Interferon gamma may improve cardiac function in Friedreich's ataxia cardiomyopathy

Vegard Bruun Wyller, Kristine Jacobsen, Mai Britt Dahl, Hilde Nilsen, Simone Proske, Thorsten Horter, Henrik Brun, International Journal of Cardiology, Available online 29 June 2016, ISSN 0167-5273, Doi:10.1016/j.ijcard.2016.06.288

Here, we report the effect of INFγ therapy in a single patient suffering from severe FRDA cardiomyopathy. In conclusion, INFγ treatment seemed to attenuate cardiomyocyte damage and improve diastolic function in our patient. No serious side effects were registered. Thus, INFγ treatment might be a promising therapy option for FRDA hypertrophic cardiomyopathy. Results from a case report must be interpreted with great caution; ideally, a randomised controlled trial should be undertaken in order to assess the effects and safety of INFγ treatment in FRDA cardiomyopathy.

PPARγ as a therapeutic target to rescue mitochondrial function in neurological disease

Juan Carlos Corona, Michael R. Duchen, Free Radical Biology and Medicine, Available online 25 June 2016, ISSN 0891-5849, doi:10.1016/j.freeradbiomed.2016.06.023.

We discuss the mechanisms underlying those beneficial effects in particular in relation to mitochondrial function, antioxidant defence, cell death and inflammation, and suggest that the PPAR-gamma agonists show significant promise as therapeutic agents in otherwise intractable neurological disease.
The effect of PPAR-gamma activation has also been studied in Friedreich’s ataxia, Pioglitazone, which seems to have fewer side effects than rosiglitazone is on a phase III clinical trial for its neuroprotective properties. The project, titled "Effect of pioglitazone administered to patients with Friedreich’s ataxia: proof of concept". However, the antecedents and possible consequences should be taken into consideration when PPAR-gamma agonist drugs are considered as possible therapeutic agents for FRDA patients.

Loss of Frataxin induces iron toxicity, sphingolipid synthesis, and Pdk1/Mef2 activation, leading to neurodegeneration

Kuchuan Chen Guang Lin Nele A Haelterman Tammy Szu-Yu Ho Tongchao Li Zhihong Li Lita Duraine Brett H Graham Manish Jaiswal Shinya Yamamoto Matthew N Rasband Hugo J Bellen, eLife 2016; DOI:10.7554/eLife.16043

Our results indicate that an iron/sphingolipid/PDk1/Mef2 pathway may play a role in FRDA. We show that loss of frataxin homolog (fh) in Drosophila leads to iron toxicity, which in turn induces sphingolipid synthesis and ectopically activates 3-phosphoinositide dependent protein kinase-1 (Pdk1) and myocyte enhancer factor-2 (Mef2)

Characterization of frataxin gene network in Friedreich's ataxia fibroblasts using the RNA-Seq technique

Noëlia Sanchez, Pierre Chapdelaine, Joël Rousseau, Frédéric Raymond, Jacques Corbeil, Jacques P. Tremblay, Mitochondrion, Available online 25 June 2016, ISSN 1567-7249, doi:10.1016/j.mito.2016.06.003

The study identified key players of FXN gene regulatory network and highlighted the role of FXN in the regulation of hemostasis, angiogenesis, interferon-induced apoptosis and DNA damage in FRDA. Since no efficient cure exists to treat FRDA patients, understanding the regulatory network of FXN is requisite to develop promising therapies for this debilitating condition.
This work provides valuable insight into the regulatory network of frataxin and may open new avenues for gene therapy of Friedreich's ataxia.

Cognition in Friedreich's ataxia: a behavioral and multimodal imaging study

Dogan, I., Tinnemann, E., Romanzetti, S., Mirzazade, S., Costa, A. S., Werner, C. J., Heim, S., Fedosov, K., Schulz, S., Timmann, D., Giordano, I. A., Klockgether, T., Schulz, J. B. and Reetz, K. (2016), Annals of Clinical and Translational Neurology. doi: 10.1002/acn3.315

Open

Is it your Disease or the Patient’s?

Sami L. Bahna, Alexandria Brackett, The American Journal of the Medical Sciences, Available online 24 May 2016, ISSN 0002-9629, doi:10.1016/j.amjms.2016.05.016.

