found that transplantation of bone marrow cells that express frataxin into the FRDA mice caused the upregulation of frataxin as well as a number of antioxidative proteins, as well as improving movement and coordination in the mice. The researchers also observed the reversal of FRDA disease pathology, along with integration of transplanted bone marrow cells into damaged nervous system tissue and transplanted cells contributing genetic material to neurons and myelinating Schwann cells.
The group found that transplantation of bone marrow cells that express frataxin into the FRDA mice caused the upregulation of frataxin as well as a number of antioxidative proteins, as well as improving movement and coordination in the mice. The researchers also observed the reversal of FRDA disease pathology, along with integration of transplanted bone marrow cells into damaged nervous system tissue and transplanted cells contributing genetic material to neurons and myelinating Schwann cells.
Monday, March 26, 2018
Assistance circulatoire et transplantation d’organes thoraciques chez l’enfant
Sébastien Hascoet, Angèle Boet, Karine Nubret, Marc Lilot, Séverine Feuillet, Nadir Benbrik, Julien Guihaire, Emmanuel Le Bret, Elie Fadel, Virginie Fouilloux, Pascal Amedro, Lucile Houyel, Bernard Kreitmann, La Presse Médicale, Available online 24 March 2018, ISSN 0755-4982, doi:10.1016/j.lpm.2018.01.014.
L’assistance circulatoire et la transplantation cardiaque et/ou pulmonaire pédiatrique sont les ultimes recours chez l’enfant ayant une défaillance cardiaque et/ou respiratoire terminale avec échec des traitements conventionnels et risque vital engagé à court terme. Actuellement, l’assistance circulatoire est utilisée en attente de récupération ou de transplantation mais pas en stratégie à long terme. Le Berlin Heart Excor est le système d’assistance ventriculaire pneumatique externe de longue durée actuellement disponible du nouveau-né jusqu’à l’âge adulte. Le pronostic à long terme après transplantation cardiaque et/ou pulmonaire pédiatrique est conditionné par la survenue d’une défaillance du greffon, par la maladie coronaire du greffon cardiaque, par les infections virales et la bronchiolite oblitérante du greffon pulmonaire, dont les incidences augmentent avec le temps. La pénurie de greffons et le risque de rejet aigu de greffon par défaut de compliance au traitement immunosuppresseur imposent un choix par les équipes spécialisées des candidats à la greffe en fonction de critères psychosociaux et biologiques. Les prochains développements attendus concernent surtout les assistances ventriculaires de longue durée avec des systèmes permettant d’envisager une plus grande autonomie et un retour à domicile de l’enfant.
Les maladies neuro-dégénératives (Friedreich, Duchenne) ou certaines maladies mitochondriales, ainsi que des séquelles graves d'accident vasculaire cérébral, sont considérées comme des contre-indications à la greffe.
L’assistance circulatoire et la transplantation cardiaque et/ou pulmonaire pédiatrique sont les ultimes recours chez l’enfant ayant une défaillance cardiaque et/ou respiratoire terminale avec échec des traitements conventionnels et risque vital engagé à court terme. Actuellement, l’assistance circulatoire est utilisée en attente de récupération ou de transplantation mais pas en stratégie à long terme. Le Berlin Heart Excor est le système d’assistance ventriculaire pneumatique externe de longue durée actuellement disponible du nouveau-né jusqu’à l’âge adulte. Le pronostic à long terme après transplantation cardiaque et/ou pulmonaire pédiatrique est conditionné par la survenue d’une défaillance du greffon, par la maladie coronaire du greffon cardiaque, par les infections virales et la bronchiolite oblitérante du greffon pulmonaire, dont les incidences augmentent avec le temps. La pénurie de greffons et le risque de rejet aigu de greffon par défaut de compliance au traitement immunosuppresseur imposent un choix par les équipes spécialisées des candidats à la greffe en fonction de critères psychosociaux et biologiques. Les prochains développements attendus concernent surtout les assistances ventriculaires de longue durée avec des systèmes permettant d’envisager une plus grande autonomie et un retour à domicile de l’enfant.
Les maladies neuro-dégénératives (Friedreich, Duchenne) ou certaines maladies mitochondriales, ainsi que des séquelles graves d'accident vasculaire cérébral, sont considérées comme des contre-indications à la greffe.
Caractéristiques cliniques ; électrophysiologiques et évolutives des formes atypiques de l’ataxie héréditaire de Friedreich : à propos sept cas
Cyrine Jeridi, Haifa Kharrat, Samia Ben Sassi, Nabli Fatma, Ines Benabdelaziz, Samir Belal, Fayçel Hentati, Revue Neurologique, Volume 174, Supplement 1, April 2018, Page S133, ISSN 0035-3787, doi:10.1016/j.neurol.2018.01.302.
Les formes atypiques de l’ataxie héréditaire de Friedreich (FRDA) représentent les tableaux cliniques qui ne répondent pas aux critères de Harding. Elles sont rares rapportées dans seulement 15 % des cas d’FRDA. L’ataxie de Friedreich avec un âge de début tardif (≥ 25 ans) et/ou des réflexes conservés ou vifs représentent les formes atypiques de la FRDA. Dans ces cas le score SARA est bas et l’amyotrophie, le déficit et les signes extraneurologiques sont rares ce qui concordent avec notre travail. La neuropathie est souvent présente L’évolution est moins sévère et plus lente que la forme typique. Devant un tableau d’ataxie atypique avec un début tardif et des réflexes vifs ou conservés l’ataxie de Freidreich doit être évoquée et une étude génétique doit être envisagée.
Les formes atypiques de l’ataxie héréditaire de Friedreich (FRDA) représentent les tableaux cliniques qui ne répondent pas aux critères de Harding. Elles sont rares rapportées dans seulement 15 % des cas d’FRDA. L’ataxie de Friedreich avec un âge de début tardif (≥ 25 ans) et/ou des réflexes conservés ou vifs représentent les formes atypiques de la FRDA. Dans ces cas le score SARA est bas et l’amyotrophie, le déficit et les signes extraneurologiques sont rares ce qui concordent avec notre travail. La neuropathie est souvent présente L’évolution est moins sévère et plus lente que la forme typique. Devant un tableau d’ataxie atypique avec un début tardif et des réflexes vifs ou conservés l’ataxie de Freidreich doit être évoquée et une étude génétique doit être envisagée.
L’accumulation intracérébrale de fer, un aspect IRM atypique de l’ataxie de Friedreich
Thomas Wirth, Marie-Céline Fleury, Odile Gebus, Jean Louis Dietemann, Christine Tranchant, Stéphane Kremer, Mathieu Anheim, Revue Neurologique, Volume 174, Supplement 1, April 2018, Page S129, ISSN 0035-3787, doi:10.1016/j.neurol.2018.01.293
L’AF devrait systématiquement être envisagée devant un syndrome cérébelleux lentement progressif même chez les sujets âgés et même en l’absence d’antécédent familial en cas de dépôt de fer au niveau du cervelet ou des noyaux gris centraux à l’IRM.
L’AF devrait systématiquement être envisagée devant un syndrome cérébelleux lentement progressif même chez les sujets âgés et même en l’absence d’antécédent familial en cas de dépôt de fer au niveau du cervelet ou des noyaux gris centraux à l’IRM.
