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Introduction to Special Issue on Mitochondrial Redox Signaling in Health and Disease

·        Juan P. Bolañosa, , 

·        Enrique Cadenasb, , 

·        Michael R. Duchenc, , 

·        Mark B. Hamptond, , 

·        Giovanni E. Manne, , 

·        Michael P. Murphyf


Mitochondria are functional entities that harbor the energy-conservation machinery that supports cell function through the coordination of mitochondrion-derived molecules involved in the regulation of cell signaling and transcription. Conversely, mitochondria are targets of an ever-increasing number of signaling pathways and their activity is also modulated by several transcription factors. The cell's energy-redox homeostasis is primarily a function of mitochondrial oxidative phosphorylation and the formation of O2.–/H2O2. Notably, other mitochondrion-driven processes contribute to cellular homeostasis, such as mitochondrial biogenesis and dynamics, mitochondrial quality control (autophagy and mitophagy), mitochondrial proteostasis and the role of the mitochondrial unfolded protein response (UPRmt), and redox signaling in the homeostatic control of mitochondrial function. This Free Radical Biology & Medicine special issue onMitochondrial Redox Signaling in Health and Disease covers some aspects of the myriad of processes embraced by mitochondrial biology and physiology, provides mechanistic insights linking mitochondrial function with cell function, and recognizes mitochondrial function as an amenable therapeutic target.



Functional and Gait Assessment in Children and Adolescents Affected by Friedreich’s Ataxia: A One-Year Longitudinal Study

·        Gessica Vasco ,

·        Simone Gazzellini,

·        Maurizio Petrarca,

·        Maria Luisa Lispi,

·        Alessandra Pisano,

·        Marco Zazza,

·        Gessica Della Bella,

·        Enrico Castelli,

·        Enrico Bertini


Friedreich’s ataxia is the most common autosomal recessive form of neurodegenerative ataxia. We present a longitudinal study on the gait pattern of children and adolescents affected by Friedreich’s ataxia using Gait Analysis and the Scale for the Assessment and Rating of Ataxia (SARA). We assessed the spectrum of changes over 12 months of the gait characteristics and the relationship between clinical and instrumental evaluations. We enrolled 11 genetically confirmed patients affected by Friedreich’s ataxia in this study together with 13 normally developing age-matched subjects. Eight patients completed a 12-month follow-up under the same protocol. By comparing the gait parameters of Friedreich’s ataxia with the control group, we found significant differences for some relevant indexes. In particular, the increased knee and ankle extension in stance revealed a peculiar biomechanical pattern, which correlated reliably with SARA Total, Gait and Sitting scores. The knee pattern showed its consistency also at the follow-up: Knee extension increased from 6.8±3.5° to -0.5±3.7° and was significantly correlated with the SARA total score. This feature anticipated the loss of the locomotor function in two patients. In conclusion, our findings demonstrate that the selective and segmental analysis of kinetic/kinematic features of ataxic gait, in particular the behavior of the knee, provides sensitive measures to detect specific longitudinal and functional alterations, more than the SARA scale, which however has proved to be a reliable and practical assessment tool. Functional outcomes measures integrated by instrumental evaluation increase their sensitivity, reliability and suitability for the follow-up of the disease progression and for the application in clinical trials and in rehabilitative programs.




Friedreich ataxia induced pluripotent stem cell-derived neurons show a cellular phenotype that is corrected by a benzamide HDAC inhibitor

1.  Franca Codazzi1,2

2.  Amelié Hu3

3.  Myriam Rai3

4.  Floramarida Salerno Scarzella2,

5.  Elisabeth Mangiameli2

6.  Ilaria Pelizzoni2

7.  Fabio Grohovaz1,2 and 

8.  Massimo Pandolfo3,*

+Author Affiliations

1.   1Vita-Salute San Raffaele University, 20132 Milan, Italy;

2.   2IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy;

3.   3Laboratoire de Neurologie Expérimentale, Université Libre de Bruxelles (ULB), 1070 Brussels, Belgium

1.   #To whom correspondence should be addressed at: Massimo Pandolfo – Laboratory of Experimental Neurology, Université Libre de Bruxelles CP-601, Route de Lennik 808, 1070 Brussels, Belgium. Tel: 32.2.555.34.29; Fax: 32.2.555.39.42;



We employed induced pluripotent stem cell (iPSC)-derived neurons obtained from Friedreich ataxia (FRDA) patients and healthy subjects, FRDA neurons and CT neurons, respectively, to unveil phenotypic alterations related to frataxin (FXN) deficiency and investigate if they can be reversed by treatments that upregulate FXN. FRDA and control iPSCs were equally capable of differentiating into a neuronal or astrocytic phenotype. FRDA neurons showed lower levels of iron-sulfur and lipoic acid-containing proteins, higher labile iron pool (LIP), higher expression of mitochondrial superoxide dismutase (SOD2), increased reactive oxygen species (ROS) and lower reduced glutathione (GSH) levels, and enhanced sensitivity to oxidants compared to CT neurons, indicating deficient iron-sulfur cluster biogenesis, altered iron metabolism, and oxidative stress.

