Friedreich Ataxia in Classical Galactosaemia

Friedreich Ataxia in Classical Galactosaemia. Siobhán Neville, Siobhan O’Sullivan, Bronagh Sweeney, Bryan Lynch, Donncha Hanrahan, Ina Knerr, Sally Ann Lynch, Ellen Crushell; JIMD Reports, 29 Jul 2015, DOI 10.1007/8904_2015_477

Both conditions are known to occur with increased frequency amongst the Irish Traveller population. Neurological symptoms are easily attributed to an underlying diagnosis of galactosaemia. It is important to consider a diagnosis of Friedreich ataxia in a child from the Irish Traveller population with galactosaemia who presents with ataxia or cardiomyopathy.

Friedreich’s Ataxia Research Collaboration Announced

Friedreich’s Ataxia Research Collaboration Announced. Medical Sciences Division, University of Oxford, 30 July 2015.

A new collaborative drug discovery project in Friedreich’s Ataxia (FA) between the University of Oxford, Ataxia UK, Pfizer Inc, UCL and Imperial College London was recently announced.
The programme will initially run for three years and aims to develop a potential new medicine or therapy for Friedreich’s ataxia that, if successful, may be tested in clinical trials.

Les médicaments orphelins : des opportunités méconnues pour les développeurs en Europe

Les médicaments orphelins : des opportunités méconnues pour les développeurs en Europe. Orphan Drugs: Underrated Opportunities for The Developers in Europe. Yves Tillet et Anne-Catherine Maillols-Perroy; Thérapie 2015 Juillet-Août; 70 (4): 351–357

Key words: Orphan Drug Act / regulation 141/2000/EC / implementing regulation 847/2000 / Commission communication (2003/C 178/02) / orphan medical product / 10 year market exclusivity / similar medicinal product / significant benefit / clinical superiority / assumption of significant benefit

Mitigation of Myocardial Ischemia-Reperfusion Injury via HIF-1α-Frataxin Signalling.

Mitigation of Myocardial Ischemia-Reperfusion Injury via HIF-1α-Frataxin Signalling. Nelson Amaral, Darlington Okonko; American Journal of Physiology - Heart and Circulatory Physiology Published 25 July 2015 Vol. no. , DOI: 10.1152/ajpheart.00553.2015

Resources, challenges and way forward in rare mitochondrial diseases research.

Resources, challenges and way forward in rare mitochondrial diseases research. Rajput NK, Singh V and Bhardwaj A. [v1; ref status: indexed, http://f1000r.es/54x] F1000Research 2015, 4:70 (doi: 10.12688/f1000research.6208.1) OPEN ACCESS

Rare diseases affect over 300 million people globally, however the true burden of these diseases on human health remains to be determined. Rare genetic variants are disease causing and lead to a personalized disease manifestation. Thus, it is time to review the disease definition considering both the molecular mechanisms involved and environmental factors leading to differential phenotypes. This will allow for a better understanding of both rare and common diseases. On the other end, a paradigm shift in drug discovery and development is also needed to translate the effort in understanding disease mechanisms to identify potential therapeutic routes. Newer models and platforms that allow involvement of patient communities in research and development is also expected to offer solutions to patients suffering from rare diseases who may then benefit from appropriate treatment options. Community collaborative approaches for research and funding offer an unprecedented opportunity for making new discoveries and translating to therapeutic interventions.

L'atàxia de Friedreich: estudi del dèficit de frataxina en miòcits cardíacs

Friedreich's ataxia: a study of frataxin deficiency in cardiac myocytes. Author: Èlia Obis Monné, Director: Jordi Tamarit Sumalla, Joaquim Ros Salvador; Thesis, date of defense:2014-12-10, Universitat de Lleida. Departament de Ciències Mèdiques Bàsiques. Tesis Doctorals en Xarxa (Universitat de Lleida)

Full text files in this thesis will be available from 2015-12-10



Frataxin deficiency in cardiac myocytes causes an alteration of the mitochondrial network and oxidative stress. Furthermore, cardiac myocytes undergo a change in the metabolic profile and accumulate large amounts of fatty acids in lipid droplets.

More information.....

