Role of neuroimaging in the diagnosis of hereditary cerebellar ataxias in childhood

Giulia Perucca, Nicolas Leboucq, Agathe Roubertie, François Rivier, Nicolas Menjot, Consuelo Valentini, Alain Bonafe, Journal of Neuroradiology, Available online 25 April 2016, ISSN 0150-9861, doi:10.1016/j.neurad.2016.03.006.

Friedreich ataxia (FA) is characterized on MRI bynormal morphology of the cerebellum and brainstem, withatrophy of the spinal cord . A rare involvementof dentate nuclei has been described. Cerebellaratrophy occurs late in the course of the disease.

Mitochondrial DNA damage induced autophagy, cell death, and disease

Bennett Van Houten, Senyene E. Hunter, and Joel N. Meyer; Frontiers in Bioscience, Landmark, 21, 42-54, January 1, 2016.
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Several human pathologies have been associated with free radical damage and subsequent mtDNA damage and mitochondrial dysfunction. These diseases include diabetes mellitus, liver diseases (e.g. hemochromatosis), cardiovascular disease (e.g. atherosclerosis) and several neurodegenerative diseases (e.g. Alzheimer’s, Parkinson’s Disease, Friedreich’s Ataxia and Huntington’s disease). In fact, multiple studies have linked human diseases associated with oxidative stress and loss of mitochondrial function to mtDNA damage

Genome Engineering with TALE and CRISPR Systems in Neuroscience

Han B. Lee, Brynn N. Sundberg, Ashley N. Sigafoos, and Karl J. Clark. Front Genet. 2016; 7: 47. doi: 10.3389/fgene.2016.00047

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These technologies mirror and extend beyond classic gene targeting methods contributing to the development of novel tools for basic and clinical neuroscience. In this Review, we discuss the recent development in genome engineering and potential applications of this technology in the field of neuroscience.

Neurodegenerative diseases and therapeutic strategies using iron chelators

Roberta J. Ward, David T. Dexter, Robert R. Crichton, Journal of Trace Elements in Medicine and Biology, Volume 31, July 2015, Pages 267-273, ISSN 0946-672X, doi: 10.1016/j.jtemb.2014.12.012.

Evidence for metal involvement in Parkinson's and Alzheimer's disease as well as Friedreich's ataxia and multiple sclerosis is presented. Preliminary results from trials of iron chelation therapy in these neurodegenerative diseases are reviewed. Considering the importance of metal ions in the normal functions of the human brain, it is not surprising that dysregulation of metal homeostasis should have harmful effects on brain function. The therapeutic utilisation of iron chelators in neurodegenerative diseases is still in its infancy.

Dual Role of ROS as Signal and Stress Agents: Iron Tips the Balance in favor of Toxic Effects

Elena Gammella, Stefania Recalcati, and Gaetano Cairo. Oxidative Medicine and Cellular Longevity, Volume 2016 (2016), Article ID 8629024, 9 pages, doi:10.1155/2016/8629024

OPEN ACCESS (Creative Commons Attribution License)

Abundant evidence shows that a number of neurodegenerative disorders are characterized by regional iron accumulation in particular areas of the central and/or peripheral nervous systems.
This is often caused by cellular iron redistribution and may result in iron-catalyzed Fenton chemistry.Friedrich's ataxia (FRDA) is a paradigmatic example because the disruption of iron homeostasis in this disease has been well defined. The disease results from loss of function mutations (most often triplet expansion) in the FXN gene that lead to decreased expression of frataxin, a mitochondrial iron-binding protein that interacts with proteins involved in the mitochondrial Fe-S cluster biogenesis. In patients, frataxin deficiency results in disruption of Fe-S cluster biosynthesis, severe mitochondrial iron overload, a hallmark of Fe-S defects, and increased sensitivity to oxidative stress.

