Structural characteristics of the central nervous system in Friedreich ataxia: an in vivo spinal cord and brain MRI study

Imis Dogan, Sandro Romanzetti, Claire Didszun, Shahram Mirzazade, Dagmar Timmann, Carsten Saft, Ludger Schöls, Matthis Synofzik, Ilaria A Giordano, Thomas Klockgether, Jörg B Schulz, Kathrin Reetz; Journal of Neurology, Neurosurgery & Psychiatry, June 2018 DOI:10.1136/jnnp-2018-318422

Neuropathological studies described reductions of dorsal root ganglia, the spinal cord at all levels and dentate nuclei.1 In vivo MRI approaches confirmed spinal cord alterations in FRDA, which were however focused on upper cervical cord areas,2 while quantitative measurements along the entire spinal cord length are lacking. We therefore aimed to investigate the morphometric pattern of the cervical and thoracic spinal cord in FRDA. In order to provide a more comprehensive picture of spinocerebellar-cerebral alterations, we additionally analysed anatomical brain MRI data and investigated the relative contribution of spinal and brain measurements for the prediction of clinical severity in FDRA.

Friedreich Ataxia: Diagnostic Yield and Minimal Frequency in South Brazil

Helena Fussiger, Maria Luiza Saraiva-Pereira, Sandra Leistner-Segal, Laura Bannach Jardim. Cerebellum (2018). doi:10.1007/s12311-018-0958-x

Friedreich ataxia (FRDA) is an autosomal recessive disorder due to mutations in the FXN gene. FRDA is characterized by the classical triad of ataxia, absent reflexes, and Babinski sign, but atypical presentations might also occur. Our aims were to describe the proportion of FRDA diagnoses in suspected families living in Rio Grande do Sul, South Brazil, and to estimate a minimum frequency of symptomatic subjects. Subjects that were evaluated by molecular analysis for FRDA at the Hospital de Clínicas de Porto Alegre were identified in our files. Patients’ clinical manifestation and phenotypes were described and compared. The number of FRDA subjects alive in the last 5 years was determined. One hundred fifty-six index cases (families) were submitted to evaluation of GAA repeats at FXN since 1997: 27 were confirmed as FRDA patients. Therefore, the diagnostic yield was 17.3%. Proportion of classical, late onset, and retained reflexes subphenotypes were similar to those described by other studies. A minimum prevalence was estimated as 0.20:100.000 inhabitants. In conclusion, we verified that this FRDA population displayed the usual clinical characteristics, but with a lower period prevalence than those obtained in populations from Europe.

Autonomic function testing in Friedreich’s ataxia

Elisabetta Indelicato, Alessandra Fanciulli, Jean-Pierre Ndayisaba, Wolfgang Nachbauer, Andreas Eigentler, Roberta Granata, Julia Wanschitz, Werner Poewe, Gregor K. Wenning, Sylvia Boesch. J Neurol (2018). Doi:10.1007/s00415-018-8946-0

FRDA patients may experience several autonomic symptoms and overall their burden correlates with disease severity. Nonetheless, clinical testing shows no major involvement of sudomotor and cardiovascular autonomic function.

Modeling Cardiac Dysfunction of Friedreich’s Ataxia Using Ventricular Sheets, Tissues and Chambers Engineered from Human Pluripotent Stem Cells

VANCOUVER, British Columbia, June 25, 2018 (GLOBE NEWSWIRE) -- Novoheart (“Novoheart” or the “Company”) (TSX-V:NVH) (FWB:3NH) is pleased to announce a presentation was delivered on June 22nd, 2018, entitled “Modeling Cardiac Dysfunction of Friedreich’s Ataxia Using Ventricular Sheets, Tissues and Chambers Engineered from Human Pluripotent Stem Cells,” at the Annual Meeting of the International Society for Stem Cell Research in Melbourne, Australia. The presentation includes data from research conducted with Pfizer Inc. on a 3D engineered human cardiac tissue disease model of Friedreich’s ataxia (FRDA), a neurodegenerative disease in which patients most often die of heart complications. The new disease model helps capture both electrical and mechanical defects of the heart observed in patients with FRDA.