L’atteinte du système nerveux périphérique au cours des ataxies cérébelleuses héréditaires autosomiques récessives (ACAR) : étude de 33 cas
Ferdaous Kharrat, Olfa Hdiji, Nouha Bouzidi, Salma Sakka, Hanen Haj Kacem, Mariem Dammak, Chokri Mhiri, Revue Neurologique, Volume 174, Supplement 1, April 2018, Page S68, ISSN 0035-3787, doi:10.1016/j.neurol.2018.01.154.
L’ENMG a montré une atteinte neurogène périphérique chez 28 patients. Les patients avec un PF (23 patients) correspondaient à 7 cas de maladie de Friedreich, 13 AVED, et 3 AOA2. L’atteinte dans ce groupe était sensitive pure dans 13 cas. Elle est de type sensitivomotrice axonale chez tous les patients avec AOA2. La majorité des patients ayant un PNF (ataxie spastique de type ARSACS, SPG11, SPG46 ; ou une AOA, avaient une atteinte sensitivomotrice axonale.
L’ENMG a montré une atteinte neurogène périphérique chez 28 patients. Les patients avec un PF (23 patients) correspondaient à 7 cas de maladie de Friedreich, 13 AVED, et 3 AOA2. L’atteinte dans ce groupe était sensitive pure dans 13 cas. Elle est de type sensitivomotrice axonale chez tous les patients avec AOA2. La majorité des patients ayant un PNF (ataxie spastique de type ARSACS, SPG11, SPG46 ; ou une AOA, avaient une atteinte sensitivomotrice axonale.
Étude de la population réunionnaise atteinte d’ataxie de Friedreich
Elisa De La Cruz, Claude Mignard, Médéric Descoins, Ariane Choumert, Revue Neurologique, Volume 174, Supplement 1, April 2018, Page S44, ISSN 0035-3787, doi:10.1016/j.neurol.2018.01.101.
La Réunion possède un cluster d’ataxie de Friedreich à faible nombre de répétition GAA, dont les caractéristiques peuvent rappeler les formes acadiennes, qui sont également le résultat d’un effet fondateur.
La Réunion possède un cluster d’ataxie de Friedreich à faible nombre de répétition GAA, dont les caractéristiques peuvent rappeler les formes acadiennes, qui sont également le résultat d’un effet fondateur.
Mitofusin-Dependent ER Stress Triggers Glial Dysfunction and Nervous System Degeneration in a Drosophila Model of Friedreich’s Ataxia
Edenharter O, Schneuwly S and Navarro JA (2018); Front. Mol. Neurosci. 11:38. doi: 10.3389/fnmol.2018.00038
We have demonstrated that Marf downregulation rescues the locomotion and the accumulation of lipid droplets triggered by targeted frataxin depletion in glia along with nervous system degeneration. The analysis of the mechanism underlying such recovery has allowed us to underscore that alterations in the ER biology are pivotal in the neurodegeneration in FRDA. Our results suggest that Marf and ER stress represent a hub in the neurodegenerative process of FRDA and uncover both as important elements substantially involved the FRDA pathology.
We have demonstrated that Marf downregulation rescues the locomotion and the accumulation of lipid droplets triggered by targeted frataxin depletion in glia along with nervous system degeneration. The analysis of the mechanism underlying such recovery has allowed us to underscore that alterations in the ER biology are pivotal in the neurodegeneration in FRDA. Our results suggest that Marf and ER stress represent a hub in the neurodegenerative process of FRDA and uncover both as important elements substantially involved the FRDA pathology.
Identification of p38 MAPK as a novel therapeutic target for Friedreich’s ataxia
M. Grazia Cotticelli, Shujuan Xia, Avinash Kaur, Daniel Lin, Yongping Wang, Eric Ruff, John W. Tobias & Robert B. Wilson; Scientific Reports volume 8, Article number: 5007 (2018) doi:10.1038/s41598-018-23168-x
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. The gene-expression profile induced by gFA11 is remarkably similar to the gene-expression profile induced by the p38 MAPK inhibitor SB203580. We found that p38 phosphorylation, indicating activation of the p38 pathway, is higher in FRDA cells than in normal control cells, and that siRNA knockdown of frataxin in normal fibroblasts also increases p38 phosphorylation. Treatment of FRDA cells with p38 inhibitors recapitulates the reversal of the slow-growth phenotype induced by clone gFA11. These data highlight the involvement of the p38 MAPK pathway in the pathogenesis of FRDA and the potential use of p38 inhibitors as a treatment for FRDA.
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. The gene-expression profile induced by gFA11 is remarkably similar to the gene-expression profile induced by the p38 MAPK inhibitor SB203580. We found that p38 phosphorylation, indicating activation of the p38 pathway, is higher in FRDA cells than in normal control cells, and that siRNA knockdown of frataxin in normal fibroblasts also increases p38 phosphorylation. Treatment of FRDA cells with p38 inhibitors recapitulates the reversal of the slow-growth phenotype induced by clone gFA11. These data highlight the involvement of the p38 MAPK pathway in the pathogenesis of FRDA and the potential use of p38 inhibitors as a treatment for FRDA.
Saturday, March 24, 2018
Mutations in PMPCB Encoding the Catalytic Subunit of the Mitochondrial Presequence Protease Cause Neurodegeneration in Early Childhood
F.-Nora Vögtle1, Björn Brändl, Austin Larson, Manuela Pendziwiat, Marisa W. Friederich, Susan M. White, Alice Basinger, Cansu Kücükköse, Hiltrud Muhle, Johanna A. Jähn, Oliver Keminer, Katherine L. Helbig, Carolyn F. Delto, Lisa Myketin, Dirk Mossmann, Nils Burger, Noriko Miyake, Audrey Burnett, Andreas van Baalen, Mark A. Lovell, Naomichi Matsumoto, Maie Walsh, Hung-Chun Yu19, Deepali N. Shinde, Ulrich Stephani, Johan L.K. Van Hove, Franz-Josef Müller, Ingo Helbig; The American Journal of Human Genetics , Volume 0 , Issue 0, n Press Corrected Proof DOI:10.1016/j.ajhg.2018.02.014
The biological pathways that MPP is involved in are closely related to the more common neurological disease Friedreich’s ataxia, which is also actively studied by researchers at CHOP. In fact, frataxin, the protein altered in Friedreich’s ataxia, is one of the main targets of MPP. The conditions however, are very different, and the PMPCB-related disorders identified by Helbig and his collaborators are more severe than Friedreich’s ataxia.
Mitochondria isolated from two fibroblast cell lines and induced pluripotent stem cells derived from one affected individual and differentiated neuroepithelial stem cells showed reduced PMPCB levels and accumulation of the processing intermediate of frataxin, a sensitive substrate for MPP dysfunction. We conclude that biallelic mutations in PMPCB cause defects in MPP proteolytic activity leading to dysregulation of iron-sulfur cluster biogenesis and triggering a complex neurological phenotype of neurodegeneration in early childhood.
The biological pathways that MPP is involved in are closely related to the more common neurological disease Friedreich’s ataxia, which is also actively studied by researchers at CHOP. In fact, frataxin, the protein altered in Friedreich’s ataxia, is one of the main targets of MPP. The conditions however, are very different, and the PMPCB-related disorders identified by Helbig and his collaborators are more severe than Friedreich’s ataxia.
Mitochondria isolated from two fibroblast cell lines and induced pluripotent stem cells derived from one affected individual and differentiated neuroepithelial stem cells showed reduced PMPCB levels and accumulation of the processing intermediate of frataxin, a sensitive substrate for MPP dysfunction. We conclude that biallelic mutations in PMPCB cause defects in MPP proteolytic activity leading to dysregulation of iron-sulfur cluster biogenesis and triggering a complex neurological phenotype of neurodegeneration in early childhood.