Time-resolved functional analysis of acute impairment of frataxin expression in an inducible cell model of Friedreich ataxia

Dörte Poburski, Josefine Barbara Boerner, Michel Koenig, Michael Ristow, René Thierbach. Biology Open 2016 : doi: 10.1242/bio.017004

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Here, we have developed a new mammalian cell model employing the Cre/loxP recombination system to induce a homozygous or heterozygous frataxin knockout in mouse embryonic fibroblasts. Induction of Cre-mediated disruption by tamoxifen was successfully tested on RNA and protein levels. The robustness of the newly established system may additionally be used for a time-resolved study of pharmacological candidates in a HTS manner.

Nrf2 activation in the treatment of neurodegenerative diseases: a focus on its role in mitochondrial bioenergetics and function

Noemí Esteras, Albena T. Dinkova-Kostova, Andrey Y. Abramov. Biological Chemistry. Volume 397, Issue 5, Pages 383–400, ISSN (Online) 1437-4315, ISSN (Print) 1431-6730, DOI: 10.1515/hsz-2015-0295, January 2016

As part of its cytoprotective activity, increasing evidence supports its role in metabolism and mitochondrial bioenergetics and function. Neurodegenerative diseases are excellent candidates for Nrf2-targeted treatments. Most neurodegenerative conditions such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, frontotemporal dementia and Friedreich’s ataxia are characterized by oxidative stress, misfolded protein aggregates, and chronic inflammation, the common targets of Nrf2 therapeutic strategies.

Cardiac Serum Biomarkers in Friedreich Ataxia May Reflect Fibrosis, Myocyte Injury, and Degree of Hypertrophy

C. Bui, R.B. Wilson, D.R. Lynch, J.W. Rossano, O. Elci, K.Y. Lin, The Journal of Heart and Lung Transplantation, Volume 35, Issue 4, Supplement, April 2016, Page S172, ISSN 1053-2498, doi:10.1016/j.healun.2016.01.479.

We hypothesized that serum markers of cardiac injury, stress, fibrosis, and inflammation are higher in FA subjects than non-FA controls, and these markers correlate with echocardiographic markers of cardiomyopathy.

Abundance and Significance of Iron, Zinc, Copper, and Calcium in the Hearts of Patients with Friedreich Ataxia

Pamela C. Kruger, Karl X. Yang, Patrick J. Parsons, Alyssa B. Becker, Paul J. Feustel, Arnulf H. Koeppen. The American Journal of Cardiology, Available online 20 April 2016, ISSN 0002-9149, doi: 10.1016/j.amjcard.2016.04.024.

Total levels of Fe in bulk extracts were not significantly higher than normal, and the concentrations of Zn also remained in the normal range. Cu levels, however, were significantly lower in FA.

Idebenone in Friedreich ataxia and Leber’s hereditary optic neuropathy: close mechanisms, similar therapy?

Manuel Schiff, Pierre Rustin. Brain (2016) aww085 DOI: 10.1093/brain/aww085 First published online: 19 April 2016

"Yet despite these studies, there is no clear consensus on the benefits of idebenone therapy for patients with Friedreich ataxia. Nevertheless, being essentially harmless idebenone has been, and is still, given to many patients with Friedreich ataxia all over the world."

However, for legal and/or marketing reasons, recent idebenone authorization for LHON resulted in some patients with Friedreich ataxia having difficulty obtaining it.

So far the occurrence of potential responders to idebenone in Friedreich ataxia has not been rigorously examined, but in view of the data obtained in LHON, defining a subgroup of therapy-responder patients appears a reasonable objective for next trials in this (and other) rare disease.

Plasma circulating cell-free mitochondrial DNA in the assessment of Friedreich's ataxia

Subrahamanyam Dantham, Achal K. Srivastava, Sheffali Gulati, Moganty R. Rajeswari, Journal of the Neurological Sciences, Available online 14 April 2016, ISSN 0022-510X, doi:10.1016/j.jns.2016.04.016.