FRDA is a hereditary, juvenile-onset neuro-muscular disease that afflicts over 1 in 50,000 people worldwide1, with symptoms including loss of muscular coordination and severe cardiac conditions. The latter, including heart failure and arrhythmias, is the main cause of death in FRDA patients2. Mouse models of FRDA have previously been created, but their non-human nature limits their application in drug development for human patients. As the first engineered 3D human cardiac tissue constructs of Friedreich’s ataxia, developed using Novoheart’s proprietary MyHeartTM Platform, the novel disease model captures key clinical symptoms seen in FRDA patients, including electrical and contractile dysfunction of the heart, thereby providing a highly effective human screening and discovery platform for developing novel therapeutics.

“We are very excited by the outcome of this study, and hope this will accelerate the development of safe and effective new therapies for FRDA patients. Also, by demonstrating the biomimetic capabilities of our MyHeartTM Platform for modeling diseased hearts, we are hoping to establish new standards for creating a proprietary library of disease models and expand our presence in drug discovery and precision medicine,” said Novoheart CSO, Dr. Kevin Costa.

Mitohormesis, an Antiaging Paradigm

Clea Bárcena, Pablo Mayoral, Pedro M. Quirós, International Review of Cell and Molecular Biology, Academic Press, ISSN 1937-6448, doi:10.1016/bs.ircmb.2018.05.002.

Mitohormesis is a term used to define a biological response where the induction of a reduced amount of mitochondrial stress leads to an increment in health and viability within a cell, tissue, or organism. The mitochondrial stress response activated by a potentially damaging stimulus requires a coordinated dialogue with the cellular nucleus, known as mitonuclear communication. This interplay induced by the hormetic response in mitochondria relies in a variety of signals among which the most relevant ones are reactive oxygen species (ROS), mitochondrial metabolites, proteotoxic signals, the mitochondria–cytosol stress response, and the release of mitokines. The activation of the mitohormetic response increases lifespan in different animal models, from worms to mammals. Further, mitohormesis also enhances healthspan, particularly improving metabolism and immune system. Although multiple mediators and stress signals have been proposed to activate this protective mechanism, beneficial outcomes of mitohormesis are most probably due to an increase in mitochondrial ROS. Activation of other protective stress mechanisms as mitochondrial unfolded protein response or the increase in the expression of mitokines are also associated with the positive benefits exerted by mitohormesis. Herein, we review the different mitohormetic signals and pathways described from worms to mammals and their effects on health and survival. The identification and description of pathways and molecules implicated in the beneficial effects of mitohormesis will help understand the complex balance between death and survival in the face of mitochondrial damage and will allow to open a novel area of therapies aimed at improving health in humans.

Frataxin‐Mediated PINK1‐Parkin‐Dependent Mitophagy in Hepatic Steatosis: The Protective Effects of Quercetin

Liu, P. , Lin, H. , Xu, Y. , Zhou, F. , Wang, J. , Liu, J. , Zhu, X. , Guo, X. , Tang, Y. and Yao, P. (2018), Mol. Nutr. Food Res.. Accepted Author Manuscript. . doi:10.1002/mnfr.201800164

Naturally occurring quercetin has been found to induce mitophagy and prevent non‐alcoholic fatty liver disease (NAFLD). However, it still remains elusive whether frataxin upregulation by quercetin contributes to the beneficial effect through mitophagy or not.

