Imis Dogan, Sandro Romanzetti, Claire Didszun, Shahram Mirzazade, Dagmar Timmann, Carsten Saft, Ludger Schöls, Matthis Synofzik, Ilaria A Giordano, Thomas Klockgether, Jörg B Schulz, Kathrin Reetz; Journal of Neurology, Neurosurgery & Psychiatry, June 2018 DOI:10.1136/jnnp-2018-318422
Neuropathological studies described reductions of dorsal root ganglia, the spinal cord at all levels and dentate nuclei.1 In vivo MRI approaches confirmed spinal cord alterations in FRDA, which were however focused on upper cervical cord areas,2 while quantitative measurements along the entire spinal cord length are lacking. We therefore aimed to investigate the morphometric pattern of the cervical and thoracic spinal cord in FRDA. In order to provide a more comprehensive picture of spinocerebellar-cerebral alterations, we additionally analysed anatomical brain MRI data and investigated the relative contribution of spinal and brain measurements for the prediction of clinical severity in FDRA.
Friday, June 29, 2018
Wednesday, June 27, 2018
Friedreich Ataxia: Diagnostic Yield and Minimal Frequency in South Brazil
Helena Fussiger, Maria Luiza Saraiva-Pereira, Sandra Leistner-Segal, Laura Bannach Jardim. Cerebellum (2018). doi:10.1007/s12311-018-0958-x
Friedreich ataxia (FRDA) is an autosomal recessive disorder due to mutations in the FXN gene. FRDA is characterized by the classical triad of ataxia, absent reflexes, and Babinski sign, but atypical presentations might also occur. Our aims were to describe the proportion of FRDA diagnoses in suspected families living in Rio Grande do Sul, South Brazil, and to estimate a minimum frequency of symptomatic subjects. Subjects that were evaluated by molecular analysis for FRDA at the Hospital de Clínicas de Porto Alegre were identified in our files. Patients’ clinical manifestation and phenotypes were described and compared. The number of FRDA subjects alive in the last 5 years was determined. One hundred fifty-six index cases (families) were submitted to evaluation of GAA repeats at FXN since 1997: 27 were confirmed as FRDA patients. Therefore, the diagnostic yield was 17.3%. Proportion of classical, late onset, and retained reflexes subphenotypes were similar to those described by other studies. A minimum prevalence was estimated as 0.20:100.000 inhabitants. In conclusion, we verified that this FRDA population displayed the usual clinical characteristics, but with a lower period prevalence than those obtained in populations from Europe.
Friedreich ataxia (FRDA) is an autosomal recessive disorder due to mutations in the FXN gene. FRDA is characterized by the classical triad of ataxia, absent reflexes, and Babinski sign, but atypical presentations might also occur. Our aims were to describe the proportion of FRDA diagnoses in suspected families living in Rio Grande do Sul, South Brazil, and to estimate a minimum frequency of symptomatic subjects. Subjects that were evaluated by molecular analysis for FRDA at the Hospital de Clínicas de Porto Alegre were identified in our files. Patients’ clinical manifestation and phenotypes were described and compared. The number of FRDA subjects alive in the last 5 years was determined. One hundred fifty-six index cases (families) were submitted to evaluation of GAA repeats at FXN since 1997: 27 were confirmed as FRDA patients. Therefore, the diagnostic yield was 17.3%. Proportion of classical, late onset, and retained reflexes subphenotypes were similar to those described by other studies. A minimum prevalence was estimated as 0.20:100.000 inhabitants. In conclusion, we verified that this FRDA population displayed the usual clinical characteristics, but with a lower period prevalence than those obtained in populations from Europe.
Autonomic function testing in Friedreich’s ataxia
Elisabetta Indelicato, Alessandra Fanciulli, Jean-Pierre Ndayisaba, Wolfgang Nachbauer, Andreas Eigentler, Roberta Granata, Julia Wanschitz, Werner Poewe, Gregor K. Wenning, Sylvia Boesch. J Neurol (2018). Doi:10.1007/s00415-018-8946-0
FRDA patients may experience several autonomic symptoms and overall their burden correlates with disease severity. Nonetheless, clinical testing shows no major involvement of sudomotor and cardiovascular autonomic function.
FRDA patients may experience several autonomic symptoms and overall their burden correlates with disease severity. Nonetheless, clinical testing shows no major involvement of sudomotor and cardiovascular autonomic function.