Iron regulatory protein deficiency compromises mitochondrial function in murine embryonic fibroblasts
Huihui Li, Hongting Zhao, Shuangying Hao, Longcheng Shang, Jing Wu, Chuanhui Song, Esther G. Meyron-Holtz, Tong Qiao & Kuanyu Li; Scientific Reportsvolume 8, Article number: 5118 (2018) doi:10.1038/s41598-018-23175-y
Overexpression of human ISCU and frataxin in Irp1 or Irp2-null cells was able to rescue the defects in iron-sulfur cluster biogenesis and mitochondrial quality.
Overexpression of human ISCU and frataxin in Irp1 or Irp2-null cells was able to rescue the defects in iron-sulfur cluster biogenesis and mitochondrial quality.
Tuesday, March 20, 2018
Frataxin overexpression in Müller cells protects retinal ganglion cells in a mouse model of ischemia/reperfusion injury in vivo
Rowena Schultz, Melanie Krug, Michel Precht, Stefanie G. Wohl, Otto W. Witte & Christian Schmeer; Scientific Reports, volume 8, Article number: 4846 (2018) doi:10.1038/s41598-018-22887-5
Müller cells are critical for retinal function and neuronal survival but can become detrimental in response to retinal ischemia and increased oxidative stress. Elevated oxidative stress increases expression of the mitochondrial enzyme frataxin in the retina, and its overexpression is neuroprotective after ischemia. Whether frataxin expression in Müller cells might improve their function and protect neurons after ischemia is unknown. The aim of this study was to evaluate the effect of frataxin overexpression in Müller cells on neuronal survival after retinal ischemia/reperfusion in the mouse in vivo.
Müller cells are critical for retinal function and neuronal survival but can become detrimental in response to retinal ischemia and increased oxidative stress. Elevated oxidative stress increases expression of the mitochondrial enzyme frataxin in the retina, and its overexpression is neuroprotective after ischemia. Whether frataxin expression in Müller cells might improve their function and protect neurons after ischemia is unknown. The aim of this study was to evaluate the effect of frataxin overexpression in Müller cells on neuronal survival after retinal ischemia/reperfusion in the mouse in vivo.
Monday, March 19, 2018
Genetic Infiltrative Cardiomyopathies
Mary E. Sweet, Luisa Mestroni, Matthew R.G. Taylor, Heart Failure Clinics, Volume 14, Issue 2, April 2018, Pages 215-224, ISSN 1551-7136, doi:10.1016/j.hfc.2017.12.003.
Friedreich ataxia: Cardiomyopathy is the presenting finding in only 5% of patients, cardiac dysfunction from congestive heart failure or arrhythmia accounts for an estimated 59% of death. Cardiac dysfunction includes left ventricular hypertrophy, systolic dysfunction, and diastolic dysfunction.
Friedreich ataxia: Cardiomyopathy is the presenting finding in only 5% of patients, cardiac dysfunction from congestive heart failure or arrhythmia accounts for an estimated 59% of death. Cardiac dysfunction includes left ventricular hypertrophy, systolic dysfunction, and diastolic dysfunction.
Sunday, March 18, 2018
Resting-state connectivity in neurodegenerative disorders: Is there potential for an imaging biomarker?
Christian Hohenfeld, Cornelius J. Werner, Kathrin Reetz, NeuroImage: Clinical, Available online 16 March 2018, ISSN 2213-1582, doi:10.1016/j.nicl.2018.03.013.
Biomarkers in whichever modality are tremendously important in diagnosing of disease, tracking disease progression and clinical trials. This applies in particular for disorders with a long disease course including pre-symptomatic stages, in which only subtle signs of clinical progression can be observed. Magnetic resonance imaging (MRI) biomarkers hold particular promise due to their relative ease of use, cost-effectiveness and non-invasivity. Studies measuring resting-state functional MR connectivity have become increasingly common during recent years and are well established in neuroscience and related fields. Its increasing application does of course also include clinical settings and therein neurodegenerative diseases. In the present review, we critically summarise the state of the literature on resting-state functional connectivity as measured with functional MRI in neurodegenerative disorders. In addition to an overview of the results, we briefly outline the methods applied to the concept of resting-state functional connectivity.
While there are many different neurodegenerative disorders cumulatively affecting a substantial number of patients, for most of the studies on resting-state fMRI is lacking. Plentiful amounts of papers are available for Alzheimer's disease (AD) and Parkinson's disease (PD), but only few works being available for the less common neurodegenerative diseases. This allows some conclusions on the potential of resting-state fMRI acting as a biomarker for the aforementioned two diseases, but only tentative statements for the others.
For rare neurodegenerative diseases, no clear conclusions can be drawn due to the few published results. Nevertheless, summarising available data points towards characteristic connectivity alterations in Huntington's disease, frontotemporal dementia, dementia with Lewy bodies, multiple systems atrophy Friedreich ataxia and the spinocerebellar ataxias.
Biomarkers in whichever modality are tremendously important in diagnosing of disease, tracking disease progression and clinical trials. This applies in particular for disorders with a long disease course including pre-symptomatic stages, in which only subtle signs of clinical progression can be observed. Magnetic resonance imaging (MRI) biomarkers hold particular promise due to their relative ease of use, cost-effectiveness and non-invasivity. Studies measuring resting-state functional MR connectivity have become increasingly common during recent years and are well established in neuroscience and related fields. Its increasing application does of course also include clinical settings and therein neurodegenerative diseases. In the present review, we critically summarise the state of the literature on resting-state functional connectivity as measured with functional MRI in neurodegenerative disorders. In addition to an overview of the results, we briefly outline the methods applied to the concept of resting-state functional connectivity.
While there are many different neurodegenerative disorders cumulatively affecting a substantial number of patients, for most of the studies on resting-state fMRI is lacking. Plentiful amounts of papers are available for Alzheimer's disease (AD) and Parkinson's disease (PD), but only few works being available for the less common neurodegenerative diseases. This allows some conclusions on the potential of resting-state fMRI acting as a biomarker for the aforementioned two diseases, but only tentative statements for the others.
For rare neurodegenerative diseases, no clear conclusions can be drawn due to the few published results. Nevertheless, summarising available data points towards characteristic connectivity alterations in Huntington's disease, frontotemporal dementia, dementia with Lewy bodies, multiple systems atrophy Friedreich ataxia and the spinocerebellar ataxias.