Latest developments in ataxias

Prats-Vinas JM, Rev Neurol. 2018 Jun 5;66(s02):S27-S31. PMID: 29876909

This article reviews the advances made in the field of ataxias over the past four years. It concludes that there is no single spectacular finding like those that have taken place in the last 25 years and they can all be attributed to the remarkable evolution of genetics and neuroimaging. Nevertheless, algorithms have been perfected that allow a more rational use of the previous techniques to reach a correct diagnosis and possible treatment. With regard to the treatments proposed to alleviate the symptoms of ataxias, there is no unquestionable evidence leading us to think that the symptoms can be reverted with the means currently available, except for a few treatable ataxias, which were already known before that time.

Social and familial difficulties as a consequence of the neurological illness of a child: the perspective of health and social work

Gonzalez-Pena A., Rev Neurol. 2018 Jun 5;66(s02):S53-S56.

When we speak of children with special needs, who require the aid of a number of professionals and who have a severe disability, it is necessary to have available a comprehensive group of different professionals (paediatrician, nurse, social worker, psychologist, etc.) who work together as a team. The specialist physician or doctor responsible for the sick child alone cannot take responsibility for all the psychosocial consequences that result from the neurological disease, which is a chronic illness that, generally speaking, means the families arrange their lives to revolve around the sick child. The set of guidelines or social work field tools for doctors such as neuropaediatricians outlined in this article could help to facilitate an increase in the quality of the care delivered, and of the lives of the children and of those who are looking after them. The children and their relatives have a social complexity as a consequence of their disease that can be detected by the doctor, who then refers them to the social worker in order to be able to deliver a more global response to care for the child's health. It is important to have the concepts clear in our minds when speaking about children with severe disability and high dependence, and also about the institutional abuse in the form of medical bureaucracy with numerous visits and a variety of professionals all requesting clinical tests.

Soft robotic devices for hand rehabilitation and assistance: a narrative review

Chia-Ye Chu and Rita M. Patterson, Journal of NeuroEngineering and Rehabilitation 2018 15:9 doi:10.1186/s12984-018-0350-6

Since the emergence of soft robotic devices for hand rehabilitation roughly 10 years ago, the field has progressed rapidly. Significant progress has been made in establishing proof-of-concept of designs of preclinical research prototypes, with clinical trials being the next logical goal. But for many devices, more work needs to be done to perfect actuator design and feedback to maximize patient safety and rehabilitation outcomes.
We hope that this review of the current approaches in designing soft robotic devices for hand rehabilitation will serve as a useful resource for future developers and facilitate the evolution of the field.

Transcranial magnetic stimulation in hereditary ataxias: diagnostic utility, pathophysiological insight and treatment

Roberto Rodríguez-Labrada, Luis Velázquez-Pérez, Ulf Ziemann, Clinical Neurophysiology, Available online 15 June 2018, ISSN 1388-2457, doi:10.1016/j.clinph.2018.06.003.

Transcranial magnetic stimulation (TMS) is a valuable technique to assess and modulate human brain function in normal and pathological conditions. This critical review surveys the contributions of TMS to the diagnosis, insight into pathophysiology and treatment of genetically confirmed hereditary ataxias, a heterogeneous group of neurodegenerative disorders that can affect motor cortex and the corticospinal tract. Most studies were conducted on small sample sizes and focused on diagnostic approaches. The available data demonstrate early involvement of the corticospinal tract and motor cortex circuitry, and support the possible efficacy of cerebellar repetitive TMS (rTMS) as therapeutic approach. Further TMS-based studies are warranted, to establish biomarkers for early diagnosis and disease monitoring, explore the involvement of the cerebello-dentato-thalamo-cortical projection, study the effects of rTMS-induced plasticity, and utilize rTMS for treatment.

