A 22-Year Follow-up Study of Long-term Cardiac Outcome and Predictors of Survival in Friedreich Ataxia

Francoise Pousset, MD; Lise Legrand, MD; Marie-Lorraine Monin, MD; Claire Ewenczyk, MD; Perrine Charles, MD, PhD; Michel Komajda, MD; Alexis Brice, MD; Massimo Pandolfo, MD; Richard Isnard, MD, PhD; Sophie Tezenas du Montcel, MD, PhD; Alexandra Durr, MD, PhD. JAMA Neurol. Published online September 28, 2015. doi:10.1001/jamaneurol.2015.1855

Survival in FRDA is determined by cardiac complications, which are dependent on the mutation. The patients with the worse cardiac evolution had longer GAA repeats. Neurological impairment was not predictive of cardiac change over time. Patients with progressive decline of the left ventricular ejection fraction had a worse prognosis. This finding demonstrates that cardiac follow-up is important in FRDA to identify individuals at risk for further cardiac complications.

Monitoring Cardiac Function During Idebenone Therapy in Friedreich's Ataxia

Di Salvo Giovanni, Pergola Valeria, Fadel Bahaa and Al Fayyadh Majid, Current Pharmaceutical Design 21-4, Page: [479 - 483] DOI: 10.2174/138161282104141204142917

This drug has the potential to preserve and even improve mitochondrial function.Studies on Idebenone treatment showed rather conflicting results on FA cardiomyopathy. The present article reviews the clinical features of FA cardiomyopathy, imaging techniques used to diagnose, follow and monitor therapy which aimed to revert FA cardiomyopathy.

Expanded GAA repeats impede transcription elongation through the FXN gene and induce transcriptional silencing that is restricted to the FXN locus

Yanjie Li, Yue Lu, Urszula Polak, Kevin Lin, Jianjun Shen, Jennifer Farmer, Lauren Seyer, Angela D. Bhalla, Natalia Rozwadowska, David R. Lynch, Jill Sergesketter Butler and Marek Napierala; Hum. Mol. Genet. (2015) doi: 10.1093/hmg/ddv397, First published online: September 23, 2015

The GAA-induced silencing effect does not influence expression of neighboring genes upstream or downstream of FXN. The results indicate that approaches aimed to reactivate frataxin expression should simultaneously address deficits in transcription initiation and elongation at the FXN locus.

FXN Promoter Silencing in the Humanized Mouse Model of Friedreich Ataxia

Chutake YK, Costello WN, Lam CC, Parikh AC, Hughes TT, Michalopulos MG, Mark A. Pook, Sanjay I. Bidichandani. (2015) FXN Promoter Silencing in the Humanized Mouse Model of Friedreich Ataxia. PLoS ONE 10(9): e0138437. doi:10.1371/journal.pone.0138437

OPEN ACCESS

Our results indicate that FXN transcriptional deficiency in the YG8sR humanized mouse model of FRDA is caused by deficient transcriptional initiation as a result of promoter silencing. While this mechanism has previously been noted in patient-derived lymphoblastoid cell lines, our present data provide supportive evidence for the existence of this mechanism of transcriptional deficiency in fibroblasts and in multiple tissues. Our data also suggest that the mechanism underlying FXN transcriptional deficiency in FRDA is unlikely to be tissue-specific.

Our data indicate that the YG8sR humanized mouse is a reasonable model for investigating the molecular mechanism(s) underlying repeat-mediated promoter silencing in FRDA. The YG8sR mouse model would also be useful for testing drugs that are designed to reverse the transcriptional initiation defect caused by promoter silencing in FRDA, such as the 2-aminobenzamide derived histone deacetylase inhibitors.

Staging of cardiomyopathy in Friedreich ataxia

Roger E. Peverill, International Journal of Cardiology, Available online 21 September 2015, ISSN 0167-5273, doi: 10.1016/j.ijcard.2015.09.047.


The combination of ECG, LGE and hsTnT with echocardiographic findings in the evaluation of these individuals is of considerable interest as it has suggested that absence of cardiac involvement in FRDA is uncommon. Whether there is any clinical significance of this finding is less certain, as it is not known whether those individuals with minor cardiac changes will ever develop cardiac symptoms or progressive cardiac disease. While the possibility of a staging system for cardiac involvement in FRDA remains of interest, the recent proposal may be considered premature given the limitations of our knowledge about the natural history of cardiac disease in FRDA.


