Keys to overcoming the challenge of diagnosing autosomal recessive spinocerebellar ataxia / Claves para afrontar el reto diagnóstico de las heredoataxias recesivas

M. Arias, Neurología, Available online 25 July 2016, ISSN 0213-4853, doi:10.1016/j.nrl.2016.06.006

Una cuidadosa evaluación clínica, acompañada de la determinación de ciertos marcadores de laboratorio, la valoración de los datos del estudio electroneuromiográfico y los hallazgos del estudio de resonancia magnética, ayudarán al clínico a establecer unas determinadas sospechas diagnósticas, que siempre procurará confirmar con la detección de la mutación genética causal. El hallazgo de la mutación es decisivo para establecer el pronóstico y consejo genético, además permitirá indicar un tratamiento eficaz en determinadas entidades. Sin diagnóstico genético no será posible realizar investigación básica ni tampoco poner en marcha ensayos terapéuticos.

A thorough assessment of clinical phenotype, laboratory tests, nerve conduction studies, and an magnetic resonance imaging study may help establish a suspected diagnosis, which should be confirmed by detecting the underlying genetic mutation. A positive genetic test result is necessary to determine prognosis and provide adequate genetic counselling, and will also permit appropriate treatment of some entities. Without a genetic diagnosis, conducting basic research and therapeutic trials will not be possible.

OCT in Central Nervous System Diseases

Editors: Grzybowski, Andrzej, Barboni, Piero (Eds.) SPRINGER, ISBN 978-3-319-24085-5

The disorders considered include multiple sclerosis, Parkinson’s disease, Alzheimer’s disease, intracranial hypertension, Friedreich’s ataxia, schizophrenia, hereditary optic neuropathies, glaucoma, and amblyopia. Individual chapters are also devoted to OCT technique, new OCT technology in neuro-ophthalmology, OCT and pharmacological treatment, and the use of OCT in animal models. By documenting the ability of OCT to provide key information on CNS diseases, this book illustrates convincingly that the eye is indeed the “window to the brain”.

Supporting Treatment Adherence in Rare Disease

PM360, Health Psychology by John Weinman, PhD and Kate Perry on May 25th, 2016

Living with a rare disease presents multiple challenges to patients and their families, including those associated with adherence to long-term treatments. As with other chronic conditions, the discipline of health psychology enables us to identify the barriers and motivators specific to individuals with rare disease—and helps us create successful interventions for improved self-management.

Four Key Considerations for Rare Disease Treatment Adherence:
1. Family involvement
2. Lack of local knowledge
3. Perceived stigma
4. Feelings of isolation

The Replication of Frataxin Gene Is Assured by Activation of Dormant Origins in the Presence of a GAA-Repeat Expansion

Stevanoni M, Palumbo E, Russo A (2016). PLoS Genet 12(7): e1006201. doi:10.1371/journal.pgen.1006201

Open access (Creative Commons Attribution License)



In this study we defined the replication program of the FXN gene in human cells, providing for the first time a wide view of origin firing and fork progression within an endogenous genomic context harboring an expanded GAA-repeat. In comparison to the normal FXN sequence, we found an altered replication timing of the mutated alleles. According to our results, the replication of expanded FXN alleles is slowed or delayed during the first half of the S-phase as compared with the wildtype sequence, while a normalization of this effect can be inferred in the second part of the S-phase.

Progression of Friedreich ataxia: quantitative characterization over 5 years

Patel, M., Isaacs, C. J., Seyer, L., Brigatti, K., Gelbard, S., Strawser, C., Foerster, D., Shinnick, J., Schadt, K., Yiu, E. M., Delatycki, M. B., Perlman, S., Wilmot, G. R., Zesiewicz, T., Mathews, K., Gomez, C. M., Yoon, G., Subramony, S. H., Brocht, A., Farmer, J. and Lynch, D. R. (2016), Annals of Clinical and Translational Neurology. doi: 10.1002/acn3.332

Open access article (Creative Commons Attribution-NonCommercial-NoDerivs License)

Objective: Friedreich ataxia (FRDA) is a progressive neurodegenerative disorder of adults and children. This study analyzed neurological outcomes and changes to identify predictors of progression and generate power calculations for clinical trials.

Non-coding RNAs as drug targets

Masayuki Matsui & David R. Corey, Nature Reviews Drug Discovery (2016), doi:10.1038/nrd.2016.117

The ability of ncRNAs to control gene expression makes them potential targets for drug development. However, the drug discovery process is never easy. Uncertainty about how ncRNAs function (and even whether they have a function) makes lead identification and development even more challenging.