Intrathecal Baclofen Therapy for Painful Muscle Spasms in a Patient with Friedreich’s Ataxia

Kalyvas A, V, Drosos E, Korfias S, Gatzonis S, Themistocleous M, Sakas D, E,. Stereotact Funct Neurosurg ;:127-130 doi:10.1159/000489220

Friedreich's ataxia (FA) is the most frequent hereditary ataxia syndrome, while painful muscle spasms and spasticity have been reported in 11-15% of FA patients. This report describes the successful management of painful spasms in a 65-year-old woman with FA via intrathecal baclofen (ITB) therapy following unsuccessful medical treatments. To our knowledge, this is the third reported case in the literature. Unfortunately, the pathophysiological characteristics of muscle spasms in FA are not well explored and understood while the therapeutic mechanisms of the different treatments are rather vague. Taking into consideration the suggested spinal atrophy in FA, the clinical resemblance of FA and chronic spinal injury muscle spasms, together with the rapid ITB therapy effectiveness in alleviating FA muscle spasms, we attempted to suggest a putative pathophysiological mechanism acting at the spinal level and possibly explained by the presence of independent spinal locomotor systems producing muscle spasms. Specifically, overexcitement of these centers, due to loss of normal regulation from upper CNS levels, may result in the uncontrolled firing of secondary motor neurons and may be the key to producing muscle spasms. However, further research under experimental and clinical settings seems to be necessary.

Scales for the clinical evaluation of cerebellar disorders

Katrin Bürk, Deborah A. Sival, Chapter 20 - Scales for the clinical evaluation of cerebellar disorders, In: Mario Manto and Thierry A.G.M. Huisman, Editor(s), Handbook of Clinical Neurology, Elsevier, 2018, Volume 154, Pages 329-339, doi:10.1016/B978-0-444-63956-1.00020-5.

Clinical scales represent an important tool not only for the initial grading/scoring of disease and assessment of progression, but also for the quantification of therapeutic effects in clinical trials. There are several scales available for the clinical evaluation of cerebellar symptoms. While some scales have been developed and evaluated for specific cerebellar disorders such as Friedreich ataxia, others reliably capture cerebellar symptoms with no respect to the underlying etiology. Each scale has its strengths and weaknesses. Extensive scales are certainly useful for thorough documentation of specific features of certain phenotypes, but this gain of information is not always essential for the purpose of a study. Therefore, compact and manageable scales like the Scale for the Assessment and Rating of Ataxia (SARA) or Brief Ataxia Rating Scale (BARS) are often preferred compared to more complex scales in observational and therapeutic studies.

Neuroimaging in Ataxias

Piccinin C.C., D’Abreu A. (2018) In: Habas C. (eds) The Neuroimaging of Brain Diseases. Contemporary Clinical Neuroscience. pp 215-232, Springer, Cham. Doi.:10.1007/978-3-319-78926-2_9

Despite each type of ataxia has its own peculiarities, most of the symptoms overlap among them, making the diagnosis difficult when considering only the clinical picture. In this context, neuroimaging has become a valuable tool to help the diagnosis but also to better understand the affected brain areas and the pathophysiology of these conditions. Techniques as voxel-based morphometry, diffusion tensor imaging, and surface-based analyses have brought to light the structural differences between the ataxic patients and controls and also helped to differentiate the diagnosis. Functional MRI and spectroscopy have detected changes in functionality and in chemical ratios.

Identification of cardioprotective drugs by medium-scale in vivo pharmacological screening on a Drosophila cardiac model of Friedreich's ataxia

Amandine Palandri, Elodie Martin, Maria Russi, Michael Rera, Hervé Tricoire, Véronique Monnier, Disease Models & Mechanisms 2018 : dmm.033811 doi: 10.1242/dmm.033811 Published 13 June 2018

In conclusion, this pharmacological screen led to the identification of 11 drugs that significantly reduced heart dilatation of frataxin-depleted hearts. This study may lead in the future to therapeutic applications and improves our knowledge of the mechanisms involved in cardiac dysfunction associated with FA disease. In particular, it suggests that decreased contractility and dilatation of frataxin depleted hearts are, at least in part, a consequence of defective sarcomeric assembly due to microtubule destabilisation. More generally, our data highlight the power of Drosophila models of cardiac diseases for pharmacological approaches. We show here that it is feasible to perform pharmacological screens in vivo on a relatively large scale, under physiological conditions and using relevant functional parameters as readouts. This type of approach could therefore be extended in the future to a wide panel of cardiac diseases.

