Rare diseases: matching wheelchair users with rare metabolic, neuromuscular or neurological disorders to electric powered indoor/outdoor wheelchairs (EPIOCs)

Lorraine H. De Souza & Andrew O. Frank. Disabil Rehabil. 2015 Dec 30:1-10. [Epub ahead of print] DOI:10.3109/09638288.2015.1106599

The complex and diverse clinical problems of those with RDs present unique challenges to the multiprofessional wheelchair team to maintain successful independent mobility and community living. Powered mobility is a major therapeutic tool for those with rare diseases enhancing independence, participation, reducing pain and other clinical features. The challenge for rehabilitation professionals is reconciling the physical disabilities with the individual’s need for function and participation whilst allowing for disease progression and/or growth.

Identification of potential mitochondrial CLPXP protease interactors and substrates suggests its central role in energy metabolism

Fabian Fischer, Julian D. Langer & Heinz D. Osiewacz; (NATURE) Scientific Reports 5, Article number: 18375 (2015) doi:10.1038/srep18375

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Among the CLPP-associated pathologies is Friedreich’s Ataxia (FRDA), a neurodegenerative disease caused by failed assembly of Fe-S clusters due to defects in the mitochondrial iron chaperone frataxin31. In a FRDA mouse model, the proteolytic component CLPP is upregulated at mid-stage of the disease. This upregulation is concomitant with a loss of mitochondrial Fe-S proteins, indicating they are targets of CLPP in FRDA. Indeed, several proteins we identified in our study contain or bind to Fe-S clusters, e.g. aconitase, biotin synthase, and complex I components such as the NADH-ubiquinone oxidoreductase 75 kDa subunit. In addition, three of the proteins found as CLPXP interactors or substrates, the cysteine desulfurase NSF1, the chaperone HSPA9, and the glutaredoxin-related protein 5, are known to be essential for Fe-S cluster biogenesis in eukaryotic cells including those of mammals. Thus, our findings support the idea that CLPXP has a functional role in FRDA and might possibly be involved in regulating Fe-S cluster assembly and Fe-S cluster proteins.

The first therapeutics based on genome-editing tools will treat diseases caused by single genes, but many other factors dictate what is currently possible.

Virginia Gewin, Medicine: Expanding possibilities, Nature 528, S10–S11 (03 December 2015) doi:10.1038/528S10a Published online 02 December 2015

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Treatments for Syndromes of Progressive Ataxia and Weakness Disorders - PMR Market Insight Report to 2020

Persistence Market Research (PMR)

Stringent regulations and standard requires for approval process of new drugs impede growth of the treatments for syndromes of progressive ataxia and weakness disorders market. The approval process takes a very long time to approve a specific drug.

Burden of mitochondrial DNA variations in Friedreich's Ataxia (FRDA) patients and sharing of mitochondrial lineage with Caucasians

Inder singh, Sunil Sakhya, Madhuri Behari, M.V. Padma Srivastava, Garima Shukla, Vinay Goyal, Achal Kumar Srivastava, Mohd. Faruq, Parkinsonism & Related Disorders, Volume 22, Supplement 2, January 2016, Page e154, ISSN 1353-8020, doi: 10.1016/j.parkreldis.2015.10.360.

Compound heterozygous FXN mutations and clinical outcome in Friedreich ataxia

Charles A. Galea, Aamira Huq, Paul J. Lockhart, Geneieve Tai, Louise A. Corben, Eppie M. Yiu, Lyle C. Gurrin, David R. Lynch, Sarah Gelbard, Alexandra Durr, Francoise Pousset, Michael Parkinson, Robyn Labrum, Paola Giunti, Susan L. Perlman, Martin B. Delatycki and Marguerite V. Evans-Galea; Annals of Neurology Accepted manuscript online: 24 DEC 2015 DOI: 10.1002/ana.24595

This integrated analysis of categorized frataxin mutations and their correlation with clinical outcome provides a definitive resource for investigating disease pathogenesis in FRDA

Diagnosis and management of hypertrophic cardiomyopathy

Antonis Pantazis MD, Annina S Vischer MD, Maria Carrillo Perez-Tome MD and Silvia Castelletti MD;  Echo Res Pract. 2015 Mar 1;2(1):R45-53. doi: 10.1530/ERP-15-0007. Epub 2015 Mar 11.

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Friedreich Ataxia:  Histological features explain that the hypertrophy derives from a striking proliferation of mitochondria within the cardiomyocytes, and a marked loss of contractile fibres. The cardiac involvement is high (more than 60% of patient affected) and usually asymptomatic.

