Friedreich’s ataxia and Advanced Heart Failure: An Ethical Conundrum in Decision Making

Peter Ivak, Alena Zumrová, Ivan Netuka, The Journal of Heart and Lung Transplantation, Available online 7 July 2016, ISSN 1053-2498, doi:10.1016/j.healun.2016.06.021

The postoperative course was uneventful and allograft function remained without rejection with preserved function through the follow-up at 100 months. Notably, her neurological status improved and at 8 years stabilized with favorable scores compared to pre-transplant baseline.

 Heart transplant; dilated cardiomyopathy

Deuterium switcheroo breathes life into old drugs

Bethany Halford, Chemical & Engineering News, Volume 94 Issue 27 pp. 32-36 Issue Date: July 4, 2016

Drugmakers juggle isotopes in hopes of achieving novelty, stability, and success. Heavier than hydrogen by a single neutron, deuterium might not seem to have much chemical heft. But the small matter of that subatomic particle makes a massive difference in the reactivity of hydrogen versus its isotope deuterium.

Currently in Friedreich ataxia's Research Pipeline: RT001 (RETROTOPE).


The strategy here is to stabilize the PUFAs and protect the cells from this oxidative damage. One approach to stabilizing the PUFAs is to create mimetics (very similar chemical substitutes) of PUFAs. Retrotope filed their IND with FDA in 2015 and announced enrollment of a 28-day, first-in-human, randomized, double-blind, controlled, ascending dose study of orally dosed RT001 to evaluate the safety, tolerability, pharmacokinetics (PK), disease state, and exploratory endpoints in patients with Friedreich’s ataxia (FA) in August 2015. This study is taking place at University of South Florida and University of California Los Angeles.

Genetic testing in neurology

Henrietta Lefroy, Victoria Harrison, Andrea H. Németh, Medicine, Available online 25 June 2016, ISSN 1357-3039, doi:10.1016/j.mpmed.2016.05.006.

Keywords: Carrier testing; confidentiality; consent; diagnostic testing; genetic testing; neurogenetics; neurology; next-generation sequencing; pre-symptomatic testing

Characteristics of patients contacting a center for undiagnosed and rare diseases

Tobias Mueller, Andreas Jerrentrup, Max Jakob Bauer, Hans Walter Fritsch and Juergen Rolf Schaefer. Orphanet Journal of Rare Diseases201611:81 DOI: 10.1186/s13023-016-0467-2

Open Access: This article is distributed under the terms of the Creative Commons Attribution 4.0 International License

Secondary coenzyme Q10 deficiencies in oxidative phosphorylation (OXPHOS) and non-OXPHOS disorders

Delia Yubero, Raquel Montero, Miguel A. Martín, Julio Montoya, Antonia Ribes, Manuela Grazina, Eva Trevisson, Juan Carlos Rodriguez-Aguilera, Iain P. Hargreaves, Leonardo Salviati, Plácido Navas, Rafael Artuch, Mitochondrion, Available online 30 June 2016, ISSN 1567-7249, http://dx.doi.org/10.1016/j.mito.2016.06.007.

Non-OXPHOS diseases may present with a CoQ deficiency, such as in multiple Acyl-CoA dehydrogenase deficiency (2 patients), apraxia with oculomotor ataxia and Friedreich’s ataxia. However, decreased levels of CoQ seemed not to be a consistent feature in some of these conditions given that patients who had the same disease were found to have both normal or reduced CoQ levels.

Mitochondrial reactive oxygen species and inflammation: Molecular mechanisms, diseases and promising therapies

Alessandro Rimessi, Maurizio Previati, Federica Nigro, Mariusz R. Wieckowski, Paolo Pinton, The International Journal of Biochemistry & Cell Biology, Available online 29 June 2016, ISSN 1357-2725, Doi:10.1016/j.biocel.2016.06.015

Open Access funded by Telethon (Italy), Under a Creative Commons license

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.