Optical coherence tomography in autosomal recessive spastic ataxia of Charlevoix-Saguenay
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; Brain, , awy028, doi:10.1093/brain/awy028
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. The patients included 146 with a genetic diagnosis of ataxia (17 autosomal spastic ataxia of Charlevoix-Saguenay, 59 Friedreich’s ataxia, 53 spinocerebellar ataxias, 17 other genetically confirmed ataxias) and 45 with cerebellar ataxia of unknown cause. The controls included 13 asymptomatic heterozygotes for SACS mutations and 88 unaffected controls. The cases with autosomal recessive spastic ataxia of Charlevoix-Saguenay included 11 previously unpublished SACS mutations, of which seven were nonsense and four missense mutations. Most patients were visually asymptomatic and had no previous history of ophthalmic complaints and normal or near normal visual test results. None had visual symptoms directly attributable to the retinal changes. Twelve of the 17 cases (70.6%) had thickened retinal nerve fibres visible on fundoscopy. All patients with autosomal recessive spastic ataxia of Charlevoix-Saguenay had thickening of the peripapillary retinal nerve fibre layer on optical coherence tomography, whereas all the remaining cases and controls except one showed normal or reduced average peripapillary retinal nerve fibre layer thickness on optical coherence tomography. We propose a cut-off value of 119 µm in average peripapillary retinal nerve fibre layer thickness, which provides a sensitivity of 100% and specificity of 99.4% amongst patients affected with ataxia. This is the largest cohort of patients with this condition to undergo systematic evaluation by optical coherence tomography. This is a useful tool in identifying cases of autosomal recessive spastic ataxia of Charlevoix-Saguenay from other causes of ataxia. Visualization of thickened retinal fibres by direct fundoscopy is less sensitive. We therefore advocate the use of this technique in the assessment of possible cases of this condition.
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. The patients included 146 with a genetic diagnosis of ataxia (17 autosomal spastic ataxia of Charlevoix-Saguenay, 59 Friedreich’s ataxia, 53 spinocerebellar ataxias, 17 other genetically confirmed ataxias) and 45 with cerebellar ataxia of unknown cause. The controls included 13 asymptomatic heterozygotes for SACS mutations and 88 unaffected controls. The cases with autosomal recessive spastic ataxia of Charlevoix-Saguenay included 11 previously unpublished SACS mutations, of which seven were nonsense and four missense mutations. Most patients were visually asymptomatic and had no previous history of ophthalmic complaints and normal or near normal visual test results. None had visual symptoms directly attributable to the retinal changes. Twelve of the 17 cases (70.6%) had thickened retinal nerve fibres visible on fundoscopy. All patients with autosomal recessive spastic ataxia of Charlevoix-Saguenay had thickening of the peripapillary retinal nerve fibre layer on optical coherence tomography, whereas all the remaining cases and controls except one showed normal or reduced average peripapillary retinal nerve fibre layer thickness on optical coherence tomography. We propose a cut-off value of 119 µm in average peripapillary retinal nerve fibre layer thickness, which provides a sensitivity of 100% and specificity of 99.4% amongst patients affected with ataxia. This is the largest cohort of patients with this condition to undergo systematic evaluation by optical coherence tomography. This is a useful tool in identifying cases of autosomal recessive spastic ataxia of Charlevoix-Saguenay from other causes of ataxia. Visualization of thickened retinal fibres by direct fundoscopy is less sensitive. We therefore advocate the use of this technique in the assessment of possible cases of this condition.
Saturday, March 17, 2018
Distinct effects of frataxin missence point mutations on mitochondrial localization, protein processing, and cellular metabolism
Clark, Elisia M., University of Pennsylvania, Philadelphia, PA, United States
National Institute of Health (NIH), National Institute of Neurological Disorders and Stroke (NINDS)
Type: Predoctoral Individual National Research Service Award.
Although the function of frataxin (FXN) remains unclear, it is a mitochondrial protein imperative for proper mitochondria function. Friedreich's ataxia patients who carry missense point mutations in FXN display phenotypic variability that is mutation selective for unclear reasons. These studies will examine the mechanism by which FRDA-associated missense mutations impair FXN processing and explore the influence they have on cellular metabolism, in addition to exploring the use of fatty acids as a potential therapeutic strategy.
National Institute of Health (NIH), National Institute of Neurological Disorders and Stroke (NINDS)
Type: Predoctoral Individual National Research Service Award.
Although the function of frataxin (FXN) remains unclear, it is a mitochondrial protein imperative for proper mitochondria function. Friedreich's ataxia patients who carry missense point mutations in FXN display phenotypic variability that is mutation selective for unclear reasons. These studies will examine the mechanism by which FRDA-associated missense mutations impair FXN processing and explore the influence they have on cellular metabolism, in addition to exploring the use of fatty acids as a potential therapeutic strategy.
Interactions of iron-bound frataxin with ISCU and ferredoxin on the cysteine desulfurase complex leading to Fe-S cluster assembly
ai Cai, Ronnie O. Frederick, Marco Tonelli, John L. Markley, Journal of Inorganic Biochemistry, Available online 15 March 2018, ISSN 0162-0134, doi:10.1016/j.jinorgbio.2018.03.007.
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+. While FXN (with or without bound Fe2+) does not bind the scaffold protein ISCU directly, the two proteins interact mutually when each is bound to the cysteine desulfurase complex ([NFS1]2:[ISD11]2:[Acp]2), abbreviated as (NIA)2, where “N” represents the cysteine desulfurase (NFS1), “I” represents the accessory protein (ISD11), and “A” represents acyl carrier protein (Acp). FXN binds (NIA)2 weakly in the absence of ISCU but more strongly in its presence. Fe2+-FXN binds to the (NIA)2-ISCU2 complex without release of iron. However, upon the addition of both l-cysteine and a reductant (either reduced FDX2 or DTT), Fe2+ is released from FXN as consistent with Fe2+-FXN being the proximal source of iron for Fe-S cluster assembly.
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+. While FXN (with or without bound Fe2+) does not bind the scaffold protein ISCU directly, the two proteins interact mutually when each is bound to the cysteine desulfurase complex ([NFS1]2:[ISD11]2:[Acp]2), abbreviated as (NIA)2, where “N” represents the cysteine desulfurase (NFS1), “I” represents the accessory protein (ISD11), and “A” represents acyl carrier protein (Acp). FXN binds (NIA)2 weakly in the absence of ISCU but more strongly in its presence. Fe2+-FXN binds to the (NIA)2-ISCU2 complex without release of iron. However, upon the addition of both l-cysteine and a reductant (either reduced FDX2 or DTT), Fe2+ is released from FXN as consistent with Fe2+-FXN being the proximal source of iron for Fe-S cluster assembly.
Thursday, March 15, 2018
Biomarcadores epigenéticos: hacia su implantación en la rutina clínica / Epigenetic biomarkers: towards their incorporation into clinical routine
José Luis García-Giménez, Gisselle Pérez-Machado, Jesús Beltrán-García, Eva García-López, Ester Berenguer-Pascual, Carlos Romá-Mateo, Federico Pallaró, Salvador Mena-Mollá; GENÉTICA MÉDICA · 14 de marzo de 2018 Núm.00 Vol.0 Genética Médica y Genómica revistageneticamedica.com
La práctica clínica requiere de nuevas técnicas que permitan la identificación de los individuos en riesgo de desarrollar una enfermedad mediante su detección eficaz y precoz, pero la clínica también necesita de herramientas que permitan predecir la evolución de la patología a lo largo del tiempo, así como su respuesta frente a un tratamiento. En la actualidad, los principales indicadores clínicos se basan en técnicas de imagen y ciertos biomarcadores que presentan limitaciones y que, en algunos casos, los biomarcadores epigenéticos han demostrado superar.
La comprensión de los mecanismos epigenéticos (metilación del ADN, modulación de las modificaciones postraduccionales de las histonas, y los ARN no codificantes) ha permitido que en las últimas décadas aparezcan multitud de nuevos candidatos para su uso como biomarcadores de diagnóstico y pronóstico de las enfermedades. Por eso, en esta revisión describimos los fundamentos de algunos biomarcadores epigenéticos y algunas técnicas y tecnologías que se están utilizando para su detección.