Expanded repeats within introns, 3ʹ untranslated regions (UTRs) or 5ʹ UTRs can produce toxic mutant RNAs (for example, as seen in myotonic dystrophy) or affect the production of proteins (for example, as seen in Friedreich ataxia and Fragile X syndrome).

Case study: Friedreich ataxia.Our laboratory has targeted steric-block locked nucleic acid (LNA) ASOs and duplex RNAs to the expanded GAA repeat in cells derived from patients with Friedreich ataxia. These compounds reduce R‑loop formation and increase frataxin mRNA and protein levels to those found in wild-type cells.

A Study to Characterize the Cardiac Phenotype of Individuals With Friedreich's Ataxia (CARFA Study)

ClinicalTrials.gov Identifier: NCT02840669, First received: July 19, 2016

Locations: Hôpital Pitié-Salpêtrière, Paris, France, Sponsors and Collaborators: Annapurna Therapeutics, Adverum Biotechnologies & Weill Medical College of Cornell University

This study is designed to characterize the cardiac manifestations of FA using cardiac magnetic resonance (CMR), echocardiography, serum cardiac biomarkers and evaluation of fatigue severity, in the context of the neurological disease.

Intervention Model: Factorial Assignment
Masking: Open Label
Primary Purpose: Diagnostic

Labile Low-Molecular-Mass Metal Complexes in Mitochondria: Trials and Tribulations of a Burgeoning Field

Paul A. Lindahl and Michael J. Moore, Biochemistry, Article ASAP, DOI: 10.1021/acs.biochem.6b00216, Publication Date (Web): July 19, 2016

Iron, copper, zinc, manganese, cobalt, and molybdenum play important roles in mitochondrial biochemistry, serving to help catalyze reactions in numerous metalloenzymes.
The iron transported through the high-affinity importers mitoferrin 1 and 2 (or Mrs3/4) is ultimately utilized in the biosynthesis of ISC and heme cofactors. Indeed, the majority of Fe that accumulates in mitochondria of frataxin-deficient cells passes through these carrier proteins.
FeIII nanoparticles accumulate in the mitochondria of yeast cells lacking the frataxin homologue (Yfh1), which also contain deficient amounts of ISCs and hemes. What is less commonly realized is that Zn-protoporphyrin IX accumulates in mitochondria from this same strain. Curiously, excess ZnSO4 in the medium prevents the accumulation of Fe in mitochondria of Δyfh1 cells, increases the growth rate of this strain, and mitigates ROS damage. Surprisingly, these responses are not caused by an increase in ISC or heme synthesis, which makes them difficult to explain.

Metal Homeostasis Regulators Suppress FRDA Phenotypes in a Drosophila Model of the Disease

Soriano S, Calap-Quintana P, Llorens JV, Al-Ramahi I, Gutiérrez L, Martínez-Sebastián MJ, Juan Botas, María Dolores Moltó. PLoS ONE 11(7): e0159209. doi:10.1371/journal.pone.0159209

Open Access (Creative Commons Attribution License)

We report several novel genetic modifiers of eye morphology and motor dysfunction in the FRDA fly model. These data provide further support for the notion that disruptions in metal homeostasis may be a primary contributor to FRDA disease pathogenesis.

Crystal Structure of Bacillus subtilis Cysteine Desulfurase SufS and Its Dynamic Interaction with Frataxin and Scaffold Protein SufU

Blauenburg B, Mielcarek A, Altegoer F, Fage CD, Linne U, Bange G, Mohamed A. Marahiel. PLoS ONE 11(7): e0158749. doi:10.1371/journal.pone.0158749

Open access (article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited).

Frenkel: one of the forerunners of neurorehabilitation? / Frenkel: ¿un precursor de la neurorrehabilitación?

Cano-de-la-Cuerda R, Rev Neurol. 2016 Jul 16;63(2):79-84.

[Article in Spanish]

Neurorehabilitation is understood as the process intended to reduce the deficiency, limitation of activity and restriction of participation experienced by people as a result of a neurological diseases, and where the professionals involved in this field will aim to reduce the functional involvement degree of the patient.

Cerebellar Dysfunction and Ataxia in Patients with Epilepsy: Coincidence, Consequence, or Cause?

Filip P, Bareš M, Brázdil M.; Tremor Other Hyperkinet Mov. 2016; 6. doi: 10.7916/D8KH0NBT

Open-access  (article distributed under the terms of the Creative Commons Attribution–Noncommercial–No Derivatives License.)