Tuesday, June 26, 2018
Modeling Cardiac Dysfunction of Friedreich’s Ataxia Using Ventricular Sheets, Tissues and Chambers Engineered from Human Pluripotent Stem Cells
VANCOUVER, British Columbia, June 25, 2018 (GLOBE NEWSWIRE) -- Novoheart (“Novoheart” or the “Company”) (TSX-V:NVH) (FWB:3NH) is pleased to announce a presentation was delivered on June 22nd, 2018, entitled “Modeling Cardiac Dysfunction of Friedreich’s Ataxia Using Ventricular Sheets, Tissues and Chambers Engineered from Human Pluripotent Stem Cells,” at the Annual Meeting of the International Society for Stem Cell Research in Melbourne, Australia. The presentation includes data from research conducted with Pfizer Inc. on a 3D engineered human cardiac tissue disease model of Friedreich’s ataxia (FRDA), a neurodegenerative disease in which patients most often die of heart complications. The new disease model helps capture both electrical and mechanical defects of the heart observed in patients with FRDA.
FRDA is a hereditary, juvenile-onset neuro-muscular disease that afflicts over 1 in 50,000 people worldwide1, with symptoms including loss of muscular coordination and severe cardiac conditions. The latter, including heart failure and arrhythmias, is the main cause of death in FRDA patients2. Mouse models of FRDA have previously been created, but their non-human nature limits their application in drug development for human patients. As the first engineered 3D human cardiac tissue constructs of Friedreich’s ataxia, developed using Novoheart’s proprietary MyHeartTM Platform, the novel disease model captures key clinical symptoms seen in FRDA patients, including electrical and contractile dysfunction of the heart, thereby providing a highly effective human screening and discovery platform for developing novel therapeutics.
“We are very excited by the outcome of this study, and hope this will accelerate the development of safe and effective new therapies for FRDA patients. Also, by demonstrating the biomimetic capabilities of our MyHeartTM Platform for modeling diseased hearts, we are hoping to establish new standards for creating a proprietary library of disease models and expand our presence in drug discovery and precision medicine,” said Novoheart CSO, Dr. Kevin Costa.
FRDA is a hereditary, juvenile-onset neuro-muscular disease that afflicts over 1 in 50,000 people worldwide1, with symptoms including loss of muscular coordination and severe cardiac conditions. The latter, including heart failure and arrhythmias, is the main cause of death in FRDA patients2. Mouse models of FRDA have previously been created, but their non-human nature limits their application in drug development for human patients. As the first engineered 3D human cardiac tissue constructs of Friedreich’s ataxia, developed using Novoheart’s proprietary MyHeartTM Platform, the novel disease model captures key clinical symptoms seen in FRDA patients, including electrical and contractile dysfunction of the heart, thereby providing a highly effective human screening and discovery platform for developing novel therapeutics.
“We are very excited by the outcome of this study, and hope this will accelerate the development of safe and effective new therapies for FRDA patients. Also, by demonstrating the biomimetic capabilities of our MyHeartTM Platform for modeling diseased hearts, we are hoping to establish new standards for creating a proprietary library of disease models and expand our presence in drug discovery and precision medicine,” said Novoheart CSO, Dr. Kevin Costa.
Monday, June 25, 2018
Mitohormesis, an Antiaging Paradigm
Clea Bárcena, Pablo Mayoral, Pedro M. Quirós, International Review of Cell and Molecular Biology, Academic Press, ISSN 1937-6448, doi:10.1016/bs.ircmb.2018.05.002.
Mitohormesis is a term used to define a biological response where the induction of a reduced amount of mitochondrial stress leads to an increment in health and viability within a cell, tissue, or organism. The mitochondrial stress response activated by a potentially damaging stimulus requires a coordinated dialogue with the cellular nucleus, known as mitonuclear communication. This interplay induced by the hormetic response in mitochondria relies in a variety of signals among which the most relevant ones are reactive oxygen species (ROS), mitochondrial metabolites, proteotoxic signals, the mitochondria–cytosol stress response, and the release of mitokines. The activation of the mitohormetic response increases lifespan in different animal models, from worms to mammals. Further, mitohormesis also enhances healthspan, particularly improving metabolism and immune system. Although multiple mediators and stress signals have been proposed to activate this protective mechanism, beneficial outcomes of mitohormesis are most probably due to an increase in mitochondrial ROS. Activation of other protective stress mechanisms as mitochondrial unfolded protein response or the increase in the expression of mitokines are also associated with the positive benefits exerted by mitohormesis. Herein, we review the different mitohormetic signals and pathways described from worms to mammals and their effects on health and survival. The identification and description of pathways and molecules implicated in the beneficial effects of mitohormesis will help understand the complex balance between death and survival in the face of mitochondrial damage and will allow to open a novel area of therapies aimed at improving health in humans.