Despite several therapies under study or in development for FRDA, evaluation of therapeutic efficacy is limited by the lack of minimally invasive biomarkers to assess disease progression and severity.
Our study identified three major findings, 1. FRDA patients showed decrease in the levels of plasma mtDNA, whereas plasma nDNA was increased. 2. Plasma mtDNA has shown to exhibit high sensitivity and specificity in discriminating FRDA patients from the healthy controls over plasma nDNA levels 3. Significant serial changes have been observed in case of plasma mtDNA upon intervention with nutrient supplement (omega-3 fatty acids).
In view of their neuro-cardio protective role and positive effect on mitochondrial metabolism in ameliorating the neuro symptoms, the Omega-3 fatty acids (Eicosapentaenoic acid and docosahexaenoic acid) have been recommended as a nutritional supplement

Two different pathogenic mechanisms, dying-back axonal neuropathy and pancreatic senescence, are present in the YG8R mouse model of Friedreich ataxia

Belén Mollá, Fátima Riveiro, Arantxa Bolinches-Amorós, Diana C. Muñoz-Lasso, Francesc Palau, Pilar González-Cabo. Disease Models and Mechanisms 2016 : doi: 10.1242/dmm.024273

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These results confirm that the lack of frataxin induces different pathogenic mechanisms in nervous system and pancreas in the mouse model of FRDA: sensory nerve dying-back and pancreatic senescence.

Original Research Proposal: Creation of an Iron Sensing FXN mRNA Therapeutic Riboswitch for the Treatment of Friedreich's Ataxia

Stephanie Mack, Das Research Group, Department of Chemistry, Carnegie Mellon University

 Location: Mellon Institute Room 355

Development of an AAV9 coding for a 3XFLAG-TALEfrat#8-VP64 able to increase in vivo the human frataxin in YG8R mice

P Chapdelaine, C Gérard, N Sanchez, K Cherif, J Rousseau, D L Ouellet, D Jauvin and J P Tremblay. Gene Ther. accepted article preview 2016 Apr 15. doi: 10.1038/gt.2016.36.

OPEN

The study indicates that an AAV coding for a TALE protein coupled with a TAD may be used to increase gene expression in vivo as a possible treatment not only for FRDA but also for other haploinsufficiency diseases.

Lymphoblast Oxidative Stress Genes as Potential Biomarkers of Disease Severity and Drug Effect in Friedreich's Ataxia

Hayashi G, Cortopassi G. PLoS ONE 11(4): e0153574. doi:10.1371/journal.pone.0153574

OPEN ACCESS

This work demonstrates that the mRNA abundance of the oxidative stress response genes NCF2 and PDLIM1 are potential biomarkers for FA. Additionally, because NCF2 and PDLIM1 respond dose-dependently to frataxin level, they supplement and confirm the antioxidant effects of therapies that raise frataxin, increasing the number of Friedreich's relevant biomarkers to three in the lymphoblast context: frataxin, NCF2, and PDLIM1. Lastly, because PDLIM1/CLP36 has recently been shown to be responsive to Nrf2 status/oxidative stress in cardiomyocytes, it could become a valuable marker of drug effect in cardiomyocytes.

Comorbid Medical Conditions in Friedreich Ataxia: Association With Inflammatory Bowel Disease and Growth Hormone Deficiency

Julianna E. Shinnick, Kimberly Schadt, Cassandra Strawser, Nicholas Wilcox, Susan L. Perlman, George R. Wilmot, Christopher M. Gomez, Katherine D. Mathews, Grace Yoon, Theresa Zesiewicz, Chad Hoyle, S. H. Subramony, Eppie M. Yiu, Martin B. Delatycki, Alicia F. Brocht, Jennifer M. Farmer, and David R. Lynch; J Child Neurol 0883073816643408, first published on April 12, 2016 as doi:10.1177/0883073816643408