En un futuro cercano, este tipo de tecnologías se incorporarán a los laboratorios clínicos y, por lo tanto, el uso de estos biomarcadores se implementará en la rutina de diagnóstico clínico, contribuyendo así a la aplicación real de la teragnosis y mejorando la medicina de precisión.
EN
Epigenetic biomarkers: towards their incorporation into clinical routine
Clinical routine requires novel techniques in order to guarantee the identification of individuals in risk of developing a disease, in terms of an efficient and early detection; however, clinical management also needs tools that permit prediction of the long-term pathological evolution, as well as its response to any particular treatment. Currently, the main clinical indicators are based in imaging techniques and certain biomarkers, which show several limitations that, to some extent, biomarkers of an epigenetic nature have shown to overcome.
Comprehension of epigenetic mechanisms (i.e. DNA methylation, modulation of posttranslational histone modifications, and non-coding RNAs) has provided the apparition, in the last decades, of multiple new candidates for their use as diagnostic and prognostic biomarkers. Thus, in this review we describe some epigenetic biomarkers and several techniques and technologies which are being used for their detection.
In the near future, this type of technologies will be incorporated into clinical laboratories and, hence, the use of these biomarkers will be implemented into clinical diagnostic routine, contributing to the real application of theragnosis and improving precision medicine.
La práctica clínica requiere de nuevas técnicas que permitan la identificación de los individuos en riesgo de desarrollar una enfermedad mediante su detección eficaz y precoz, pero la clínica también necesita de herramientas que permitan predecir la evolución de la patología a lo largo del tiempo, así como su respuesta frente a un tratamiento. En la actualidad, los principales indicadores clínicos se basan en técnicas de imagen y ciertos biomarcadores que presentan limitaciones y que, en algunos casos, los biomarcadores epigenéticos han demostrado superar.
La comprensión de los mecanismos epigenéticos (metilación del ADN, modulación de las modificaciones postraduccionales de las histonas, y los ARN no codificantes) ha permitido que en las últimas décadas aparezcan multitud de nuevos candidatos para su uso como biomarcadores de diagnóstico y pronóstico de las enfermedades. Por eso, en esta revisión describimos los fundamentos de algunos biomarcadores epigenéticos y algunas técnicas y tecnologías que se están utilizando para su detección.
En un futuro cercano, este tipo de tecnologías se incorporarán a los laboratorios clínicos y, por lo tanto, el uso de estos biomarcadores se implementará en la rutina de diagnóstico clínico, contribuyendo así a la aplicación real de la teragnosis y mejorando la medicina de precisión.
EN
Epigenetic biomarkers: towards their incorporation into clinical routine
Clinical routine requires novel techniques in order to guarantee the identification of individuals in risk of developing a disease, in terms of an efficient and early detection; however, clinical management also needs tools that permit prediction of the long-term pathological evolution, as well as its response to any particular treatment. Currently, the main clinical indicators are based in imaging techniques and certain biomarkers, which show several limitations that, to some extent, biomarkers of an epigenetic nature have shown to overcome.
Comprehension of epigenetic mechanisms (i.e. DNA methylation, modulation of posttranslational histone modifications, and non-coding RNAs) has provided the apparition, in the last decades, of multiple new candidates for their use as diagnostic and prognostic biomarkers. Thus, in this review we describe some epigenetic biomarkers and several techniques and technologies which are being used for their detection.
In the near future, this type of technologies will be incorporated into clinical laboratories and, hence, the use of these biomarkers will be implemented into clinical diagnostic routine, contributing to the real application of theragnosis and improving precision medicine.
Wednesday, March 14, 2018
Large-scale computational drug repositioning to find treatments for rare diseases
Rajiv Gandhi Govindaraj, Misagh Naderi, Manali Singha, Jeffrey Lemoine & Michal Brylinski. npj Systems Biology and Applications 4, Article number: 13 (2018) doi:10.1038/s41540-018-0050-7
Computer-aided drug repositioning, i.e., finding new indications for existing drugs, is a cheaper and faster alternative to traditional drug discovery offering a promising venue for orphan drug research. Structure-based matching of drug-binding pockets is among the most promising computational techniques to inform drug repositioning. In order to find new targets for known drugs ultimately leading to drug repositioning, we recently developed eMatchSite, a new computer program to compare drug-binding sites. In this study, eMatchSite is combined with virtual screening to systematically explore opportunities to reposition known drugs to proteins associated with rare diseases.
Computer-aided drug repositioning, i.e., finding new indications for existing drugs, is a cheaper and faster alternative to traditional drug discovery offering a promising venue for orphan drug research. Structure-based matching of drug-binding pockets is among the most promising computational techniques to inform drug repositioning. In order to find new targets for known drugs ultimately leading to drug repositioning, we recently developed eMatchSite, a new computer program to compare drug-binding sites. In this study, eMatchSite is combined with virtual screening to systematically explore opportunities to reposition known drugs to proteins associated with rare diseases.
Genetic testing for clinically suspected spinocerebellar ataxias: report from a tertiary referral centre in India
Sowmya Devatha Venkatesh, Mahesh Kandasamy, Nagaraj S. Moily, Radhika Vaidyanathan, Lakshmi Narayanan Kota, Syama Adhikarla, Ravi Yadav, Pramod Kumar Pal, Sanjeev Jain, Meera Purushottam. J Genet (2018). doi:10.1007/s12041-018-0911-2
The prevalence of the syndromes of SCA varies across the world and is known to be linked to the instability of trinucleotide repeats within the high-end normal alleles, along with susceptible haplotype. We estimated sizes of the CAG or GAA repeat expansions at the SCA1, SCA2, SCA3, SCA12 and frataxin loci among 864 referrals of subjects to genetic counselling and testing (GCAT) clinic, National Institute of Mental Health and Neurosciences, Bengaluru, India, with suspected SCA. The most frequent mutations detected were SCA1 (n=100 (11.6%)) and SCA2 (n=98 (11.3%)) followed by SCA3 (n=40 (4.6%)), FRDA (n=20 (2.3%)) and SCA12 (n=8 (0.9%)).
The prevalence of the syndromes of SCA varies across the world and is known to be linked to the instability of trinucleotide repeats within the high-end normal alleles, along with susceptible haplotype. We estimated sizes of the CAG or GAA repeat expansions at the SCA1, SCA2, SCA3, SCA12 and frataxin loci among 864 referrals of subjects to genetic counselling and testing (GCAT) clinic, National Institute of Mental Health and Neurosciences, Bengaluru, India, with suspected SCA. The most frequent mutations detected were SCA1 (n=100 (11.6%)) and SCA2 (n=98 (11.3%)) followed by SCA3 (n=40 (4.6%)), FRDA (n=20 (2.3%)) and SCA12 (n=8 (0.9%)).
Tuesday, March 13, 2018
Bone marrow transplantation stimulates neural repair in Friedreich's ataxia mice
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 and Alastair Wilkins; Annals of Neurology, Accepted manuscript online: 13 MAR 2018 DOI: 10.1002/ana.25207
Our data provide proof-of-concept of gene replacement therapy, via allogeneic bone marrow transplantation, that reverses neurological features of Friedreich's ataxia with the potential for rapid clinical translation.
Our data provide proof-of-concept of gene replacement therapy, via allogeneic bone marrow transplantation, that reverses neurological features of Friedreich's ataxia with the potential for rapid clinical translation.