Paper review:: The Cardiomyopathy in Friedreich’s Ataxia – New Biomarker for Staging Cardiac Involvement. Frank Weidemann, Dan Liu, Kai Hu, Cristiane Florescu, Markus Niemann, Sebastian Herrmann, Bastian Kramer, Stephan Klebe, Kathrin Doppler, Nurcan Üçeyler, Christian Oliver Ritter, Georg Ertl, Stefan Störk, International Journal of Cardiology, Available online 15 May 2015, ISSN 0167-5273, doi:10.1016/j.ijcard.2015.05.074.

Delayed-onset Friedreich's ataxia revisited

Lecocq, C., Charles, P., Azulay, J.-P., Meissner, W., Rai, M., N'Guyen, K., Péréon, Y., Fabre, N., Robin, E., Courtois, S., Guyant-Maréchal, L., Zagnoli, F., Rudolf, G., Renaud, M., Sévin-Allouet, M., Lesne, F., Alaerts, N., Goizet, C., Calvas, P., Eusebio, A., Guissart, C., Derkinderen, P., Tison, F., Brice, A., Koenig, M., Pandolfo, M., Tranchant, C., Dürr, A. and Anheim, M. (2015). Mov. Disord.. doi: 10.1002/mds.26382

Typical- and delayed-onset Friedreich's ataxia are different and Friedreich's ataxia is heterogeneous. Late-onset Friedreich's ataxia and very-late-onset Friedreich's ataxia appear to belong to the same clinical and molecular continuum and should be considered together as “delayed-onset Friedreich's ataxia.” 

Does tandem walking discriminate better than normal walking among children with DCD, ataxia and healthy controls? A preliminary analysis performed with IMUs on the trunk

D. Trojaniello, A. Mannini, D. Sival, H.J. Blok, A.M. Sabatini, U. Della Croce, Gait & Posture, Volume 42, Supplement 2, September 2015, Page S10, ISSN 0966-6362,doi: 10.1016/j.gaitpost.2015.07.028.

Significant differences were found between FRDA and H children and FRDA and DCD children for most of IMU-St and IMUSp variables. Variables extracted from both IMU-Sp and IMUSt during TW were able to discriminate between FRDA and DCD children and between FRDA and H children.

Friedreich Ataxia: From the Eye of a Molecular Biologist

Muthuswamy, Srinivasan MSc; Agarwal, Sarita PhD; Neurologist: September 2015 - Volume 20 - Issue 3 - p 51–55 doi: 10.1097/NRL.0000000000000054
Review Article

Protein replacement therapy for mitochondrial disorders

M. Rapoport, D. Marcus, A. Saada, T. Erlich, R. Hadad, H. Greif, M. Lichtenstein, H. Lorberboum-Galski, Mitochondrion, Volume 24, Supplement, September 2015, Page S35, ISSN 1567-7249, doi:10.1016/j.mito.2015.07.096.

The approach is to fuse the Mitochondrial targeting Sequence (MTS), with the delivery peptide TAT [HIV-transactivator of transcription (TAT) peptide]. This novel approach has been tested using different mitochondrial proteins implicated in mitochondrial human diseases: Lipoamide Dehydrogenase (LAB), C6ORF66 and Frataxin, and have been evaluated in vitro, in patients' cells and in vivo, in mouse models. In patient's cells and in mice tissues, including the brain, AT-MTS-Mitochondrial fusion proteins arrive at the cells and their mitochondria rapidly and efficiently, getting an improvement of the mitochondrial functions and life span in animal models.

Repurposing riluzole to treat hereditary cerebellar ataxia

Heather Wood; Nature Reviews Neurology (2015) doi:10.1038/nrneurol.2015.161 Published online 15 September 2015

Given the limited availability of new therapies for neurological disease, repurposing of existing drugs is an approach that is being increasingly explored. A randomized controlled trial, conducted in Italy provides evidence that this drug could also be beneficial in patients with hereditary cerebellar ataxia, spinocerebellar ataxia and Friedreich ataxia.