Diagnoses with more than twice the prevalence in this Friedreich ataxia cohort than the general population were growth hormone deficiency, ulcerative colitis, Crohn’s disease, and inflammatory bowel disease. However, patients with Friedreich ataxia did not have a higher incidence of other neurological disorders such as epilepsy or migraine; other sleep disorders besides sleep apnea; other cardiovascular disorders such as coronary artery disease, hypercholesterolemia, or hypertension; or psychiatric disorders such as anxiety

Researchers from Mount Sinai and Sage Bionetworks Report Analysis of Nearly 600,000 Genomes for Resilience Project

Icahn School of Medicine at Mount Sinai, New York, NY – April 11, 2016 /Press Release/ ––

As part of a global collaboration, scientists from the Icahn School of Medicine at Mount Sinai and Sage Bionetworks conducted the largest genome study to date and reported the first systematic search across hundreds of Mendelian disorders in hundreds of thousands of individuals apparently not afflicted with any of these disorders to identify those carrying disease protective factors. Genome analysis of these resilient people could uncover naturally occurring, protective mechanisms that would serve as novel treatments for people affected by these diseases.

In this study, researchers analyzed DNA from 12 previously collected data sets, using a newly developed targeted sequencing panel to screen 874 genes for 584 distinct genetic diseases. The diseases, which were mostly metabolic conditions, neurological diseases, or developmental disorders, present in childhood with severe symptoms. All genomes analyzed were from adults who had never been diagnosed with any of these diseases. A sophisticated, in-depth analysis process identified 13 healthy people with genetic variants associated with eight diseases.

Interview with Dr. Javier Diaz-Nido talking about Friedreich's Ataxia (SPA)

Spanish

 

From minute 3.40 until minute 15

http://mvod.lvlt.rtve.es/resources/TE_SENTREP/mp3/7/0/1460534569907.mp3

 http://www.rtve.es/alacarta/audios/entre-probetas/entre-probetas-ataxia-friedreich-13-04-16/3566612/

Italian program for independent research on drugs: 10 year follow-up of funded studies in the area of rare diseases

Giuseppe Traversa, Lucia Masiero, Luciano Sagliocca and Francesco Trotta. Orphanet Journal of Rare Diseases 2016 11:36 DOI: 10.1186/s13023-016-0420-4

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Our data suggest that adequately powered randomized trials can represent the gold standard also for rare diseases. There are also important implications for clinical practice, as can be expected by projects characterized by clinical endpoints and extensive follow-up. It is unlikely that many of these studies may have been conducted in a for profit perspective, given the absence of commercial interest.
We documented that, even though it takes time to set up and conduct a funding program for independent research, the overall results are highly rewarding. Independent funding is crucial in supporting studies aimed at answering questions that are relevant for clinical practice despite the lack of sufficient commercial interest.

Statistical Enrichment of Epigenetic States Around Triplet Repeats that Can Undergo Expansions

Alexandra Essebier, Patricia Vera Wolf, Minh Duc Cao, Bernard J. Carroll, Sureshkumar Balasubramanian and Mikael Bodén, Front. Neurosci., 08 March 2016 doi:10.3389/fnins.2016.00092

Friedreich ataxia (FRDA) is a loss-of-function disease caused by an expanded intronic GAA repeat in the Frataxin (FXN) gene, and in our analysis it displayed the greatest number of epigenetic marks in its distance profile. Based on our statistical analyses of epigenetic marks around the repeat, specific hypotheses can be drawn to address this transition. For example, this is consistent with the findings that suggest that the inhibitors of histone deacetylase increase FXN expression levels. It would be interesting to assess whether blocking histone methyl transferase to prevent H3K9ac and H3K27ac would promote the stability of the GAA repeat.

Roles of Fe–S proteins: from cofactor synthesis to iron homeostasis to protein synthesis

Debkumar Pain, Andrew Dancis, Current Opinion in Genetics & Development, Volume 38, June 2016, Pages 45-51, ISSN 0959-437X, doi:10.1016/j.gde.2016.03.006.

