Bastien Roche, Anne-Laure Simon, Sophie Guilmin-Crépon, Priscilla Boizeau, Béatrice Andriss, Corinne Alberti, Ana Presedo, Brice Ilharreborde, Isabelle Husson, Gait & Posture, 2018, doi:10.1016/j.gaitpost.2018.08.017.
The GAITRite system allows feasible and reliable measurements of gait parameters in young patients with FRDA. Lower reliability found for the weakest parameters was attributed to the software automatic errors and the ankle laxity noted in every patient.
Wednesday, August 22, 2018
Investigating Molecular Mechanisms Underlying Mild Phenotype in Friedreich Ataxia Patients with G130V Missense Mutation
Clark, Elisia. University of Pennsylvania, ProQuest Dissertations Publishing, 2018. 10748306. A DISSERTATION in Pharmacology Presented to the Faculties of the University of Pennsylvania in Partial Ful fillment of the Requirements for the Degree of Doctor of Philosophy.
Tuesday, August 14, 2018
Vitamin E hydroquinone is an endogenous regulator of ferroptosis via redox control of 15-lipoxygenase
Hinman A, Holst CR, Latham JC, Bruegger JJ, Ulas G, McCusker KP, et al. (2018) Vitamin E hydroquinone is an endogenous regulator of ferroptosis via redox control of 15-lipoxygenase. PLoS ONE 13(8): e0201369. https://doi.org/10.1371/journal.pone.0201369
Genetic basis of hypertrophic cardiomyopathy in children
tefan Rupp, Moataz Felimban, Anne Schänzer, Dietmar Schranz, Christoph Marschall, Martin Zenker, Thushiha Logeswaran, Christoph Neuhäuser, Josef Thul, Christian Jux, Andreas Hahn; Clin Res Cardiol (2018). doi:10.1007/s00392-018-1354-8
42 patients with the diagnoses of HCM made before age 18 years were treated in our center from 2000 to 2016. Genetic analysis was performed in 36 subjects, a genetic defect was detected in 29 (78%) patients. 15 individuals (42%) had pathogenic variants in genes encoding sarcomere proteins, and 5 (14%) in genes coding for components of the RAS/MAPK signaling pathway. 4 subjects (11%) had mutations in the GAA gene (Pompe disease), and 3 (8%) had Frataxin repeat expansions (Friedreich’s ataxia). One patient each showed a mutation in BAG3 and LMNA. Discussion of unsolved HCM cases after performing next-generation sequencing (28 genes) in an interdisciplinary board unraveled the genetic cause in 9 subjects (25%).
A definite genetic diagnosis can be reached in nearly 80% with HCM of childhood onset. Next-generation sequencing in conjunction with a multidisciplinary cooperation can enhance the diagnostic yield substantially. This may be important for risk stratification, treatment planning and genetic counseling.
42 patients with the diagnoses of HCM made before age 18 years were treated in our center from 2000 to 2016. Genetic analysis was performed in 36 subjects, a genetic defect was detected in 29 (78%) patients. 15 individuals (42%) had pathogenic variants in genes encoding sarcomere proteins, and 5 (14%) in genes coding for components of the RAS/MAPK signaling pathway. 4 subjects (11%) had mutations in the GAA gene (Pompe disease), and 3 (8%) had Frataxin repeat expansions (Friedreich’s ataxia). One patient each showed a mutation in BAG3 and LMNA. Discussion of unsolved HCM cases after performing next-generation sequencing (28 genes) in an interdisciplinary board unraveled the genetic cause in 9 subjects (25%).
A definite genetic diagnosis can be reached in nearly 80% with HCM of childhood onset. Next-generation sequencing in conjunction with a multidisciplinary cooperation can enhance the diagnostic yield substantially. This may be important for risk stratification, treatment planning and genetic counseling.
Monday, August 13, 2018
Nonataxia symptoms in Friedreich Ataxia. Report from the Registry of the European Friedreich's Ataxia Consortium for Translational Studies (EFACTS)
Kathrin Reetz, Imis Dogan, Christian Hohenfeld, Claire Didszun, Paola Giunti, Caterina Mariotti, Alexandra Durr, Sylvia Boesch, Thomas Klopstock, Francisco Javier Rodríguez de Rivera Garrido, Ludger Schöls, Ilaria Giordano, Katrin Bürk, Massimo Pandolfo, Jörg B. Schulz, the EFACTS Study Group, Neurology Aug 2018, DOI: 10.1212/WNL.0000000000006121
The most frequent clinical features beyond afferent ataxia were abnormal eye movements (90.5%), scoliosis (73.5%), deformities of the feet (58.8%), urinary dysfunction (42.8%), cardiomyopathy and cardiac hypertrophy (40.3%), followed by decreased visual acuity (36.8%); less frequent features were, among others, depression (14.1%) and diabetes (7.1%). Most of these features were more common in the typical-onset group compared to the late-onset group. Logistic regression models for the presence of these symptoms demonstrated the predictive value of GAA repeat length on the shorter allele and age at onset, but also severity of ataxia signs, sex, and presence of neonatal problems.