Sunday, March 11, 2018
New Insights into the Role of Neuron-Specific Enolase in Neuro-Inflammation, Neurodegeneration, and Neuroprotection.
Haque A, Polcyn R, Matzelle D, Banik NL. Brain Sci. 2018 Feb;8(2) . doi:10.3390/brainsci8020033. PMID: 29463007; PMCID: PMC5836052.
Elevated NSE is thought to be a marker of oxidative damage and is the underlying parameter of several neurodegenerative disorders, including Huntington disease (HD), Friedreich ataxia, hereditary spastic paraplegia, rare familial forms Parkinson disease (PD), Alzheimer disease (AD), and amyotrophic lateral sclerosis (ALS).
Regulation of NSE via Cat X or other avenues may be important therapeutic strategies for prevention of inflammation and neurodegeneration in SCI and many other neurodegenerative diseases. Future studies should focus on the regulation of NSE for optimum attenuation of neuro-inflammation and promotion of neuroprotection in neurodegenerative conditions.
Elevated NSE is thought to be a marker of oxidative damage and is the underlying parameter of several neurodegenerative disorders, including Huntington disease (HD), Friedreich ataxia, hereditary spastic paraplegia, rare familial forms Parkinson disease (PD), Alzheimer disease (AD), and amyotrophic lateral sclerosis (ALS).
Regulation of NSE via Cat X or other avenues may be important therapeutic strategies for prevention of inflammation and neurodegeneration in SCI and many other neurodegenerative diseases. Future studies should focus on the regulation of NSE for optimum attenuation of neuro-inflammation and promotion of neuroprotection in neurodegenerative conditions.
Saturday, March 10, 2018
Pitfalls in molecular diagnosis of Friedreich ataxia
Giulia Barcia, Myriam Rachid, Maryse Magen, Zahra Assouline, Michel Koenig, Benoit Funalot, Christine Barnerias, Agnès Rötig, Arnold Munnich, Jean-Paul Bonnefont, Julie Steffann, European Journal of Medical Genetics, Available online 9 March 2018, ISSN 1769-7212, doi:10.1016/j.ejmg.2018.03.004.
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. Due to this deletion TP-PCR failed to amplify the GAA expansion. This exceptional configuration induced misinterpretation of the molecular defect in this patient, who was first reported as having no FXN expansion. NGS analysis of a panel of 212 genes involved in nuclear mitochondrial disorders further revealed an intragenic deletion encompassing exons 4–5 of the FXN gene. Modified TP-PCR analysis confirmed the presence of a classical (GAA)n expansion located in trans. This case points out the possible pitfalls in molecular diagnosis of FRDA in affected patients and their relatives: detection of the FXN expansion may be impaired by several non-pathological or pathological variants around the FXN (GAA)n repeat. We propose a new molecular strategy to accurately detect expansion by TP-PCR in FRDA patients.
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. Due to this deletion TP-PCR failed to amplify the GAA expansion. This exceptional configuration induced misinterpretation of the molecular defect in this patient, who was first reported as having no FXN expansion. NGS analysis of a panel of 212 genes involved in nuclear mitochondrial disorders further revealed an intragenic deletion encompassing exons 4–5 of the FXN gene. Modified TP-PCR analysis confirmed the presence of a classical (GAA)n expansion located in trans. This case points out the possible pitfalls in molecular diagnosis of FRDA in affected patients and their relatives: detection of the FXN expansion may be impaired by several non-pathological or pathological variants around the FXN (GAA)n repeat. We propose a new molecular strategy to accurately detect expansion by TP-PCR in FRDA patients.
Friday, March 9, 2018
Molecular genetic testing for hereditary ataxia-What every neurologist should know
Stephanie E. Wallace, Thomas D. Bird Neurology: Clinical Practice Feb 2018, 8 (1) 27-32; DOI: 10.1212/CPJ.0000000000000421
The majority of individuals with hereditary ataxias have nucleotide repeat expansions, pathogenic variants that are not detectable with clinical exome sequencing. Multigene panels that include specific assays to determine nucleotide repeat lengths should be considered first in individuals with hereditary ataxia.
The majority of individuals with hereditary ataxias have nucleotide repeat expansions, pathogenic variants that are not detectable with clinical exome sequencing. Multigene panels that include specific assays to determine nucleotide repeat lengths should be considered first in individuals with hereditary ataxia.
Thursday, March 8, 2018
In the Clinic-Cerebellar Ataxia: How to Treat Cerebellar Ataxia — What the AAN Evidence-Based Guideline Suggests
Samson, Kurt. Neurology Today: March 8, 2018 - Volume 18 - Issue 5 - p 34–36 doi: 10.1097/01.NT.0000531206.29854.dd
A systematic review of studies on cerebellar motor dysfunction and ataxia revealed a dearth of good evidence for therapies. In part, the author panel found that the heterogeneous nature of the disorders that comprise cerebellar ataxia make it difficult to study.
A systematic review of studies on cerebellar motor dysfunction and ataxia revealed a dearth of good evidence for therapies. In part, the author panel found that the heterogeneous nature of the disorders that comprise cerebellar ataxia make it difficult to study.
Channelopathies influence on neurotransmitters monitorable by real time in situ voltammetry, a review and research proposal
Crespi F (2018). Med Clin Arch 2: DOI: 10.15761/MCA.1000128
It has been observed that 5-hydroxytryptophan, serotonin precursor, is more effective than placebo improving neurological symptoms in patients with Friedreich ataxia (FA). FA is an autosomal recessive genetic illness responsible for progressive damage to the nervous system in the spinal cord, in particular of sensory neurons basal for leading muscle motion of the arms and legs via link with the cerebellum.
It has been observed that 5-hydroxytryptophan, serotonin precursor, is more effective than placebo improving neurological symptoms in patients with Friedreich ataxia (FA). FA is an autosomal recessive genetic illness responsible for progressive damage to the nervous system in the spinal cord, in particular of sensory neurons basal for leading muscle motion of the arms and legs via link with the cerebellum.
Iron–sulfur clusters: from metals through mitochondria biogenesis to disease
Cardenas-Rodriguez, M., Chatzi, A. & Tokatlidis, K. J Biol Inorg Chem (2018). doi:10.1007/s00775-018-1548-6
Frataxin is involved in Fe–S clusters biogenesis. Thus, alterations linked to iron metabolism are present in FRDA. The pathophysiology of FRDA comprises deficit of aconitase and respiratory chain complexes, presence of oxidative damage markers in blood and urine, and intracellular iron accumulation [82, 84, 85, 86]. Currently, no successful treatment is available for FRDA. One main reason for this is the lack of understood detailed understanding of mechanisms of Fe–S cluster biogenesis and appropriate disease models.
Frataxin is involved in Fe–S clusters biogenesis. Thus, alterations linked to iron metabolism are present in FRDA. The pathophysiology of FRDA comprises deficit of aconitase and respiratory chain complexes, presence of oxidative damage markers in blood and urine, and intracellular iron accumulation [82, 84, 85, 86]. Currently, no successful treatment is available for FRDA. One main reason for this is the lack of understood detailed understanding of mechanisms of Fe–S cluster biogenesis and appropriate disease models.