European medical research escapes stifling privacy laws

Alison Abbott. Nature, Breaking News. doi:10.1038/nature.2015.19054 16 December 2015

Proposed legislation had threatened the use of genomic and clinical data in medical studies.

Longitudinal magnetic resonance imaging study shows progressive pyramidal and callosal damage in Friedreich's ataxia

Thiago J.R. Rezende Msc, Cynthia B. Silva MD, PhD, Clarissa L. Yassuda MD, PhD, Brunno M. Campos Msc, Anelyssa D'Abreu MD, PhD, Fernando Cendes MD, PhD, Iscia Lopes-Cendes MD PhD andMarcondes C. França Jr. MD, PhD; Mov Disord. 2015 Dec 21. doi: 10.1002/mds.26436. [Epub ahead of print]

Patients with Friedreich’s ataxia present more widespread gray and white matter damage than previously reported, including not only infratentorial areas, but also supratentorial structures.

The novel triterpenoid RTA 408 protects human retinal pigment epithelial cells against H2O2-induced cell injury via NF-E2-related factor 2 (Nrf2) activation

Xiaobin Liu, Keith Ward, Christy Xavier, Jamieson Jann, Abbot F. Clark, Iok-Hou Pang, Hongli Wu, Redox Biology, Available online 19 December 2015, ISSN 2213-2317, doi:10.1016/j.redox.2015.12.005.

Study about RTA 408 for degenerative eye diseases. Currently there is an ongoing clinical trial for the FA. Although the work is focused on age-related macular degeneration, includes important insights on the action mechanism of RTA 408.

RTA 408 represents a novel class of therapeutics that has the potential to increase Nrf2 expression and thereby increase expression of antioxidant enzymes. RTA 408 is a member of the synthetic oleanane triterpenoid compounds. It is currently under clinical investigation for the prevention of cataract surgery-induced loss of corneal endothelial cells, prevention of radiation-induced dermatitis in breast cancer patients undergoing radiotherapy, treatment of solid tumors including melanoma and lung cancer, and treatment of Friedreich’s Ataxia and mitochondrial myopathies. The present study investigates the connection between RTA 408 and the Nrf2 pathway as well as multiple antioxidant enzymes in RPE cells. This will help determine whether RTA 408 may serve as a potent therapy for AMD and other degenerative eye diseases.

Functional and gait assessment in children with Friedreich ataxia: Comparison of quantitative and functional evaluation

G. Vasco, M. Petrarca, S. Gazzellini, M.L. Lispi, G. Della Bella, S. Carniel, M. Zazza, E. Castelli, E. Bertini; Gait & Posture, Volume 42, Supplement 3, December 2015, Pages S45-S46, ISSN 0966-6362, doi: 10.1016/j.gaitpost.2015.03.083.

The spatial and temporal parameters revealed to be the most sensitive quantitative indicators and have a good correlation with SARA.

Otoneurological findings prevalent in hereditary ataxias

Bianca Simone Zeigelboim, Helio Afonso Ghizoni Teive, Geslaine Santos, Maria Izabel Severiano, Vinicius Ribas Fonseca, João Henrique Faryniuk, Parkinsonism & Related Disorders, Volume 22, Supplement 2, January 2016, Page e152, ISSN 1353-8020, doi:10.1016/j.parkreldis.2015.10.356.

A retrospective cross-sectional study was conducted with 19 Friedreich's ataxia. The most evident neuro-otological symptoms were dizziness, lack of coordination of movement, and imbalance when walking.

Vitamin E therapy beyond cancer: tocopherol versus tocotrienol

Hong Yong Peh, W.S. Daniel Tan, Wupeng Liao, W.S. Fred Wong, Pharmacology & Therapeutics, Available online 17 December 2015, ISSN 0163-7258, doi:10.1016/j.pharmthera.2015.12.003.

Modifications to tocotrienols were performed as well: Vatiquinone (EPI-743), structurally similar to α-tocotrienol metabolite α-tocotrienol quinone, was developed for the treatment of Leigh syndrome and other inherited mitochondrial diseases by Edison Pharmaceuticals Inc. Currently, EPI-743 was approved by FDA (United States of America Food and Drug Administration) in July 2014 for the treatment of Leigh syndrome and an ongoing Phase-IIb clinical trial for Friedreich’s ataxia

[Memantine for optic nerve atrophy in Friedreich's Ataxia]- Memantin bei Optikusatrophie in Friedreich-Ataxie

S. Peter , K. Manousaridis, S. Boesch, S. Mennel; Der Ophthalmologe pp 1-4, [Article in German] DOI 10.1007/s00347-015-0191-7

Despite the limitations of this single and time limited case observational study, memantine should be discussed as an option for treatment of acute optic nerve atrophy in Friedreich’s ataxia.