Impairment of Fe–S cluster assembly creates diseases in diverse and surprising ways: the loss of function of lipoic acid synthase, the heme biosynthetic pathway in red cell precursors is specifically targeted and tRNA modifications arising from action of the cysteine desulfurase and/or Fe–S cluster proteins are lost. These defects can then result in cancer, neurologic dysfunction or type 2 diabetes.

The Structure of the Complex Between Yeast Frataxin and Ferrochelatase: Characterization and pre-Steady State Reaction of Ferrous Iron Delivery and Heme Synthesis

Christopher G. Soderberg, Mallory E. Gillam, Eva-Christina Ahlgren, Gregory A. Hunter, Oleksandr Gakh, Grazia Isaya, Gloria C. Ferreira and Salam Al-Karadaghi, The Journal of biological chemistry: 2016 First Published on March 29, 2016, doi: 10.1074/jbc.M115.701128

They support the proposal that frataxin-mediated delivery of this potentially toxic substrate (Fe2+)overcomes formation of reactive oxygen species.

Effects of Genetic Severity on Glucose Homeostasis in Friedreich Ataxia

Charles J. Isaacs BA, Karlla W. Brigatti MS, Olena Kucheruk RN MPH, Sarah Ratcliffe PhD, Tom Sciascia MD, Shana E. McCormack MD, Steven M. Willi MD and David R. Lynch MD PhD, Muscle & Nerve, Accepted manuscript online: 7 APR 2016 DOI: 10.1002/mus.25136

Genetic severity impacts the global homeostatic profile, whereas relative contributions of insulin secretion and action vary from patient-to-patient.

Accessing the accelerated approval pathway for rare disease therapeutics

Emil D Kakkis, Sara Kowalcyk & Max G Bronstein, Nature Biotechnology 34, 380–383 (2016) doi:10.1038/nbt.3530

Improvements must be made to the qualification process for biomarkers as primary endpoints in pivotal clinical studies of treatments for the rarest of diseases.

Mouvements oculaires anormaux : aide au diagnostic étiologique/topographique en neurologie

Abnormal eye movements: Etiologic/topographic diagnostic tool in neurology / Mouvements oculaires anormaux : aide au diagnostic étiologique/topographique en neurologie
FMC, Volume 7, Issue 1, February 2016, Pages 16-24, ISSN 1878-7762, doi:10.1016/j.praneu.2015.12.003.

Acquired neurological nystagmus and other abnormal eye movements may be valuable diagnostic tools. We provide a “practical” approach, with the objective of highlighting for neurologists the importance of abnormal eye movement observation in order to improve the subtlety of clinical diagnosis.

Les nystagmus acquis centraux ou les autres types de mouvements oculaires anormaux d’origine neurologique ont pour certains une valeur séméiologique intéressante. Nous proposons une approche « pratique » visant à sensibiliser le neurologue à l’observation de mouvements oculaires anormaux pour améliorer la finesse du diagnostic clinique.

New tool enables scientists to interpret 'dark matter' DNA

Gladstone Institutes. "New tool enables scientists to interpret 'dark matter' DNA: Breakthrough technology opens the door to identifying new drug targets that could treat many genetic diseases." ScienceDaily. ScienceDaily, 4 April 2016. .

Scientists at the Gladstone Institutes have invented a new way to read and interpret the human genome. The computational method, called TargetFinder, can predict where non-coding DNA--the DNA that does not code for proteins--interacts with genes. This technology helps researchers connect mutations in the so-called genomic "dark matter" with the genes they affect, potentially revealing new therapeutic targets for genetic disorders.

"Our ability to predict the gene targets of enhancers so accurately enables us to link mutations in enhancers to the genes they target," said Pollard. "Having that link is the first step towards using these connections to treat diseases."