Role of ROS and Nutritional Antioxidants in Human Diseases

Zewen Liu, Zhangpin Ren, Jun Zhang, Chia-Chen Chuang, Eswar Kandaswamy, Tingyang Zhou, and Li Zuo; Front Physiol. 2018; 9: 477. doi:10.3389/fphys.2018.00477

The combination of vitamin E and coenzyme Q10 improves energy generation in some cases of Friedreich ataxia by attenuating OS and restoring mitochondrial function. Numerous studies have been performed to investigate the therapeutic effects of natural antioxidants on neurodegenerative disorders; however, mixed results have been yielded.

RNA Editing and Retrotransposons in Neurology

Heinz Krestel and Jochen C. Meier;  Front Mol Neurosci. 2018; 11: 163. doi:10.3389/fnmol.2018.00163

Friedreich ataxia is the best known and most commonly inherited form of spinocerebellar ataxia. It can be caused by mutations or, in 98% of cases, by GAA trinucleotide-repeat expansions located at the center of an AluSq element in intron 1 of the frataxin (FXN) gene. Friedreich ataxia is the only known disease caused by abnormal expansion of a GAA trinucleotide-repeat sequence. It was suggested that GAA repeats arose by mutation or A-to-G conversion from poly(A) tracts of Alu elements. Many longer GAA repeats in the human genome can be found in the 3′ poly(A) tracts of Alu elements, but it was suggested that A-to-G conversion that led to poly-GAA repeats in Friedreich ataxia arose in the central linker region of Alu elements. Beyond GAA repeats, Alu elements were in general described to be a source for microsatellites. Expansion of trinucleotide repeats was proposed to have arisen in Friedreich ataxia rather by in-tandem duplication up to a certain repeat length. From a certain repeat length onwards, genetic instability was proposed to contribute to additional repeat expansion, which is known in Neurology as anticipation. GAA repeat expansions affect pre-mRNA processing by inducing the accumulation of upstream splicing intermediates. No interaction of RNA editing with these genetic rearrangements in Friedreich ataxia has been reported.

Epigenetic Regulation in Neurodegenerative Diseases

Amit Berson, Raffaella Nativio, Shelley L. Berger, Nancy M. Bonini, Trends in Neurosciences, Available online 7 June 2018, ISSN 0166-2236, doi:10.1016/j.tins.2018.05.005.

Mechanisms of epigenetic regulation, including DNA methylation, chromatin remodeling, and histone post-translational modifications, are involved in multiple aspects of neuronal function and development. Recent discoveries have shed light on critical functions of chromatin in the aging brain, with an emerging realization that the maintenance of a healthy brain relies heavily on epigenetic mechanisms. Here, we present recent advances, with a focus on histone modifications and the implications for several neurodegenerative diseases including Alzheimer’s disease (AD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS). We highlight common and unique epigenetic mechanisms among these situations and point to emerging therapeutic approaches.

Adding a temporal dimension to the study of Friedreich's ataxia: the effect of frataxin overexpression in a human cell model

Tommaso Vannocci, Roberto Notario Manzano, Ombretta Beccalli, Barbara Bettegazzi, Fabio Grohovaz, Gianfelice Cinque, Antonio de Riso, Luca Quaroni, Franca Codazzi, Annalisa Pastore
Disease Models & Mechanisms 2018 : dmm.032706 doi: 10.1242/dmm.032706 Published 24 May 2018