RNA-based drugs, very promising research (RaNA Therapeutics)

RNA-based drugs, very promising research (RaNA Therapeutics). EXOME News, Ben Fidler July 23rd, 2015 and The Boston Globe (Bussines)  by Jack Newsham Globe Correspondent  July 23, 2015

RaNA Therapeutics, a Cambridge-based drug startup, announced today will help fund the preclinical work needed to get at least two programs into human trials in 2017. So far the company has touted potential therapies for spinal muscular atrophy and Friedreich’s Ataxia. These therapies are RNA-based drugs meant to switch back on genes that are silenced in certain diseases, and thus don’t produce critical proteins (like spinal motor neuron in the case of people with SMA, and frataxin for those with Friedreich’s). (EXOME)


The company said Thursday that it raised the funds from a group of new and existing investors led by MRL Ventures, an arm of the drug giant Merck, and the Baupost Group. RaNA plans to have one or two treatments for spinal muscular atrophy and Friedreich’s ataxia in clinical trials by 2017. (The Boston Globe)


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A study of up to 12 years of follow-up of Friedreich ataxia utilising four measurement tools

A study of up to 12 years of follow-up of Friedreich ataxia utilising four measurement tools. Geneieve Tai, Louise A Corben, Lyle Gurrin, Eppie M Yiu1, Andrew Churchyard, Michael Fahey, Brian Hoare, Sharon Downie, Martin B Delatycki;
J Neurol Neurosurg Psychiatry 2015;86:660-666 doi:10.1136/jnnp-2014-308022

Individuals with larger GAA1 repeat sizes and earlier ages of disease onset were shown to deteriorate at a faster rate and were associated with greater FARS and ICARS scores and lower FIM and MBI scores, which are indicative of greater disease severity.

Haptic wearables as sensory replacement, sensory augmentation and trainer – a review

Haptic wearables as sensory replacement, sensory augmentation and trainer – a review. Peter B. Shull and Dana D. Damian; Journal of NeuroEngineering and Rehabilitation 2015, 12:59 doi:10.1186/s12984-015-0055-z
OPEN ACCESS

Sensory impairments decrease quality of life and can slow or hinder rehabilitation. Small, computationally powerful electronics have enabled the recent development of wearable systems aimed to improve function for individuals with sensory impairments. The purpose of this review is to synthesize current haptic wearable research for clinical applications involving sensory impairments. This review found that wearable haptic devices improved function for a variety of clinical applications including: rehabilitation, prosthetics, vestibular loss, osteoarthritis, vision loss and hearing loss

Specialized Cortex Glial Cells Accumulate Lipid Droplets in Drosophila melanogaster.

Specialized Cortex Glial Cells Accumulate Lipid Droplets in Drosophila melanogaster. Viktor Kis,* Benjámin Barti, Mónika Lippai, and Miklós Sass; PLoS One. 2015; 10(7): e0131250.
Published online 2015 July 6. doi: 10.1371/journal.pone.0131250 OPEN ACCESS

While a large portion of the Drosophila neurodegeneration mutants (bubblegum, swiss cheese, loechrig, ApoD, frataxin, sicily) [19–23] affect lipid metabolism and disturb LD homeostasis, neither the cellular, nor the spatio-temporal distribution of LDs has been described to date in Drosophila. In this paper, we used the brain of the fruitfly to study lipid droplet anatomy in the larval nervous system.

Oxidative Stress and the Homeodynamics of Iron Metabolism

Oxidative Stress and the Homeodynamics of Iron Metabolism. Nikolaus Bresgen and Peter M. Eckl; Biomolecules 2015, 5(2), 808-847; doi:10.3390/biom5020808

In conclusion, cellular iron homeodynamics is based on a well-orchestrated interaction of iron uptake, intracellular transport, iron storage, usage and export, which is embedded in cellular metabolic and surveillance control. Under stress conditions, this orchestration changes in order to maintain homeodynamics and protect the cell from severe destabilization.

Gene Expression Profile in Peripheral Blood Cells of Friedreich Ataxia Patients

Gene Expression Profile in Peripheral Blood Cells of Friedreich Ataxia Patients. Agessandro Abrahao, Jose Luiz Pedroso, Patricia de Carvalho Aguiar and Orlando Barsottini; Neurology April 6, 2015 vol. 84 no. 14 Supplement P2.122

We found a robust downregulation of FXN, but no statistically significant differences were found between FRDA and controls for the remaining genes. Except for FXN, our study did not find a differential gene expression profile in PBCs of FRDA patients and a reliable gene expression profile biomarker obtained from an easily accessible tissue remains unclear.

Clinical Trial: Biomarkers in Friedreich's Ataxia

Clinical Trial: Biomarkers in Friedreich's Ataxia ClinicalTrials.gov Identifier: NCT02497534. First received: July 7, 2015

Sponsor: University of Florida

The purpose of this project is to characterize measures of cardiac performance and neuromuscular physiology in FA patients using novel techniques, including echocardiography and magnetic resonance imaging (MRI), metabolic exercise testing, and neurophysiological outcomes.

This study is not yet open for participant recruitment.