Perturbation of cellular proteostasis networks identifies pathways that modulate precursor and intermediate but not mature levels of frataxin

Joseph F. Nabhan, Renea L. Gooch, Eugene L. Piatnitski Chekler, Betsy Pierce & Christine E. Bulawa; (Nature) Scientific Reports 5, Article number: 18251 (2015) doi:10.1038/srep18251

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 Interestingly, a number of treatments caused a change in total amount of FXN protein, without an effect on mature FXN. Our results imply that regulation of FXN protein levels is complex and that total amounts can be modulated chemically and genetically without altering the absolute amount of mature FXN protein.

Eye movements in neurodegenerative diseases.

MacAskill, Michael R.; Anderson, Tim J.; Current Opinion in Neurology, Published Ahead-of-Print. December 4, 2015 doi: 10.1097/WCO.0000000000000274

Epigenetic Biomarkers and Diagnostics

Edited by: José Luis García-Giménez (Center for Biomedical Network Research on Rare Diseases (CIBERER), Madrid, Spain; Medicine and Dentistry School; Biomedical Research Institute INCLIVA, University of Valencia, Spain). Academic Press, Boston, 2016, doi:10.1016/B978-0-12-801899-6.01001-9, Available online 8 December 2015

Chapter 3 - Epigenetic Mechanisms as Key Regulators in Disease: Clinical Implications, Abdelhalim Boukaba, Fabian Sanchis-Gomar and José Luis García-Giménez, doi:10.1016/B978-0-12-801899-6.00003-6
Alterations in the epigenetic machineries deregulate different epigenetic substrates, which in turn might be implemented as clinical epigenetic biomarkers for diagnosis, prognosis, and monitoring a wide variety of pathological conditions.

Chapter 20 – DNA Methylation in Neurodegenerative Diseases, Sahar Al-Mahdawi, Sara Anjomani Virmouni and Mark A. Pook, Pages doi:10.1016/B978-0-12-801899-6.00020-6.
This review focuses on our current understanding of the role of DNA methylation and its potential as a biomarker in neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, Huntington’s disease, fragile X-associated tremor/ataxia syndrome, Friedreich ataxia, and spinocerebellar ataxia type 7

Chapter 21 - The Histone Code and Disease: Posttranslational Modifications as Potential Prognostic Factors for Clinical Diagnosis, Nicolas G. Simonet, George Rasti and Alejandro Vaquero, 417-445, doi:10.1016/B978-0-12-801899-6.00021-8.
In this chapter, we summarize the current knowledge on the implications of histone PTMs in diverse human pathologies. We focus on the identified changes in histone modifications and associated enzymes in human diseases, as well as on their potential role in clinical diagnosis.

Disease-Associated Repeat Instability and Mismatch Repair

Monika H.M. Schmidt, Christopher E. Pearson, DNA Repair, Available online 12 December 2015, ISSN 1568-7864, doi: 10.1016/j.dnarep.2015.11.008.

The formation of other unusual DNA and R-loop structures is proposed to play a key role in MMR-mediated instability. A complex correlation is emerging between tissues showing varying amounts of repeat instability and MMR expression levels. Notably, naturally occurring polymorphic variants of DNA repair genes can have dramatic effects upon the levels of repeat instability, which may explain the variation in disease age-of-onset, progression and severity. An increasing grasp of these factors holds prognostic and therapeutic potential.

Pharmacology and Clinical Drug Candidates in Redox Medicine

V. Thao-Vi Dao, Ana I. Casas, Ghassan J. Maghzal, Tamara Seredenina, Nina Kaludercic, Natalia Robledinos-Anton, Fabio Di Lisa, Roland Stocker, Pietro Ghezzi, Vincent Jaquet, Antonio Cuadrado and Harald H.H.W. Schmidt; Antioxid Redox Signal. 2015 November 10; 23(14): 1113–1129. doi: 10.1089/ars.2015.6430

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Other lines of research have focused on targeting NRF2 in degenerative diseases where low-grade chronic inflammation is present. One very potent synthetic triterpenoid, CDDO-methyl ester, bardoxolone methyl, has been studied in great detail for treatment of diabetic nephropathy. The initial excitement about this compound was set back by a small yet significant increase in the risk of heart failure. Importantly though, this effect appears not to be related to NRF2 targeting, but rather to alteration of endothelin signaling, leading to reduction in urine volume and sodium excretion in some patients with advanced chronic kidney disease. Bardoxolone methyl is now being studied in new indications for pulmonary arterial hypertension, melanoma, and Friedreich's ataxia.