Friedreich Ataxia Scientific News: Monthly update: February 7- March 8, 2018
Friedreich Ataxia Scientific News
Monthly update: February 7- March 8, 2018
Thursday, March 8, 2018
Small RNA-seq analysis of
circulating miRNAs to identify phenotypic variability in Friedreich’s ataxia
patients
Friday, March 2, 2018
Neuroimagem na ataxia de Friedreich
= novas abordagens e aplicações clínicas = Neuroimaging in Friedreich's ataxia
= new approaches and clinical aplication
Thursday, March 1, 2018
Tuesday, February 27, 2018
Monday, February 26, 2018
Friday, February 23, 2018
Thursday, February 22, 2018
Wednesday, February 21, 2018
Tuesday, February 20, 2018
Meet Our Scientists. Ernest Giralt:
"There are many diseases caused by failures in the protein-protein
interactions”
Friday, February 16, 2018
Thursday, February 15, 2018
Comprehensive systematic review
summary: Treatment of cerebellar motor dysfunction and ataxia Report of the
Guideline Development, Dissemination, and Implementation Subcommittee of the
American Academy of Neurology
Tuesday, February 13, 2018
Restless
legs syndrome and periodic leg movements in patients with movement disorders:
Specific considerations
Wednesday, February 7, 2018
Small RNA-seq analysis of circulating miRNAs to identify phenotypic variability in Friedreich’s ataxia patients
Marta Seco-Cervera, Dayme González-Rodríguez, José Santiago Ibáñez-Cabellos, Lorena Peiró-Chova, Federico V Pallardó & José Luis García-Giménez; Sci. Data 5:180021 doi: 10.1038/sdata.2018.21 (2018).
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. Furthermore, we present the rationale, experimental methodology, and analytical procedures for dataset analysis. This dataset will facilitate the identification of miRNA signatures and provide new molecular explanation for pathological mechanisms occurring during the natural history of FRDA. Since miRNA levels change with disease progression and pharmacological interventions, miRNAs will contribute to the design of new therapeutic strategies and will improve clinical decisions.
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. Furthermore, we present the rationale, experimental methodology, and analytical procedures for dataset analysis. This dataset will facilitate the identification of miRNA signatures and provide new molecular explanation for pathological mechanisms occurring during the natural history of FRDA. Since miRNA levels change with disease progression and pharmacological interventions, miRNAs will contribute to the design of new therapeutic strategies and will improve clinical decisions.
Wednesday, March 7, 2018
Therapeutic Potential of NAD-Boosting Molecules: The In Vivo Evidence
Luis Rajman, Karolina Chwalek, David A. Sinclair, Cell Metabolism, Volume 27, Issue 3, 6 March 2018, Pages 529-547, ISSN 1550-4131, doi:10.1016/j.cmet.2018.02.011.
Nicotinamide adenine dinucleotide (NAD), the cell’s hydrogen carrier for redox enzymes, is well known for its role in redox reactions. More recently, it has emerged as a signaling molecule. By modulating NAD+-sensing enzymes, NAD+ controls hundreds of key processes from energy metabolism to cell survival, rising and falling depending on food intake, exercise, and the time of day. NAD+ levels steadily decline with age, resulting in altered metabolism and increased disease susceptibility. Restoration of NAD+ levels in old or diseased animals can promote health and extend lifespan, prompting a search for safe and efficacious NAD-boosting molecules that hold the promise of increasing the body’s resilience, not just to one disease, but to many, thereby extending healthy human lifespan.
Nicotinamide adenine dinucleotide (NAD), the cell’s hydrogen carrier for redox enzymes, is well known for its role in redox reactions. More recently, it has emerged as a signaling molecule. By modulating NAD+-sensing enzymes, NAD+ controls hundreds of key processes from energy metabolism to cell survival, rising and falling depending on food intake, exercise, and the time of day. NAD+ levels steadily decline with age, resulting in altered metabolism and increased disease susceptibility. Restoration of NAD+ levels in old or diseased animals can promote health and extend lifespan, prompting a search for safe and efficacious NAD-boosting molecules that hold the promise of increasing the body’s resilience, not just to one disease, but to many, thereby extending healthy human lifespan.
Friedreich Ataxia: Clinical Report of an Uncommon Point Mutation (R165C)
Rosa María García Tercero*, Javier Gualda Heras, Catalina Diaz Urrea, Pedro Barredo Benitez, Adolfo Heras Pérez, Fátima López González, Blanca serrano Serrano, Elena Elvira Soler and Carmina Díaz Marín; J Neurol Disord 2018, 6:1 DOI:10.4172/2329-6895.1000376
Despite of been inherited as a recessive disease, Friedreich ataxia (FRDA) there is not such clinical homogeneity as in other recessive disorders and due to the atypical presentation of our patient, another sensitives neuropathies were taken into account and a differential diagnosis were made with them (hereditary sensory and autonomic neuropathy, Fabry disease, Familial amyloidotic polyneuropathy, Adrenomyeloneuropathy etc.) but the normality of the probes that have been done and the lack of another symptoms related with these diseases caused that Friedreich ataxia was suspected. With this case we make relevance that not all patients have an early onset, or a severe phenotype and a good neurologic exploration is important to recognize them. Once the diagnosis is made, it is necessary to follow them in consults paying attention to heart problems and giving them genetic counseling.
Despite of been inherited as a recessive disease, Friedreich ataxia (FRDA) there is not such clinical homogeneity as in other recessive disorders and due to the atypical presentation of our patient, another sensitives neuropathies were taken into account and a differential diagnosis were made with them (hereditary sensory and autonomic neuropathy, Fabry disease, Familial amyloidotic polyneuropathy, Adrenomyeloneuropathy etc.) but the normality of the probes that have been done and the lack of another symptoms related with these diseases caused that Friedreich ataxia was suspected. With this case we make relevance that not all patients have an early onset, or a severe phenotype and a good neurologic exploration is important to recognize them. Once the diagnosis is made, it is necessary to follow them in consults paying attention to heart problems and giving them genetic counseling.
Friday, March 2, 2018
Neuroimagem na ataxia de Friedreich = novas abordagens e aplicações clínicas = Neuroimaging in Friedreich's ataxia = new approaches and clinical aplication
Rezende, Thiago Junqueira Ribeiro de; Advisor: França Junior, Marcondes Cavalcante. TESE DIGITAL (2017)(POR)
Abstract: Friedreich¿s ataxia (FRDA) is the most common autosomal-recessive ataxia worldwide; it is characterized by early onset, sensory abnormalities and slowly progressive ataxia. Besides that, most of neuroimaging studies have been focused only in infratentorial structures of adult patients. Furthermore, studies comparing different phenotypes of disease does not exist. Therefore, the objective of this study is to assess, using multimodal magnetic (MRI) resonance imaging, patients with Friedreich ataxia to better comprehend the progression of brain damage, to identify the pattern of damage across disease phenotypes, to identify areas with abnormal iron deposits in the brain and to characterize the structures initially damaged in early disease stages. To accomplish that, we enrolled 25 adult patients with classical FRDA, 13 patients with late-onset FRDA and 12 pediatric patients. The FARS scale was employed to quantify the disease severity. To assess the structural damage in gray and white matter, we acquired T1-weighted, T2-weighted and DTI images of the brain. To evaluate these images, we used the following tools: FreeSurfer, T1 MultiAtlas, SPM, DTI MultiAtlas, SpineSeg and TBSS. After group comparisons, there was widespread microstructural damage in the cerebral white matter, including cerebellar peduncles, corpus callosum and pyramidal tracts of patients with FRDA. We also found gray matter volumetric reduction in the dentate nuclei of the cerebellum, brainstem and motor cortex. We did not find volumetric reduction over time, but there was progressive white matter microstructural damage in the corpus callosum, pyramidal tracts and superior cerebellar peduncles after 1 year of follow-up. Regarding the disease phenotypes, we found that both classical FRDA and LOFA have similar, but not identical neuroimaging signatures. Although subtle, the structural differences might help to explain the phenotypic differences seen in both conditions. The corticospinal tracts are damaged in both conditions, but more severely in the late-onset FRDA group, which may explain why pyramidal signs are more evident in the latter subgroup. We failed to identify iron deposits in brain regions other than the dentate nuclei of patients with FRDA. Finally, we found that the spinal cord and inferior cerebellar peduncles are the structures compromised in pediatric patients with FRDA.