The most frequent clinical features beyond afferent ataxia were abnormal eye movements (90.5%), scoliosis (73.5%), deformities of the feet (58.8%), urinary dysfunction (42.8%), cardiomyopathy and cardiac hypertrophy (40.3%), followed by decreased visual acuity (36.8%); less frequent features were, among others, depression (14.1%) and diabetes (7.1%). Most of these features were more common in the typical-onset group compared to the late-onset group. Logistic regression models for the presence of these symptoms demonstrated the predictive value of GAA repeat length on the shorter allele and age at onset, but also severity of ataxia signs, sex, and presence of neonatal problems.
Friday, August 10, 2018
Gene therapy for neurological disorders: progress and prospects
Benjamin E. Deverman, Bernard M. Ravina, Krystof S. Bankiewicz, Steven M. Paul & Dinah W. Y. Sah; Nature Reviews Drug Discovery, Published: 10 August 2018 doi:10.1038/nrd.2018.110
Here, we discuss key considerations and challenges in the future design and development of therapeutic AAV vectors, highlighting the most promising targets and recent clinical advances.
Here, we discuss key considerations and challenges in the future design and development of therapeutic AAV vectors, highlighting the most promising targets and recent clinical advances.
Friday, August 3, 2018
Longitudinal analysis of contrast acuity in Friedreich ataxia
Ali G. Hamedani, Lauren A. Hauser, Susan Perlman, Katherine Mathews, George R. Wilmot, Theresa Zesiewicz, S.H. Subramony, Tetsuo Ashizawa, Martin B. Delatycki, Alicia Brocht, David R. Lynch; Neurol Genet. 2018 Jul 23;4(4):e250. doi: 10.1212/NXG.0000000000000250. eCollection 2018 Aug.
Low-contrast visual acuity decreases linearly over time in Friedreich ataxia, and the rate of decrease is greater at higher GAA repeat lengths. Contrast sensitivity has the potential to serve as a biomarker and surrogate outcome in future studies of Friedreich ataxia.
Low-contrast visual acuity decreases linearly over time in Friedreich ataxia, and the rate of decrease is greater at higher GAA repeat lengths. Contrast sensitivity has the potential to serve as a biomarker and surrogate outcome in future studies of Friedreich ataxia.
Targeting Nrf2 to Suppress Ferroptosis and Mitochondrial Dysfunction in Neurodegeneration
Abdalkader M, Lampinen R, Kanninen KM, Malm TM, Liddell JR. Front Neurosci. 2018;12 . PMCID: PMC6048292.
Ferroptosis is a newly described form of regulated cell death, distinct from apoptosis, necroptosis and other forms of cell death. Ferroptosis is induced by disruption of glutathione synthesis or inhibition of glutathione peroxidase 4, exacerbated by iron, and prevented by radical scavengers such as ferrostatin-1, liproxstatin-1, and endogenous vitamin E. Ferroptosis terminates with mitochondrial dysfunction and toxic lipid peroxidation. Although conclusive identification of ferroptosis in vivo is challenging, several salient and very well established features of neurodegenerative diseases are consistent with ferroptosis, including lipid peroxidation, mitochondrial disruption and iron dysregulation. Accordingly, interest in the role of ferroptosis in neurodegeneration is escalating and specific evidence is rapidly emerging. One aspect that has thus far received little attention is the antioxidant transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2). This transcription factor regulates hundreds of genes, of which many are either directly or indirectly involved in modulating ferroptosis, including metabolism of glutathione, iron and lipids, and mitochondrial function. This potentially positions Nrf2 as a key deterministic component modulating the onset and outcomes of ferroptotic stress. The minimal direct evidence currently available is consistent with this and indicates that Nrf2 may be critical for protection against ferroptosis. In contrast, abundant evidence demonstrates that enhancing Nrf2 signaling is potently neuroprotective in models of neurodegeneration, although the exact mechanism by which this is achieved is unclear. Further studies are required to determine to extent to which the neuroprotective effects of Nrf2 activation involve the prevention of ferroptosis
Ferroptosis is a newly described form of regulated cell death, distinct from apoptosis, necroptosis and other forms of cell death. Ferroptosis is induced by disruption of glutathione synthesis or inhibition of glutathione peroxidase 4, exacerbated by iron, and prevented by radical scavengers such as ferrostatin-1, liproxstatin-1, and endogenous vitamin E. Ferroptosis terminates with mitochondrial dysfunction and toxic lipid peroxidation. Although conclusive identification of ferroptosis in vivo is challenging, several salient and very well established features of neurodegenerative diseases are consistent with ferroptosis, including lipid peroxidation, mitochondrial disruption and iron dysregulation. Accordingly, interest in the role of ferroptosis in neurodegeneration is escalating and