R loops: new modulators of genome dynamics and function

José M. Santos-Pereira & Andrés Aguilera, Nature Reviews Genetics (2015) doi:10.1038/nrg3961, Published online 15 September 2015

R loops are also a major threat to genome stability. For this reason, several DNA and RNA metabolism factors prevent R-loop formation in cells. Dysfunction of these factors causes R-loop accumulation, which leads to replication stress, genome instability, chromatin alterations or gene silencing. Importantly, Friedreich ataxia (FRDA) and fragile X syndrome (FXS) occur as a result of repeat expansions in the frataxin (FXN) and fragile X mental retardation 1 (FMR1) genes, respectively; this leads to gene silencing through H3K9me2 deposition on the expanded regions, which thus become fragile. Such expansions accumulate R loops, providing a new link among heterochromatin, R loops and replication-dependent fragility. 

Jones Tendon Transfer

Richard Derner, Jeffrey Holmes, Clinics in Podiatric Medicine and Surgery, Available online 12 September 2015, ISSN 0891-8422, http://dx.doi.org/10.1016/j.cpm.2015.06.004.

Charcot-Marie-Tooth (CMT), poliomyelitis, Roussy-Le´vy syndrome, and Friedreich ataxia are the most common lower motor neuron diseases causing disorders of the foot and lower extremities.

MRI Texture Analysis Reveals Bulbar Abnormalities in Friedreich Ataxia

T.A. Santos, C.E.B. Maistro, C.B. Silva, M.S. Oliveira, M.C. França Jr and G. Castellano; AJNR Am J Neuroradiol. Published online before print September 10, 2015, doi: 10.3174/ajnr.A4455

Gray level co-occurrence matrix–based texture analysis showed statistically significant differences for the medulla oblongata of patients with Friedreich ataxia compared with controls. These results highlight the medulla as an important site of damage in Friedreich ataxia. 

Characterisation of the retinal pigment epithelium in Friedreich ataxia

Duncan E. Crombie, Nicole Van Bergen, Kathryn C. Davidson, Sara Anjomani Virmouni, Penny A. Mckelvie, Vicki Chrysostomou, Alison Conquest, Louise A. Corben, Mark A. Pook, Tejal Kulkani, Ian Trounce, Martin F. Pera, Martin B. Delatycki, Alice Pébay; Biochemistry and Biophysics Reports, Available online 11 September 2015, ISSN 2405-5808, http://dx.doi.org/10.1016/j.bbrep.2015.09.003

OPEN ACCESS

Redox- and non-redox-metal-induced formation of free radicals and their role in human disease

Marian Valko , Klaudia Jomova, Christopher J. Rhodes, Kamil Kuča, Kamil Musílek; Archives of Toxicology, First online: 07 September 2015 DOI:10.1007/s00204-015-1579-5

Frataxin is a mitochondrial iron chaperone protein and plays a key role in the insertion of ferrous ions during the assembly of iron–sulfur clusters in the mitochondrial respiratory chain. The defect leads to the release of mitochondrial iron with in turn may catalyze hydroxyl radical formation via Fenton chemistry.

OUHSC professor, researcher gets $300,000 grant for research

The Oklahoma Daily; Wed Sep 9, 2015.

The three-year grant of $300,000 will fund research into promising therapies for a neuromuscular disease known as Friedreich's ataxia. Sanjay Bidichandani, is a professor of pediatrics at the OU College of Medicine and has worked at OU in the field of genetic research since 2000. Bidichandani’s research will evaluate the effectiveness of a new drug class known as HDAC inhibitors. 

Prospects of gene and cell therapy for managing cardiac complications in Friedreich ataxia

Charles J Isaacs, Julianna E Shinnick, Kimberly Schadt, David R Lynch & Kimberly Y Lin; Expert Opinion on Orphan Drugs, Published online: 02 Sep 2015 DOI: 10.1517/21678707.2015.1083854

The state of research into gene and cell therapy for cardiac issues in FRDA is one that deserves cautious optimism. As these therapies move closer to testing in humans, researchers will need to identify proper dosing and delivery methods based on the nature of the patient’s disease, as well as which patient groups are most likely to realize benefits from proposed treatments. Future studies must further assess risk in larger animals and plan ways to minimize risk in human trials.

Quantitative evaluation of gait ataxia by accelerometers

Shinichi Shirai, Ichiro Yabe, Masaaki Matsushima, Yoichi M. Ito, Mitsuru Yoneyama, Hidenao Sasaki, Journal of the Neurological Sciences, Available online 3 September 2015, ISSN 0022-510X, http://dx.doi.org/10.1016/j.jns.2015.09.004.