When the illness has several clinical and/or laboratory features but not all features are present in every patient it is usually called a syndrome rather than a disease.

Strictly speaking, apostrophe “s” reflects possessiveness. It is correct when the syndrome or disease is named after the first described patient e.g. Lou Gehrig’s disease. Much more commonly, a syndrome or disease has been linked to the name of the physician or scientist who first described it, as an honorific eponym, e.g. Friedreich ataxia. In such instances, an apostrophe or an “s” should not be used.

Cortico-cerebellar dysfunctions underlying executive deficits in Friedreich’s ataxia

22nd Annual Meeting of the Organization for Human Brain Mapping. Poster Session Tuesday, June 28, 2016. Imis Dogan, Eugenie Tinnemann, Sandro Romanzetti, Shahram Mirzazade, Ana Costa, Cornelius Werner, Stefan Heim, Kathrin Fedosov, Stefanie Schulz, Dagmar Timman-Braun, Ilaria Giordano, Thomas Klockgether, Jörg Schulz, Kathrin Reetz.

Neuropsychological test data provides evidence of executive impairment in individuals with FRDA, in particular pertaining to phonemic verbal fluency and social cognition. During phonological processing, the observed pattern of increased cerebellar and cortical neural response accompanied by impaired cortico-cerebellar functional coupling indicates dysfunctions in cerebro-cerebellar pathways and functional reorganization, which may be driven by disease-related cerebellar damage.

The New Genetic Inheritance: Mechanisms of Inheritance That Mendel Would Not Have Predicted With Sweet Peas

R. Douglas Wilson, Journal of Obstetrics and Gynaecology Canada, Available online 7 June 2016, ISSN 1701-2163, doi:10.1016/j.jogc.2016.04.091.

Most importantly this update is intended to help readers know when they need assistance from a reproductive geneticist for making decisions and providing choices.
TNR disorders are due to genomic instability/expansion. The effects of the TNR expansion are varied with loss of gene expression, a gain of gene function, or abnormal RNA processing. TNR disorders include conditions such as fragile X syndrome, myotonic dystrophy, Huntington disease, spinal bulbar muscular atrophy, and Friedreich ataxia (as well as other inherited ataxias)

Directions for new developments on statistical design and analysis of small population group trials

Ralf-Dieter Hilgers, Kit Roes, Nigel Stallard and for the IDeAl, Asterix and InSPiRe project groups. Orphanet Journal of Rare Diseases 201611:78 DOI: 10.1186/s13023-016-0464-5.

Open Access. Creative Commons Attribution 4.0 International License

This paper aims to raise awareness of the ongoing research and stimulate other groups to work on statistical methodology on design and analysis of clinical trials in small populations. Having well informed researchers, physicians and biostatisticians will result in the use of more efficient methods to conduct a clinical trial in small population groups and thus bring approved treatments faster to our patients.

Oxidative stress in neurological disease: Is it the cause, consequence, or trigger of a chronic progressive form?

J.A. Serra, E.R. Marschoff, R.O. Domínguez, Neurología (English Edition), Available online 17 June 2016, ISSN 2173-5808, doi:10.1016/j.nrleng.2016.06.003.

Systemic oxidative stress (OS) is basically an imbalance between the production of such oxi-dants as reactive oxygen species (ROS) and reactive nitrogenspecies (RNS), and the capacity to neutralise their detrimental effects through both exogenous (diet and medication) and endogenous antioxidants.
Systemic OS is increased in such entities as Alzheimer disease(AD), Parkinson’s disease (PD), amyotrophic lateral sclero-sis (ALS), chronic vascular encephalopathy (CVE), epilepsy,and Friedreich ataxia, among others. Reaching a balance between ROS andantioxidants may possibly diminish the risk of progression of these entities. Therefore, an emphasis should be made on the development of pharmacological studies aimed atminimising systemic OS.

Promising gene therapies pose million-dollar conundrum

Erika Check Hayden, Nature 534, 305–306 (16 June 2016) doi:10.1038/534305a.