Regional Cerebral Disease Progression in Friedreich's Ataxia: A Longitudinal Diffusion Tensor Imaging Study

Regional Cerebral Disease Progression in Friedreich's Ataxia: A Longitudinal Diffusion Tensor Imaging Study. Mascalchi, M., Toschi, N., Giannelli, M., Ginestroni, A., Della Nave, R., Tessa, C., Piacentini, S., Dotti, M. T., Aiello, M., Nicolai, E., Soricelli, A., Salvi, F. and Diciotti, S., Journal of Neuroimaging.(2015) doi: 10.1111/jon.12270

DTI can track brain microstructural changes in FRDA and can be considered a potential biomarker of disease progression.

Science Heroes: Annalisa Pastore: A love story with the double helix that started at 17

Science Heroes: Annalisa Pastore: A love story with the double helix that started at 17. Frontiers Blog, Posted on July 14, 2015

This led her to—at least partially— identify the role of the protein, resulting from the expression of frataxin, in the disease mechanism. These findings could ultimately open the door to designing a new strategy to treat Friedreich’s ataxia, and other neurodegenerative diseases.

Redox signalling and mitochondrial stress responses; lessons from inborn errors of metabolism.

Redox signalling and mitochondrial stress responses; lessons from inborn errors of metabolism. Rikke K. J. Olsen, Nanna Cornelius, and Niels Gregersen; J Inherit Metab Dis. 2015; 38(4): 703–719.
Published online 2015 May 30. doi: 10.1007/s10545-015-9861-5

Springer OPEN Choice

Based on our own and other’s studies we re-introduce the ROS triangle model and discuss how inborn errors of mitochondrial metabolism, by production of pathological amounts of ROS, may cause disturbed redox signalling and induce chronic cell stress with non-resolving or compromised cell repair responses and increased susceptibility to cell stress induced cell death.

TORC1 Inhibition by Rapamycin Promotes Antioxidant Defences in a Drosophila Model of Friedreich’s Ataxia

TORC1 Inhibition by Rapamycin Promotes Antioxidant Defences in a Drosophila Model of Friedreich’s Ataxia. Pablo Calap-Quintana, Sirena Soriano, José Vicente Llorens, Ismael Al-Ramahi, Juan Botas, María Dolores Moltó, María José Martínez-Sebastián; PLoS ONE 10(7): e0132376. doi:10.1371/journal.pone.0132376

OPEN ACCESS

We found that genetic reduction in TOR Complex 1 (TORC1) signalling improves the impaired motor performance phenotype of FRDA model flies. Pharmacologic inhibition of TORC1 signalling by rapamycin also restored this phenotype and increased the lifespan and ATP levels. These results point to the TORC1 pathway as a new potential therapeutic target for FRDA and as a guide to finding new promising molecules for disease treatment.

Familial segmental spinal myoclonus: a rare clinical feature of Friedreich’s ataxia

Familial segmental spinal myoclonus: a rare clinical feature of Friedreich’s ataxia. Rajendra Singh Jain, Sunil Kumar and Shankar Tejwani, SpringerPlus 2015, 4:330 doi:10.1186/s40064-015-1121-5

OPEN ACCESS


Spinal segmental myoclonus (SSM) is a unique and rare manifestation of FRDA. This might be the first case report of SSM in FRDA patient.

Dynamics in the sense of dignity over the course of illness: A longitudinal study into the perspectives of seriously ill patients

Dynamics in the sense of dignity over the course of illness: A longitudinal study into the perspectives of seriously ill patients. Isis E. van Gennip, H. Roeline W. Pasman, Mariska G. Oosterveld-Vlug, Dick L. Willems, Bregje D. Onwuteaka-Philipsen; International Journal of Nursing Studies, Available online 27 June 2015, ISSN 0020-7489, http://dx.doi.org/10.1016/j.ijnurstu.2015.06.010.

Single-molecule spectroscopy of protein conformational dynamics in live eukaryotic cells

Single-molecule spectroscopy of protein conformational dynamics in live eukaryotic cells. Iwo König, Arash Zarrine-Afsar, Mikayel Aznauryan, Andrea Soranno, Bengt Wunderlich, Fabian Dingfelder, Jakob C Stüber, Andreas Plückthun, Daniel Nettels & Benjamin Schuler; Nature Methods (2015)doi:10.1038/nmeth.3475 Published online 06 July 2015

Advances in methodology are making it gradually more feasible to investigate biomolecular processes in their native cellular environment. The ultimate goal is to reach quantitative molecular understanding with the same rigor as in test-tube experiments.The results on protein GB1 and frataxin indicated a remarkable robustness in the conformational stabilities and even folding kinetics of these proteins in cells compared to in simple buffered solutions. We therefore expect that single-molecule spectroscopy will play an important role in bridging the gap between our quantitative understanding of biomolecules in vitro and in vivo.