Effect of power-assisted hand-rim wheelchair propulsion on shoulder load in experienced wheelchair users: A pilot study with an instrumented wheelchair

Marieke G.M. Kloosterman, Jaap H. Buurke, Wiebe de Vries, Lucas H.V. Van der Woude, Johan S. Rietman, Medical Engineering & Physics, Available online 22 August 2015, ISSN 1350-4533, http://dx.doi.org/10.1016/j.medengphy.2015.07.004.

According to the guidelines, in order to create a better balance between mechanical loading and the work-capacity of the shoulder complex during propulsion, power-assisted propulsion on a treadmill is effective in reducing the majority of the potential risk factors of shoulder injury. Therefore, the use of power-assisted wheelchairs might be indicated for subjects prone to developing overuse injuries due to hand-rim propulsion or subjects with difficulties driving a hand-rim wheelchair primarily due to lack of upper-extremity power.

Friedreich ataxia in Norway – an epidemiological, molecular and clinical study

Iselin Marie Wedding, Mette Kroken, Sandra Pilar Henriksen, Kaja Kristine Selmer, Torunn Fiskerstrand, Per Morten Knappskog, Tone Berge and Chantal ME Tallaksen; Orphanet Journal of Rare Diseases 2015, 10:108 doi:10.1186/s13023-015-0328-4

OPEN ACCESS

Twenty-nine Friedreich ataxia patients were identified in Norway, of which 23 were ethnic Norwegian, corresponding to a prevalence of 1:176 000 and 1:191 000, respectively. The highest prevalence was seen in the north. Carrier frequency of 1:196 (95 % CI = [1:752–1:112]) was found.

Pilot Study of a 3d Motion Device- Feasibility Assessment in Patients with Parkinson’s Disease and Friedreich’s Ataxia

Disease Category: Friedreich's Ataxia
Location: University of South Florida- Mosani Center for Advnaced Healthcare, Tampa, FL 33612 United States

This study includes the use of a 3D motion device that measures movement in three directions. It is being used as part of this research study to find out if it accurately tracks motion so it can be used in other ataxia research trials in the future.

EUCHROMATIC REGION TARGETING METHODS FOR MODULATING GENE EXPRESSION

United States Patent Application 20150232858, Inventors: Ozsolak, Fatih (Boston, MA, US), RaNA Therapeutics, Inc. (Cambridge, MA, US). Publication Date: 08/20/2015


According to some aspects of the invention, methods and compositions are provided herein that are useful for increasing gene expression in a targeted and specific manner. Aspects of the invention are based on the identification of euchromatic regions of genes that overlap with sequences encoding antisense RNA transcripts. It has been found that oligonucleotides that are complementary to these particular euchromatic regions of target genes are useful for increasing expression of target genes when delivered to cells. In some embodiments, oligonucleotides are provided that are complementary with these euchromatic regions and that have chemistries suitable for delivery, hybridization and stability within cells. Furthermore, in some embodiments, oligonucleotide chemistries are provided that are useful for controlling the pharmacokinetics, biodistribution, bioavailability and/or efficacy of the oligonucleotides in vivo. Accordingly, in some embodiments, oligonucleotides provided herein are useful for the treatment of diseases or conditions associated with decreased levels of target genes.....

Friedreich's Ataxia Symposium, Date: Oct 12

Date: Oct 12, 7:30 a.m.-4:00 p.m. (ET). DoubleTree by Hilton Hotel Philadelphia – Valley Forge. 301 West DeKalb Pike, King of Prussia, PA 19406

The Friedreich’s Ataxia Center of Excellence at The Children’s Hospital of Philadelphia is pleased to present this one-day symposium providing patients and families with up-to-date clinical information on therapeutic approaches and current research being conducted in the field of Friedreich’s ataxia.

University of South Florida and Friedreich's Ataxia Research Alliance to host scientific symposium

EurekAlert. Pharma, biotech leaders to discuss new clinical studies testing drugs and gene therapy for FA. University of South Florida (USF Health)

Tampa, FL (Sept 1, 2015) -- The University of South Florida (USF) will again bring together leading researchers and patients searching for a treatment for Friedreich's ataxia and related disorders at the seventh annual scientific symposium "Understanding Energy for A Cure." The symposium will be held 5 to 8:30 p.m., Thursday, Sept. 17, at the USF Marshall Student Center Ballroom, USF Cedar Circle, Tampa, FL 33620.