Economists, investors and medical insurers can’t figure out how to pay for cutting-edge drugs.
Many of the treatments deliver corrective genes using a modified virus that is considered safer than vectors used in earlier attempts. But many of the target disorders are rare, limiting the population that can be treated. And there are often no previously approved drugs that work similarly, removing the pressure on companies to lower their prices.

Deep sequencing of mitochondrial genomes reveals increased mutation load in Friedreich's ataxia

Angela D. Bhalla, Alireza Khodadadi-Jamayran, Yanjie Li, David R. Lynch and Marek Napierala. Annals of Clinical and Translational Neurology. doi: 10.1002/acn3.322

Open access Creative Commons Attribution-NonCommercial-NoDerivs License

Next-generation sequencing of FRDA mitochondrial genomes revealed a widespread increase in mutation load in patient fibroblasts. Although mtDNA damage alone can have profound consequences within the cell, low expression of FXN may also affect the nuclear genome as recent studies have demonstrated shortening of telomeres in cells derived from FRDA patients.

Diagnosis and management of adult hereditary cardio-neuromuscular disorders: A model for the multidisciplinary care of complex genetic disorders

R. Brian Sommerville, Margherita Guzzi Vincenti, Kathleen Winborn, Anne Casey, Nathan O. Stitziel, Anne M. Connolly, Douglas L. Mann, Trends in Cardiovascular Medicine, Available online 14 June 2016, ISSN 1050-1738, Doi:10.1016/j.tcm.2016.06.005.

We advocate the development of interdisciplinary cardio-neuromuscular clinics to optimize the care for these patients.
Friedreich Ataxia: Although progressive debilitating ataxia is the most prominent clinical finding in FRDA and generally precedes the onset of cardiac symptoms, heart failure and arrhythmias account for at least 60% of the mortality in FRDA. Importantly, in patients with advanced neurological disease, a subclinical hypertrophic cardiomyopathy may be present despite the absence of overt cardiac symptoms.

Obstructive Form of Hypertrophic Cardiomyopathy-Left Ventricular Outflow Tract Gradient: Novel Methods of Provocation, Monitoring of Biomarkers, and Recent Advances in the Treatment.

Pawel Petkow Dimitrow and Renata Rajtar-Salwa. Biomed Res Int. 2016; 2016: 1575130. Published online 2016 May 10. doi: 10.1155/2016/1575130

Open access article distributed under the Creative Commons Attribution License

From a practical point of view, the effective monitoring, including biochemical biomarkers indicating reduction of LVOT gradient, is important because this parameter has become a risk factor for sudden death in the 2014 ESC guideline. In this context, the maximized physiological LVOT gradient provocation stimulus seems to be an important diagnostic element. Novel invasive therapeutic techniques have been recently dynamically developed, providing attractive treatment opportunities.
Septal myectomy may be a viable option to relieve symptoms and interrupt progression of heart disease also in selected Friedreich's ataxia patients.

STEADFAST Long-Term Safety Extension

ClinicalTrials.gov. First received: June 2, 2016. ClinicalTrials.gov Identifier: NCT02797080. Sponsor: Horizon Pharma Ireland, Ltd., Dublin Ireland.
Official Title: Long-Term Safety Extension Study of ACTIMMUNE® (Interferon γ-1b) in Children and Young Adults With Friedreich's Ataxia

 Phase 3

ACTIMMUNE® will be administered three times per week by subcutaneous injection. The initial dose will be individualized for each participant and will be determined by the investigator, provided that the initial dose does not exceed the maximum tolerated dose in HZNP-ACT-302 (NCT02593773). The investigator may subsequently adjust the dose for any participant if deemed clinically appropriate, provided that the dose does not exceed 100 μg/m2.

Oxidative Stress and altered lipid metabolism in Friedreich ataxia

Jordi Tamarit, Èlia Obis, Joaquim Ros, Free Radical Biology and Medicine, Available online 11 June 2016, ISSN 0891-5849, doi: 10.1016/j.freeradbiomed.2016.06.007.

Lipid metabolism is compromised in FA and therefore is emerging as a new potential therapeutic target. Current approaches are also meant to restore mitochondrial function, improve energy metabolism and decrease oxidative stress. Ongoing clinical trials will reveal the potential of these therapeutic strategies to attenuate disease progression.