Regulating biobanking with children’s tissue: a legal analysis and the experts’ view

Elcke J Kranendonk, M Corrette Ploem and Raoul C M Hennekam; European Journal of Human Genetics (2016) 24, 30–36; doi:10.1038/ejhg.2015.59; published online 15 April 2015

The results of this analysis show that experts have no clear consensus about the appropriate rules for storage of and research with children’s material in biobanks. Development of a framework that provides a fair balance between fundamental paediatric research and privacy protection is necessary.

Antioxidants in Translational Medicine.

Harald H.H.W. Schmidt, Roland Stocker, Claudia Vollbracht, Gøran Paulsen, Dennis Riley, Andreas Daiber and Antonio Cuadrado; Antioxid Redox Signal. 2015 November 10; 23(14): 1130–1143.
doi: 10.1089/ars.2015.6393

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Friedreich Ataxia (Chapter 13)

Mary Kay Koenig, Chapter 13 - In Mitochondrial Case Studies, edited by Russell P. SanetoSumit ParikhBruce H. Cohen, Academic Press, Boston, 2016, Pages 103-112, ISBN 9780128008775, doi:10.1016/B978-0-12-800877-5.00013-9.

Diagnostic considerations, clinical presentation, pathophysiology, and treatment options are discussed.

Analyzing the Effects of a G137V Mutation in the FXN Gene

Nathalie Faggianelli, Rita Puglisi, Liana Veneziano, Silvia Romano, Marina Frontali, Tommaso Vannocci, Silvia Fortuni, Roberto Testi and Annalisa Pastore, Front. Mol. Neurosci., 25 November 2015 | doi:10.3389/fnmol.2015.00066

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This study analyze the effects of a point mutation G137V

IFN-γ for Friedreich ataxia: present evidence.

McKenzie Wells, Lauren Seyer, Kimberly Schadt & David R Lynch; Neurodegenerative Disease Management, Posted online on December 4, 2015, doi:10.2217/nmt.15.52

Systematic review and clinical recommendations for dosage of supported home-based standing programs for adults with stroke, spinal cord injury and other neurological conditions

Ginny Paleg and Roslyn Livingstone. BMC Musculoskelet Disord. 2015; 16: 358. Published online 2015 Nov 17. doi: 10.1186/s12891-015-0813-x

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GIFT-1, a phase IIa clinical trial to test the safety and efficacy of IFNγ administration in FRDA patients.

Christian Marcotulli, Silvia Fortuni, Gaetano Arcuri, Barbara Tomassini, Luca Leonardi, Francesco Pierelli, Roberto Testi, Carlo Casali; Neurological Sciences pp 1-4 First online: 30 November 2015, DOI: 10.1007/s10072-015-2427-3

IFNγ was generally well tolerated, the main adverse event was hyperthermia/fever. Although, increases in frataxin levels could be detected in a minority of patients, these changes were not significant.
Frataxin levels was mesured in peripheral blood multinuclear cells, this are a cell compartment easily accessible but not involved in the disease, In opinion of the researchers it's questionable if it's a real mirror of what happens in sensory neurons, additional and better biomarkers are needed.

Dr Evans–Galea, a leader in the field of gene therapy, talks about the challenges she has faced, but also the increasing visibility of female scientists in her field, and her professional mission: finding a cure for Friedrich ataxia

www.theguardian.com, interview by Brigid Delaney, Tuesday 1 December

The FXN gene was first discovered in the 90s, and there are potential treatments in development. Since then, it has become like a puzzle I couldn’t put down.

La phase de double appui : paramètre prédictif de la dégradation de la marche dans l’ataxie de Friedreich ?

B. Roche, R. Martin, I. Husson, Neurophysiologie Clinique/Clinical Neurophysiology, Volume 45, Issues 4–5, November 2015, Pages 403-404, ISSN 0987-7053, doi: 10.1016/j.neucli.2015.10.040

Alors que l’ICARS n’a pas saisi de dégradation significative, le tapis de marche GAITRite a révélé quant à lui une détérioration significative du double appui, paramètre représentatif, quand il augmente, d’une instabilité à la marche.