We prove that overexpression of the frataxin gene affects the cellular metabolism. It also lead to a significant increase of oxidative stress and labile iron pool levels. These cellular alterations are similar to those observed when the gene is partially silenced, as it occurs in Friedreich's ataxia's patients. Our data suggest that the levels of frataxin must be tightly regulated and fine-tuned, any imbalance leading to oxidative stress and toxicity.
Viral approaches (AAV), take advantage of a human exogenous FXN gene under the control of strong promoters that induce overexpression of the therapeutic genes. Although the mouse models showed great improvements, the lack of a tight control on the levels of expression could generate the effects detailed in this work with unknown long-term consequences for patients treated this way. Recent studies have taken advantage of the novel CRISPR gene editing approach to produce the desired gene correction as an alternative, gene correction of the endogenous FXN gene by reduction of the GAA expansion seems to be preferable. This strategy has the advantage that frataxin levels would be restored to physiological levels. It is however essential for these studies to determine the effects of different levels of frataxin.

Rehabilitation robots for the treatment of sensorimotor deficits: a neurophysiological perspective

Roger Gassert and Volker Dietz; Journal of NeuroEngineering and Rehabilitation 2018 15:46 doi:10.1186/s12984-018-0383-x

Future rehabilitation approaches will not only profit from the inclusion of robots, but also from an advanced understanding of neurophysiological mechanisms underlying normal and impaired sensorimotor functions, enabled by the use of robots as scientific tools. Resulting insights will benefit the development of advanced rehabilitation robots, and further promote collaboration between engineers, therapists and clinical neurophysiologists.

Oligonucleotides Hold Promise as a Therapy for Friedreich's Ataxia: Friedreich's ataxia currently is incurable, but synthetic antisense oligonucleotides have demonstrated promising results in increasing frataxin gene expression and restoring it to normal levels

AJMG. Volume176, Issue6 June 2018 Pages 1282-1282 doi:10.1002/ajmg.a.38850

Another important point that was demonstrated in this and previous papers is that oligonucleotides increase the expression of FXN. According to Dr. Corey, “That corrects a fundamental defect in the disease specifically at the gene level, so it is a plausible compound for moving forward.”

However, right now the compounds are in the earliest stages, and more evidence is needed that the treatment is safe and effective. “We need to find animal models to begin testing it, and a company needs to be encouraged to develop it,” Dr. Corey says.

Modelling the dorsal root ganglia using human pluripotent stem cells: A platform to study peripheral neuropathies

Serena Viventi, Mirella Dottori, The International Journal of Biochemistry & Cell Biology, Volume 100, July 2018, Pages 61-68, ISSN 1357-2725, doi:10.1016/j.biocel.2018.05.005.

Sensory neurons of the dorsal root ganglia (DRG) are the primary responders to stimuli inducing feelings of touch, pain, temperature, vibration, pressure and muscle tension. They consist of multiple subpopulations based on their morphology, molecular and functional properties. Our understanding of DRG sensory neurons has been predominantly driven by rodent studies and using transformed cell lines, whereas less is known about human sensory DRG neurons simply because of limited availability of human tissue. Although these previous studies have been fundamental for our understanding of the sensory system, it is imperative to profile human DRG subpopulations as it is becoming evident that human sensory neurons do not share the identical molecular and functional properties found in other species. Furthermore, there are wide range of diseases and disorders that directly/indirectly cause sensory neuronal degeneration or dysfunctionality. Having an in vitro source of human DRG sensory neurons is paramount for studying their development, unique neuronal properties and for accelerating regenerative therapies to treat sensory neuropathies. Here we review the major studies describing generation of DRG sensory neurons from human pluripotent stem cells and fibroblasts and the gaps that need to be addressed for using in vitro-generated human DRG neurons to model human DRG tissue.
There are vast ranges of diseases and conditions, usually progressive, which can affect DRG sensory neurons. The underlying causes of DRG degeneration may be either directly intrinsic to DRG neurons or indirectly associated with other pathologies. Some inherited genetic diseases inducing DRG degeneration include Friedreich’s Ataxia and Charcot Marie Tooth Disease