Intracellular Delivery of Proteins with Cell-Penetrating Peptides for Therapeutic Uses in Human Disease

Ana Dinca, Wei-Ming Chien and Michael T. Chin. Int. J. Mol. Sci. 2016, 17(2), 263; doi:10.3390/ijms17020263

Review
OPEN ACCESS

Cell-penetrating peptides (CPPs), a group of small peptides capable of promoting transport of molecular cargo across the plasma membrane, have become important tools in promoting the cellular uptake of exogenously delivered proteins. Although the molecular mechanisms of uptake are not firmly established, CPPs have been empirically shown to promote uptake of various molecules, including large proteins over 100 kiloDaltons (kDa).

Genome-editing Technologies for Gene and Cell Therapy

Morgan L Maeder and Charles A Gersbach, Molecular Therapy (2016); 24 3, 430–446. doi:10.1038/mt.2016.10

OPEN ACCES (Creative Commons CC-BY license)

Common DNA targeting platforms for genome editing.

Gene therapy has historically been defined as the addition of new genes to human cells. However, the recent advent of genome-editing technologies has enabled a new paradigm in which the sequence of the human genome can be precisely manipulated to achieve a therapeutic effect. This includes the correction of mutations that cause disease, the addition of therapeutic genes to specific sites in the genome, and the removal of deleterious genes or genome sequences. This review presents the mechanisms of different genome-editing strategies and describes each of the common nuclease-based platforms, including zinc finger nucleases, transcription activator-like effector nucleases (TALENs), meganucleases, and the CRISPR/Cas9 system. We then summarize the progress made in applying genome editing to various areas of gene and cell therapy, including antiviral strategies, immunotherapies, and the treatment of monogenic hereditary disorders.

New developments and controversies in iron metabolism and iron chelation therapy.

Christina N Kontoghiorghe and George J Kontoghiorghes, World J Methodol. 2016 March 26; 6(1): 1–19. Published online 2016 March 26. doi: 10.5662/wjm.v6.i1.1

Open-Access

"Similar issues in relation to chelating drug development were raised with the journal Annals of Neurology regarding the use of (Ferriprox) in Friedreich ataxia patients where the lack of crucial diagnostic and therapeutic outcome procedures in relation to focal iron levels and lack of iron balance studies were questioned. The need for personalised medicine was also raised since there is wide variation in the severity of the disease and level of focal iron deposits in the heart and brain of Friedreich ataxia patients. In this case the editors of the journal referred to “expensive studies to track iron scores” and “the company developing the drug spends millions of dollars”. It should be noted that the original proposal for the use of (Ferriprox) in Friedreich ataxia patients was suggested many years ago and  was developed following academic initiatives.

The introduction of Deferiprone (Ferriprox) for the treatment of non iron loaded patients by targeting focal toxic iron deposits, e.g., in Friedreich ataxia and toxic labile iron, e.g., in diabetic and non-diabetic glomerular disease is a reflection of the antioxidant and safety potential of this drug. The safety of (Ferriprox) in many categories of non iron loaded diseases has also been confirmed in clinical trials involving patients with the anaemia of chronic disease, renal dialysis, infections, Parkinson’s and other neurodegenerative diseases, etc. As in many other cases of drug development the introduction prospects of Ferriprox in these diseases is based on commercial and not ethical criteria.

Clinical Experience With Deferiprone Treatment for Friedreich Ataxia.

Elincx-Benizri S, Glik A, Merkel D, Arad M, Freimark D, Kozlova E, Cabantchik I, Hassin-Baer S. J Child Neurol. March 29, 2016, doi: 10.1177/0883073816636087

The authors conclude that combined therapy of a low dose of deferiprone with idebenone is relatively safe, might improve neurological function, and seems to improve heart hypertrophy, warranting further studies.

Assessment and management of cavus foot deformity

J. Grice, H. Willmott, H. Taylor, Orthopaedics and Trauma, Available online 8 March 2016, ISSN 1877-1327, doi:10.1016/j.mporth.2016.02.001.

Careful examination should be performed and underlying neurological conditions sought. We outline an á la carte approach to surgical management, in which deformity of the ankle and hindfoot is addressed before moving on to assessment and correction of the mid- and forefoot.