Other spinocerebellar ataxias might also be accompanied by epilepsy, although this is probably a coincidence. There was a case report of mesiotemporal epilepsy in an SCA13 patient and one of nocturnal frontal lobe epilepsy in an SCA17 patient. There was also a description of epilepsy in patients with Friedreich ataxia. A list of all possible conditions exceeds the scope of this article.

Stalled DNA Replication Forks at the Endogenous GAA Repeats Drive Repeat Expansion in Friedreich’s Ataxia Cells

Jeannine Gerhardt, Angela D. Bhalla, Jill Sergesketter Butler, James W. Puckett, Peter B. Dervan, Zev Rosenwaks, Marek Napierala, Cell Reports, Available online 14 July 2016, ISSN 2211-1247, doi:10.1016/j.celrep.2016.06.075.

Using single-molecule analysis of replicated DNA, we detected that expanded GAA repeats present a substantial obstacle for the replication machinery at the FXN locus in FRDA cells. Furthermore, aberrant origin activation and lack of a proper stress response to rescue the stalled forks in FRDA cells cause an increase in 3′-5′ progressing forks, which could enhance repeat expansion and hinder FXN transcription by head-on collision with RNA polymerases.

Downregulation of GSTK1 Is a Common Mechanism Underlying Hypertrophic Cardiomyopathy

Nishimura Yuhei, Sasagawa Shota, Okabe Shiko, Murakami Soichiro, Ashikawa Yoshifumi, Yuge Mizuki, Kawaguchi Koki, Kawase Reiko, Okamoto Ryuji, Ito Masaaki, TANAKA TOSHIO; Front. Pharmacol., 14 June 2016, doi:10.3389/fphar.2016.00162

Open-access (article distributed under the terms of the Creative Commons Attribution License).

 HCM has multiple etiologies, including mutation in sarcomeric genes such as myosin heavy chain 7 (MYH7) and tropomyosin 1 (TPM1) and in non-sarcomeric genes such as PLN and FXN.Haploinsufficiency of FXN is a major cause of FA. FA is associated with progressive HCM, and this is a common cause of death in FA patients. FXN is an iron-binding protein targeted to the mitochondrial matrix, and consistent with this, mitochondrial function is impaired in FA.  Comparative transcriptomics could represent a new frontier in the search for novel biomarkers and/or therapeutic targets in diseases with multiple etiologies because it facilitates the identification of dysregulated genes common to all disease etiologie. We identified five genes dysregulated in all five HCM transcriptome datasets, among which glutathione S-transferase kappa 1 (Gstk1) was the only gene downregulated. We demonstrate here that knockout of gstk1 in zebrafish increased the expression of HCM marker genes and decreased the cardiac EDV and, to a lesser extent, the ESV, suggesting that downregulation of GSTK1 may be a common mechanism underlying HCM of various etiologies.

Big Data in medical research and EU data protection law: challenges to the consent or anonymise approach

Mostert M, Bredenoord AL, Biesaart MC, van Delden JJ., European Journal of Human Genetics (2016) 24, 956–960; doi:10.1038/ejhg.2015.239; published online 11 November 2015

In recent years, both medical research and the legal landscape have been changing as a result of the rapid developments in information technology (IT). Medical researchers are collecting, re-using and linking health-related and genomic data on an unprecedented scale, based on the presupposition that this research will significantly improve human health. Developments in IT have however led to an increasing concern about the effectiveness of existing data protection law, and the need for a more consistent and comprehensive protection of personal data was recognised in the European Union (EU).

The role of R-loops in the pathology of trinucleotide expansion diseases

Matthias Groh, Natalia Gromak (Supervisor), Thesis, ORA Oxford University Research Archive

Friedreich ataxia and fragile X syndrome are among 40 human diseases associated with expansion of repeated DNA sequences. In both disorders repeat expansion leads to gene silencing, the molecular mechanism of which is not well understood.

Vestibulo-ocular reflex dynamics with head-impulses discriminates spinocerebellar ataxias types 1, 2 and 3 and Friedreich ataxia

Luis, L., Costa, J., Muñoz, E., de Carvalho, M., Carmona, S., Schneider, E., Gordon, C.R., Valls-Solé, J.; Journal of Vestibular Research, vol. 26, no. 3, pp. 327-334, 2016, DOI: 10.3233/VES-160579

Although the diagnosis of inherited ataxias is ultimately genetic, this usually means an extensive and expensive process. This justifies the search for distinct clinical signs that may potentially help orient molecular diagnosis. A correlation between VOR and SARA raises the possibility of using VOR gain as a neurophysiologic biomarker for disease severity.

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