Source: Single-molecule spectroscopy of protein conformational dynamics in live eukaryotic cells

Ultra-structural hair alterations in Friedreich's ataxia: A scanning electron microscopic investigation

Ultra-structural hair alterations in Friedreich's ataxia: A scanning electron microscopic investigation. Turkmenoglu, F. P., Kasirga, U. B. and Celik, H. H., Microsc. Res. Tech.. Article first published online: 3 JUL 2015 doi: 10.1002/jemt.22531

«SARAgrama»: una propuesta de representación gráfica en la evolución de las ataxias

«SARAgrama»: una propuesta de representación gráfica en la evolución de las ataxias. « SARAgraph»: A proposed graphic system for representing ataxia progression . I. Pulido-Valdeolivas, D. Gómez-Andrés, I. Sanz-Gallego, J. Arpa-Gutiérrez, Neurología (English Edition), Available online 11 June 2015,

MRI abnormalities of the cerebellar cortex and nuclei in SCA3, SCA6, and Friedreich’s ataxia

MRI abnormalities of the cerebellar cortex and nuclei in SCA3, SCA6, and Friedreich’s ataxia. M.R. Stefanescu, M. Dohnalek, S. Maderwald, M. Thürling, M. Minnerop, A. Beck, M. Schlamann, J. Diedrichsen, M.E. Ladd, D. Timmann, Clinical Neurophysiology, Volume 126, Issue 8, August 2015, Page e73, ISSN 1388-2457, http://dx.doi.org/10.1016/j.clinph.2015.04.094

Do large purine repeat sequences play a role in transcriptional regulation of genes associated with neurological disorders?

Do large purine repeat sequences play a role in transcriptional regulation of genes associated with neurological disorders?. Himanshu Narayan Singh, Moganty R. Rajeswari, Gene, Available online 3 July 2015, ISSN 0378-1119, http://dx.doi.org/10.1016/j.gene.2015.07.007.

Iron-Starvation-Induced Mitophagy Mediates Lifespan Extension upon Mitochondrial Stress in C. elegans

Iron-Starvation-Induced Mitophagy Mediates Lifespan Extension upon Mitochondrial Stress in C. elegans. Alfonso Schiavi, Silvia Maglioni, Konstantinos Palikaras, Anjumara Shaik, Flavie Strapazzon, Vanessa Brinkmann, Alessandro Torgovnick, Natascha Castelein, Sasha De Henau, Bart P. Braeckman, Francesco Cecconi, Nektarios Tavernarakis, Natascia Ventura; Current Biology, Available online 2 July 2015, ISSN 0960-9822, http://dx.doi.org/10.1016/j.cub.2015.05.059.

Mitochondrial autophagy is an evolutionarily conserved response to frataxin silencing, mitophagy is activated in response to mitochondrial stress. Mitophagy induction is part of an adaptive iron starvation response induced as a protective mechanism against mitochondrial stress, thus suggesting novel potential therapeutic strategies for the treatment of mitochondrial disorders.

Targeting lipid peroxidation and mitochondrial imbalance in Friedreich's ataxia

Targeting lipid peroxidation and mitochondrial imbalance in Friedreich's ataxia. Rosella Abeti, Ebru Uzun, Indhushri Renganathan, Tadashi Honda, Mark A. Pook, Paola Giunti, Pharmacological Research, Available online 2 July 2015, ISSN 1043-6618, http://dx.doi.org/10.1016/j.phrs.2015.05.015.

Two different categories of protective compounds: deuterised poly-unsaturated fatty acids (dPUFAs) and Nrf2-inducers have been shown to protect the cell from damage induced by lipid peroxidation and the latter trigger Nrf2 antioxidant pathway.

Keep the fire burning: Current avenues in the quest of treating mitochondrial disorders

Keep the fire burning: Current avenues in the quest of treating mitochondrial disorders. Christin Tischner, Tina Wenz, Mitochondrion, Available online 30 June 2015, ISSN 1567-7249, http://dx.doi.org/10.1016/j.mito.2015.06.002.

Modeling diseases of noncoding unstable repeat expansions using mutant pluripotent stem cells

Modeling diseases of noncoding unstable repeat expansions using mutant pluripotent stem cells. Shira Yanovsky-Dagan, Hagar Mor-Shaked and Rachel Eiges, World J Stem Cells 2015 June 26; 7(5): 823-838

Frataxin levels in peripheral tissue in Friedreich ataxia

Frataxin levels in peripheral tissue in Friedreich ataxia. Lazaropolous, M., Dong, Y., Clark, E., Greeley, N. R., Seyer, L. A., Brigatti, K. W., Christie, C., Perlman, S. L., Wilmot, G. R., Gomez, C. M., Mathews, K. D., Yoon, G., Zesiewicz, T., Hoyle, C., Subramony, S. H., Brocht, A. F., Farmer, J. M., Wilson, R. B., Deutsch, E. C. and Lynch, D. R.; Annals of Clinical and Translational Neurology. doi: 10.1002/acn3.225