specific evidence is rapidly emerging. One aspect that has thus far received little attention is the antioxidant transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2). This transcription factor regulates hundreds of genes, of which many are either directly or indirectly involved in modulating ferroptosis, including metabolism of glutathione, iron and lipids, and mitochondrial function. This potentially positions Nrf2 as a key deterministic component modulating the onset and outcomes of ferroptotic stress. The minimal direct evidence currently available is consistent with this and indicates that Nrf2 may be critical for protection against ferroptosis. In contrast, abundant evidence demonstrates that enhancing Nrf2 signaling is potently neuroprotective in models of neurodegeneration, although the exact mechanism by which this is achieved is unclear. Further studies are required to determine to extent to which the neuroprotective effects of Nrf2 activation involve the prevention of ferroptosis
Novoheart, Pfizer develop 3-D model of Friedreich ataxia
VANCOUVER, British Columbia – June 25, 2018 (GLOBE NEWSWIRE) – Novoheart (“Novoheart” or the “Company”) (TSXV: 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.
“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.
“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.
Wednesday, August 1, 2018
The Effects of Game Based Exercise Training on Balance and Postural Control in Patients With Ataxia
ClinicalTrials.gov Identifier: NCT03607058
Patients who meet the inclusion criteria will be divided into two groups randomly: 'Kinect and exercise training' and 'exercise training'. The assessments will be made by a blind investigator four times, before and after the implementation of both protocols. The evaluations will take approximately 1 hour. The demographic information of the cases will be recorded. Designed as cross over study, two treatment protocols will be used in this study. The first protocol will be Xbox Kinect application plus exercise program, the second protocol will be only exercise program. At the beginning of the study, 2 groups will be allocated (Group A and Group B) randomly. For group A, the Xbox Kinect application plus exercise program will be applied for the first 8 weeks. For group B, only exercise program will be applied therapy first 8 weeks. All assessments will be repeated before and after each therapy period. Exercise program will consist of selected balance, coordination and walking exercises according to the individual needs of patients. . After 1 week washout period, patients will be included in the other group. All patients will take the treatment 1-hour, 3 days in a week for 8 weeks.
Study Type : Interventional (Clinical Trial)
Estimated Enrollment : 13 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double (Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Ataksik Hastalarda Oyun Temelli Egzersiz Eğitiminin Denge ve Postural Kontrol Üzerine Etkisi
Actual Study Start Date : October 18, 2017
Estimated Primary Completion Date : September 2018
Estimated Study Completion Date : September 2018
Locations: Turkey, Hacettepe University, Faculty of Health Sciences, Department of Physiotherapy and Rehabilitation
Patients who meet the inclusion criteria will be divided into two groups randomly: 'Kinect and exercise training' and 'exercise training'. The assessments will be made by a blind investigator four times, before and after the implementation of both protocols. The evaluations will take approximately 1 hour. The demographic information of the cases will be recorded. Designed as cross over study, two treatment protocols will be used in this study. The first protocol will be Xbox Kinect application plus exercise program, the second protocol will be only exercise program. At the beginning of the study, 2 groups will be allocated (Group A and Group B) randomly. For group A, the Xbox Kinect application plus exercise program will be applied for the first 8 weeks. For group B, only exercise program will be applied therapy first 8 weeks. All assessments will be repeated before and after each therapy period. Exercise program will consist of selected balance, coordination and walking exercises according to the individual needs of patients. . After 1 week washout period, patients will be included in the other group. All patients will take the treatment 1-hour, 3 days in a week for 8 weeks.
Study Type : Interventional (Clinical Trial)
Estimated Enrollment : 13 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double (Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Ataksik Hastalarda Oyun Temelli Egzersiz Eğitiminin Denge ve Postural Kontrol Üzerine Etkisi
Actual Study Start Date : October 18, 2017
Estimated Primary Completion Date : September 2018
Estimated Study Completion Date : September 2018
Locations: Turkey, Hacettepe University, Faculty of Health Sciences, Department of Physiotherapy and Rehabilitation
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