Classifications of neurogenetic diseases: An increasingly complex problem

J.-M. Vallat, C. Goizet, M. Tazir, P. Couratier, L. Magy, S. Mathis. Revue Neurologique, Available online 27 May 2016, ISSN 0035-3787, doi:org/10.1016/j.neurol.2016.04.005.

Neurodegenerative disorders represent a wide group of diseases affecting the central and/or peripheral nervous system. Many of these disorders were described in the 19th century, but our genetic knowledge of them is recent (over the past 25 years). However, the continual discovery of disease-causing gene mutations has led to difficulties in the classification of these diseases.
The nomenclature used in each case also requires the name of the mutated gene: for example Friedreich’s ataxia becomes ‘‘AR-CA-FXN’’. Nevertheless, these designations could allow some exceptions to be retained, such as names that are very well known, such as Friedreich’s ataxia and ataxia–telangiectasia.

NRF2 activators: how do they work and how advanced is their clinical use?

Antonio Cuadrado, Free Radical Biology and Medicine, Volume 96, Supplement 1, July 2016, Pages S6-S7, ISSN 0891-5849, doi:10.1016/j.freeradbiomed.2016.04.043

The transcription factor, nuclear factor (erythroid-derived 2)-like 2 (NRF2) is a master regulator of cell homeostasis that regulates the expression of antioxidant and cytoprotective genes. The synthetic triterpenoid CDDO-methyl ester (also known as bardoxolone methyl) is being studied for therapy of diabetic nephropathy, pulmonary arterial hypertension, melanoma and Friedreich ataxia.

Responsible implementation of expanded carrier screening

Lidewij Henneman, Pascal Borry, Davit Chokoshvili, Martina C Cornel, Carla G van El, Francesca Forzano, Alison Hall, Heidi C Howard, Sandra Janssens, Hülya Kayserili, Phillis Lakeman, Anneke Lucassen, Sylvia A Metcalfe, Lovro Vidmar, Guido de Wert, Wybo J Dondorp and Borut Peterlin on behalf of the European Society of Human Genetics (ESHG).European Journal of Human Genetics (2016) 24, e1–e12; doi:10.1038/ejhg.2015.271; published online 16 March 2016

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.

There are currently 1300 known recessive (autosomal and X-linked) diseases and about 100 of these have a prevalence of >1/100 000. Several important conditions, for example, Duchenne/Becker muscular dystrophy and Friedreich ataxia are not included in any of the commercial panels, presumably due to technological limitations of the microarray-based testing approach (eg, trinucleotide repeat mutations). We propose that, pending convincing evidence to the contrary, retaining a ‘serious congenital and childhood onset disorders’ scope is important in panel design.

Histone deacetylase inhibitors modulating non-epigenetic players: The novel molecular targets for therapeutic intervention

Shabir Ahmad Ganai. Current Drug Targets, Volume 17 DOI: 10.2174/1389450117666160527143257

Emerging evidences suggest that acetylation of non-histone proteins plays a critical role in various cellular processes including mRNA stability, protein localization and degradation. Abnormal turnover or expression of non-histone proteins like nuclear factor- kappaB (NF-кB), heat shock protein 90 (HSP90) and frataxin fuels various diseases including cancer.

Quantifying benefit-risk preferences for new medicines in rare disease patients and caregivers

T. Morel, S. Aymé, D. Cassiman, S. Simoens, M. Morgan and M. Vandebroek. Orphanet Journal of Rare Diseases 2016 DOI: 10.1186/s13023-016-0444-9

This study aimed to explore what they consider of value when choosing between hypothetical therapeutic options and to quantify both their benefit-risk preferences and the influence of disease context.

Our study data confirmed that patients and their caregivers were willing to accept greater risk or side effects associated with a new medicine, for instance, in the hope for some extra chance in drug response or greater health improvement potential. Attitudes about benefit-risk may change over time with disease progression or context of care.

In that context, we believe that patients and caregivers should be increasingly involved as active research partners in the development of clinical outcomes assessments – including patient-reported outcomes (PRO) measures – that directly evaluate how the patient feels, functions or survives. If a treatment effect is not meaningful to the patient, it is not a benefit to the patient.