Abstract: Friedreich¿s ataxia (FRDA) is the most common autosomal-recessive ataxia worldwide; it is characterized by early onset, sensory abnormalities and slowly progressive ataxia. Besides that, most of neuroimaging studies have been focused only in infratentorial structures of adult patients. Furthermore, studies comparing different phenotypes of disease does not exist. Therefore, the objective of this study is to assess, using multimodal magnetic (MRI) resonance imaging, patients with Friedreich ataxia to better comprehend the progression of brain damage, to identify the pattern of damage across disease phenotypes, to identify areas with abnormal iron deposits in the brain and to characterize the structures initially damaged in early disease stages. To accomplish that, we enrolled 25 adult patients with classical FRDA, 13 patients with late-onset FRDA and 12 pediatric patients. The FARS scale was employed to quantify the disease severity. To assess the structural damage in gray and white matter, we acquired T1-weighted, T2-weighted and DTI images of the brain. To evaluate these images, we used the following tools: FreeSurfer, T1 MultiAtlas, SPM, DTI MultiAtlas, SpineSeg and TBSS. After group comparisons, there was widespread microstructural damage in the cerebral white matter, including cerebellar peduncles, corpus callosum and pyramidal tracts of patients with FRDA. We also found gray matter volumetric reduction in the dentate nuclei of the cerebellum, brainstem and motor cortex. We did not find volumetric reduction over time, but there was progressive white matter microstructural damage in the corpus callosum, pyramidal tracts and superior cerebellar peduncles after 1 year of follow-up. Regarding the disease phenotypes, we found that both classical FRDA and LOFA have similar, but not identical neuroimaging signatures. Although subtle, the structural differences might help to explain the phenotypic differences seen in both conditions. The corticospinal tracts are damaged in both conditions, but more severely in the late-onset FRDA group, which may explain why pyramidal signs are more evident in the latter subgroup. We failed to identify iron deposits in brain regions other than the dentate nuclei of patients with FRDA. Finally, we found that the spinal cord and inferior cerebellar peduncles are the structures compromised in pediatric patients with FRDA.
Iron Sulfur and Molybdenum Cofactor Enzymes Regulate the Drosophila Life Cycle by Controlling Cell Metabolism
Marelja Z, Leimkühler S and Missirlis F (2018); Front. Physiol. 9:50. doi: 10.3389/fphys.2018.00050
Despite general agreement that frataxin is required for a functional nervous system, disagreement has been expressed on the cause, with different authors favoring oxidative stress (Llorens et al., 2007; Anderson et al., 2008; Kondapalli et al., 2008), iron toxicity (Soriano et al., 2013; Navarro et al., 2015), altered mitochondrial metabolism (Navarro et al., 2010; Tricoire et al., 2014; Calap-Quintana et al., 2015; Soriano et al., 2016), sphingolipid signaling (Chen et al., 2016b), and failure to maintain neuronal membrane potential (Shidara and Hollenbeck, 2010). We do not see any contradiction in the various positive claims made in the above-cited literature, whereas the negative claim that is often repeated—refuting a role for oxidative stress in explaining the phenotypes—normally arises because of failure to rescue the phenotypes with some transgenes as opposed to others.
Despite general agreement that frataxin is required for a functional nervous system, disagreement has been expressed on the cause, with different authors favoring oxidative stress (Llorens et al., 2007; Anderson et al., 2008; Kondapalli et al., 2008), iron toxicity (Soriano et al., 2013; Navarro et al., 2015), altered mitochondrial metabolism (Navarro et al., 2010; Tricoire et al., 2014; Calap-Quintana et al., 2015; Soriano et al., 2016), sphingolipid signaling (Chen et al., 2016b), and failure to maintain neuronal membrane potential (Shidara and Hollenbeck, 2010). We do not see any contradiction in the various positive claims made in the above-cited literature, whereas the negative claim that is often repeated—refuting a role for oxidative stress in explaining the phenotypes—normally arises because of failure to rescue the phenotypes with some transgenes as opposed to others.
Thursday, March 1, 2018
Coenzyme Q10 Supplementation in Aging and Disease
Hernández-Camacho JD, Bernier M, López-Lluch G and Navas P. Front. Physiol. 9:44. doi: 10.3389/fphys.2018.00044
Coenzyme Q (CoQ) is an essential component of the mitochondrial electron transport chain and an antioxidant in plasma membranes and lipoproteins. It is endogenously produced in all cells by a highly regulated pathway that involves a mitochondrial multiprotein complex. Defects in either the structural and/or regulatory components of CoQ complex or in non-CoQ biosynthetic mitochondrial proteins can result in a decrease in CoQ concentration and/or an increase in oxidative stress. Besides CoQ10 deficiency syndrome and aging, there are chronic diseases in which lower levels of CoQ10 are detected in tissues and organs providing the hypothesis that CoQ10 supplementation could alleviate aging symptoms and/or retard the onset of these diseases. Here, we review the current knowledge of CoQ10 biosynthesis and primary CoQ10 deficiency syndrome, and have collected published results from clinical trials based on CoQ10 supplementation. There is evidence that supplementation positively affects mitochondrial deficiency syndrome and the symptoms of aging based mainly on improvements in bioenergetics. Cardiovascular disease and inflammation are alleviated by the antioxidant effect of CoQ10. There is a need for further studies and clinical trials involving a greater number of participants undergoing longer treatments in order to assess the benefits of CoQ10 treatment in metabolic syndrome and diabetes, neurodegenerative disorders, kidney diseases, and human fertility.
Coenzyme Q (CoQ) is an essential component of the mitochondrial electron transport chain and an antioxidant in plasma membranes and lipoproteins. It is endogenously produced in all cells by a highly regulated pathway that involves a mitochondrial multiprotein complex. Defects in either the structural and/or regulatory components of CoQ complex or in non-CoQ biosynthetic mitochondrial proteins can result in a decrease in CoQ concentration and/or an increase in oxidative stress. Besides CoQ10 deficiency syndrome and aging, there are chronic diseases in which lower levels of CoQ10 are detected in tissues and organs providing the hypothesis that CoQ10 supplementation could alleviate aging symptoms and/or retard the onset of these diseases. Here, we review the current knowledge of CoQ10 biosynthesis and primary CoQ10 deficiency syndrome, and have collected published results from clinical trials based on CoQ10 supplementation. There is evidence that supplementation positively affects mitochondrial deficiency syndrome and the symptoms of aging based mainly on improvements in bioenergetics. Cardiovascular disease and inflammation are alleviated by the antioxidant effect of CoQ10. There is a need for further studies and clinical trials involving a greater number of participants undergoing longer treatments in order to assess the benefits of CoQ10 treatment in metabolic syndrome and diabetes, neurodegenerative disorders, kidney diseases, and human fertility.
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