Mitohormesis is a term used to define a biological response where the induction of a reduced amount of mitochondrial stress leads to an increment in health and viability within a cell, tissue, or organism. The mitochondrial stress response activated by a potentially damaging stimulus requires a coordinated dialogue with the cellular nucleus, known as mitonuclear communication. This interplay induced by the hormetic response in mitochondria relies in a variety of signals among which the most relevant ones are reactive oxygen species (ROS), mitochondrial metabolites, proteotoxic signals, the mitochondria–cytosol stress response, and the release of mitokines. The activation of the mitohormetic response increases lifespan in different animal models, from worms to mammals. Further, mitohormesis also enhances healthspan, particularly improving metabolism and immune system. Although multiple mediators and stress signals have been proposed to activate this protective mechanism, beneficial outcomes of mitohormesis are most probably due to an increase in mitochondrial ROS. Activation of other protective stress mechanisms as mitochondrial unfolded protein response or the increase in the expression of mitokines are also associated with the positive benefits exerted by mitohormesis. Herein, we review the different mitohormetic signals and pathways described from worms to mammals and their effects on health and survival. The identification and description of pathways and molecules implicated in the beneficial effects of mitohormesis will help understand the complex balance between death and survival in the face of mitochondrial damage and will allow to open a novel area of therapies aimed at improving health in humans.
Sunday, June 24, 2018
Frataxin‐Mediated PINK1‐Parkin‐Dependent Mitophagy in Hepatic Steatosis: The Protective Effects of Quercetin
Liu, P. , Lin, H. , Xu, Y. , Zhou, F. , Wang, J. , Liu, J. , Zhu, X. , Guo, X. , Tang, Y. and Yao, P. (2018), Mol. Nutr. Food Res.. Accepted Author Manuscript. . doi:10.1002/mnfr.201800164
Naturally occurring quercetin has been found to induce mitophagy and prevent non‐alcoholic fatty liver disease (NAFLD). However, it still remains elusive whether frataxin upregulation by quercetin contributes to the beneficial effect through mitophagy or not.
Naturally occurring quercetin has been found to induce mitophagy and prevent non‐alcoholic fatty liver disease (NAFLD). However, it still remains elusive whether frataxin upregulation by quercetin contributes to the beneficial effect through mitophagy or not.
Sunday, June 17, 2018
Latest developments in ataxias
Prats-Vinas JM, Rev Neurol. 2018 Jun 5;66(s02):S27-S31. PMID: 29876909
This article reviews the advances made in the field of ataxias over the past four years. It concludes that there is no single spectacular finding like those that have taken place in the last 25 years and they can all be attributed to the remarkable evolution of genetics and neuroimaging. Nevertheless, algorithms have been perfected that allow a more rational use of the previous techniques to reach a correct diagnosis and possible treatment. With regard to the treatments proposed to alleviate the symptoms of ataxias, there is no unquestionable evidence leading us to think that the symptoms can be reverted with the means currently available, except for a few treatable ataxias, which were already known before that time.
This article reviews the advances made in the field of ataxias over the past four years. It concludes that there is no single spectacular finding like those that have taken place in the last 25 years and they can all be attributed to the remarkable evolution of genetics and neuroimaging. Nevertheless, algorithms have been perfected that allow a more rational use of the previous techniques to reach a correct diagnosis and possible treatment. With regard to the treatments proposed to alleviate the symptoms of ataxias, there is no unquestionable evidence leading us to think that the symptoms can be reverted with the means currently available, except for a few treatable ataxias, which were already known before that time.
Social and familial difficulties as a consequence of the neurological illness of a child: the perspective of health and social work
Gonzalez-Pena A., Rev Neurol. 2018 Jun 5;66(s02):S53-S56.
When we speak of children with special needs, who require the aid of a number of professionals and who have a severe disability, it is necessary to have available a comprehensive group of different professionals (paediatrician, nurse, social worker, psychologist, etc.) who work together as a team. The specialist physician or doctor responsible for the sick child alone cannot take responsibility for all the psychosocial consequences that result from the neurological disease, which is a chronic illness that, generally speaking, means the families arrange their lives to revolve around the sick child. The set of guidelines or social work field tools for doctors such as neuropaediatricians outlined in this article could help to facilitate an increase in the quality of the care delivered, and of the lives of the children and of those who are looking after them. The children and their relatives have a social complexity as a consequence of their disease that can be detected by the doctor, who then refers them to the social worker in order to be able to deliver a more global response to care for the child's health. It is important to have the concepts clear in our minds when speaking about children with severe disability and high dependence, and also about the institutional abuse in the form of medical bureaucracy with numerous visits and a variety of professionals all requesting clinical tests.