Open Access
This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://​creativecommons.​org/​licenses/​by/​4.​0/​)

The hereditary ataxias: Where are we now? Four decades of local research

D C Smith, L J Greenberg, A Bryer. South African Medical Journal 2016;106(6):S38. DOI:10.7196/SAMJ.2016.v106i6.10989

The hereditary ataxias have been studied at the University of Cape Town for more than 40 years, following from initial clinical investigations by Beighton and colleagues in the early 1970s.
Thirty-seven of these individuals (from 30 families) had molecularly confirmed FRDA. To the best of our knowledge, no individuals of indigenous black African ethnic origin have been given a confirmed molecular diagnosis of FRDA. The vast majority of confirmed FRDA patients in SA are of European ancestry, along with a single family of Indian origin.

The significance of intercalated discs in the pathogenesis of Friedreich cardiomyopathy

Arnulf H. Koeppen, Alyssa B. Becker, Paul J. Feustel, Benjamin B. Gelman, Joseph E. Mazurkiewicz. Journal of the Neurological Sciences, Available online 4 June 2016, ISSN 0022-510X, doi: 10.1016/j.jns.2016.06.006.

Highlights
-The most frequent cause of death in Friedreich ataxia is cardiomyopathy
-Abnormal intercalated discs contribute to Friedreich cardiomyopathy
-Intercalated discs and gap junctions are normal in long-surviving patients

Aspects éthico-sociétaux liés à l’utilisation de la technique d’édition du génome CRISPR-Cas9 (FR)

INSERM (Institut National de la santé et de la recherche médicale). Comité éthique Inserm février 2016.

Saisine concernant les questions liées au développement de la technologie CRISPR (clustered regularly interspaced short palindromic repeat)-Cas9.
L’ingénierie du génome ou « Editer le génome » (traduit ainsi de l’anglais « genome editing ») consiste à ajouter, enlever, modifier une ou quelques bases dans une séquence d’ADN. Si la séquence correspond à un gène, la conséquence en sera la modification d’expression de ce gène, soit son « invalidation » (perte de fonction, knock-down), soit la modification de la séquence protéique de la protéine qu’il code et dans certains cas le changement d’activité ou de localisation ou de durée de vie ou au contraire la correction d’une fonction altérée, selon le contexte biologique.
De quoi s’agit-il ?, CRISPR-Ccas 9 est en quelque sorte un ciseau moléculaire capable d’induire une cassure double brin de l’ADN en un site choisi du génome.

Le principe de précaution peut être invoqué lorsqu’un phénomène, un produit ou un procédé peut avoir des effets potentiellement dangereux, identifiés par une évaluation scientifique et objective, si cette évaluation ne permet pas de déterminer le risque avec suffisamment de certitude.

10 top patient groups oppose REGROW Act that would gut stem cell oversight

The Niche, Knoepfler lab stem cell blog. June 1, 2016.

The REGROW Act would drastically weaken FDA regulation of experimental stem cell therapies.

Patient Groups Opposing REGROW

Cystic Fibrosis Foundation
Friedreich’s Ataxia Research Alliance
Friends of Cancer Research
Global Genes
Michael J. Fox Foundation for Parkinson’s Research
Myotonic Dystrophy Foundation
National MS Society
National Organization for Rare Disorders
National Patient Advocate Foundation
Prevent Cancer Foundation

US FDA Grants Orphan Drug Designation for Retrotope's RT001 in the Treatment of Friedreich's Ataxia

LOS ALTOS, CA -- (Marketwired) -- 06/01/16 -- Retrotope announced today that the U.S. Food and Drug Administration (FDA) Office of Orphan Products Development granted orphan drug designation for its stabilized fatty acid drug (RT001) for the treatment of Friedreich's ataxia (FA).

Epoetin Alpha Improves Upper-Limb Dexterity in Patients With Friedreich’s Ataxia: Presented at EAN

FirstWord Pharma, By Chris Berrie.

COPENHAGEN, Denmark -- May 31, 2016 -- Epoetin alpha does not modify frataxin levels or improve physical performance in patients with the debilitating, degenerative neuromuscular disorder known as Friedreich’s ataxia, although it progressively ameliorates upper-limb dexterity compared with placebo, according to results presented at the 2nd Congress of the European Academy of Neurology (EAN).