When we speak of children with special needs, who require the aid of a number of professionals and who have a severe disability, it is necessary to have available a comprehensive group of different professionals (paediatrician, nurse, social worker, psychologist, etc.) who work together as a team. The specialist physician or doctor responsible for the sick child alone cannot take responsibility for all the psychosocial consequences that result from the neurological disease, which is a chronic illness that, generally speaking, means the families arrange their lives to revolve around the sick child. The set of guidelines or social work field tools for doctors such as neuropaediatricians outlined in this article could help to facilitate an increase in the quality of the care delivered, and of the lives of the children and of those who are looking after them. The children and their relatives have a social complexity as a consequence of their disease that can be detected by the doctor, who then refers them to the social worker in order to be able to deliver a more global response to care for the child's health. It is important to have the concepts clear in our minds when speaking about children with severe disability and high dependence, and also about the institutional abuse in the form of medical bureaucracy with numerous visits and a variety of professionals all requesting clinical tests.
Soft robotic devices for hand rehabilitation and assistance: a narrative review
Chia-Ye Chu and Rita M. Patterson, Journal of NeuroEngineering and Rehabilitation 2018 15:9 doi:10.1186/s12984-018-0350-6
Since the emergence of soft robotic devices for hand rehabilitation roughly 10 years ago, the field has progressed rapidly. Significant progress has been made in establishing proof-of-concept of designs of preclinical research prototypes, with clinical trials being the next logical goal. But for many devices, more work needs to be done to perfect actuator design and feedback to maximize patient safety and rehabilitation outcomes.
We hope that this review of the current approaches in designing soft robotic devices for hand rehabilitation will serve as a useful resource for future developers and facilitate the evolution of the field.
Since the emergence of soft robotic devices for hand rehabilitation roughly 10 years ago, the field has progressed rapidly. Significant progress has been made in establishing proof-of-concept of designs of preclinical research prototypes, with clinical trials being the next logical goal. But for many devices, more work needs to be done to perfect actuator design and feedback to maximize patient safety and rehabilitation outcomes.
We hope that this review of the current approaches in designing soft robotic devices for hand rehabilitation will serve as a useful resource for future developers and facilitate the evolution of the field.
Transcranial magnetic stimulation in hereditary ataxias: diagnostic utility, pathophysiological insight and treatment
Roberto Rodríguez-Labrada, Luis Velázquez-Pérez, Ulf Ziemann, Clinical Neurophysiology, Available online 15 June 2018, ISSN 1388-2457, doi:10.1016/j.clinph.2018.06.003.
Transcranial magnetic stimulation (TMS) is a valuable technique to assess and modulate human brain function in normal and pathological conditions. This critical review surveys the contributions of TMS to the diagnosis, insight into pathophysiology and treatment of genetically confirmed hereditary ataxias, a heterogeneous group of neurodegenerative disorders that can affect motor cortex and the corticospinal tract. Most studies were conducted on small sample sizes and focused on diagnostic approaches. The available data demonstrate early involvement of the corticospinal tract and motor cortex circuitry, and support the possible efficacy of cerebellar repetitive TMS (rTMS) as therapeutic approach. Further TMS-based studies are warranted, to establish biomarkers for early diagnosis and disease monitoring, explore the involvement of the cerebello-dentato-thalamo-cortical projection, study the effects of rTMS-induced plasticity, and utilize rTMS for treatment.
Transcranial magnetic stimulation (TMS) is a valuable technique to assess and modulate human brain function in normal and pathological conditions. This critical review surveys the contributions of TMS to the diagnosis, insight into pathophysiology and treatment of genetically confirmed hereditary ataxias, a heterogeneous group of neurodegenerative disorders that can affect motor cortex and the corticospinal tract. Most studies were conducted on small sample sizes and focused on diagnostic approaches. The available data demonstrate early involvement of the corticospinal tract and motor cortex circuitry, and support the possible efficacy of cerebellar repetitive TMS (rTMS) as therapeutic approach. Further TMS-based studies are warranted, to establish biomarkers for early diagnosis and disease monitoring, explore the involvement of the cerebello-dentato-thalamo-cortical projection, study the effects of rTMS-induced plasticity, and utilize rTMS for treatment.
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