Treatment with the benzamide HDAC inhibitor 109 significantly upregulated FXN expression and increased iron-sulfur and lipoic acid-containing protein levels, downregulated SOD2 levels, normalized LIP and ROS levels, and almost fully protected FRDA neurons from oxidative stress-mediated cell death.

Our findings suggest that correction of frataxin deficiency may not only stop disease progression, but also lead to clinical improvement by rescuing still surviving, but dysfunctional neurons.




R Loops and Links to Human Disease

·        Patricia Richard, , 

·        James L. Manley



Aberrant R-loop structures are increasingly being realized as an important contributor to human disease. R loops, which are mainly co-transcriptional, abundant RNA/DNA hybrids, form naturally and can indeed be beneficial for transcription regulation at certain loci. However, their unwanted persistence elsewhere or in particular situations can lead to DNA double-strand breaks, chromosome rearrangements, and hypermutation, which are all sources of genomic instability. Mutations in genes involved in R-loop resolution or mutations leading to R-loop formation at specific genes affect the normal physiology of the cell. We discuss here the examples of diseases for which a link with R loops has been described, as well as how disease-causing mutations might participate in the development and/or progression of diseases that include repeat-associated conditions, other neurological disorders, and cancers.

Graphical Abstract


·        DSB, DNA double-strand break; 

·        RNAP, RNA polymerase; 

·        FXS, fragile X syndrome;

·        FXTAS, fragile X-associated tremor/ataxia syndrome; 

·        ssDNA, single-stranded DNA; 

·        G-Q, G-quadruplex; 

·        KD, knockdown; 

·        TDRD3, tudor domain-containing protein 3; 

·        FA,Fanconi anemia; 

·        ALS, amyotrophic lateral sclerosis; 

·        FTD, frontotemporal dementia;

·        ATXN2, Ataxin-2; 

·        SCA2, spinocerebellar ataxia type 2; 

·        TDP-43, TAR DNA-binding protein 43; 

·        SETX, senataxin; 

·        AOA2, ataxia with oculomotor apraxia type 2; 

·        AGS,Aicardi–Goutières syndrome; 

·        PWS, Prader–Willi syndrome                                                                                                        -------------------------------------------------------------


Biomarkers and progress of antioxidant therapy for rare mitochondrial disorders

Lucia ChicoDaniele OrsucciAnnalisa Lo GerfoLetizia MarconiMichelangelo Mancuso &Gabriele Siciliano


Introduction: In mitochondrial disorders, a group of genetic diseases associated with decreased energy production and redox imbalance, the pathogenic role of oxidative stress has been pivotal in fostering antioxidant therapy in the attempt to modify the natural history of the conditions.

Areas covered: This review focuses on oxidative stress biomarkers and discusses antioxidant treatment as a potential drug strategy for effective management of mitochondrial disorders.

Expert opinion: New approaches and strategies will be needed to treat patients with mitochondrial disorders. Clinical variability of mitochondrial disorders, low sample size due to their rarity, lacking data on disease natural history and the high variance of the outcome measures so far used are all factors that, in addition to the complexity of the investigated pathway and the huge number of potential combinations of antioxidants, make it necessary to optimize treatment strategy, refine the target and improve the investigation tools. New molecules have recently been studied, such as Nrf2 inducers. Combinations of antioxidant substances also seem to have a rationale in this context. Promising results come from the stimulation of mitochondrial biogenesis or by-pass the genetic block of OXPHOS complexes by alternative enzymes NADH dehydrogenase/CoQ reductase and CoQ/O2 oxidase. Finally, gene therapy approaches seem to open interesting scenarios, targeted to repair the mutated gene to complement its defect. Going ahead with well-controlled clinical trials is still necessary to define the effectiveness of current potential therapies and to design future, hopefully more effective, interventions for mitochondrial disorders.




Optimization of pyrimidinol antioxidants as mitochondrial protective agents: ATP production and metabolic stability

·        Arnaud Chevalier

·        Mohammad Parvez Alam

·        Omar M. Khdour

·        Margaret Schmierer

·        Pablo M. Arce,

·        Cameron D. Cripe

·        Sidney M. Hecht


Previously we described a novel series of pyrimidinol antioxidants and their structural optimization as potential therapeutic agents for neurodegenerative and mitochondrial disorders. Our initial lead compound was a potent antioxidant in vitro, but was subsequently found to exhibit poor stability to oxidative metabolism. The current study focused on balancing potency with metabolic stability through structural modification, and involved modifications at positions 2 and 4 of the pyrimidinol redox core, likely sites of oxidative metabolism. Eight new analogues have been prepared and their ability to suppress lipid peroxidation and reactive oxygen species (ROS), and to preserve mitochondrial membrane potential (Δψm) and support ATP production, has been investigated. The metabolic stability of the prepared compounds was also assessed in vitro using bovine liver microsomes to obtain preliminary insight on this class of compounds. This study revealed the complexity of balancing reasonable metabolic stability with efficient antioxidant properties. While a few analogues appear promising, especially in terms of metabolic stability, a 4-isopropoxy derivative conserved the favorable biological activity and exhibited good metabolic stability. The favorable metabolic stability conferred by the combination of the azetidine and isopropoxy moieties in analogue 6 makes this compound an excellent candidate for further evaluation.

Graphical abstract


·        Mitochondria; 

·        Cytoprotection; 

·        Lipid peroxidation; 

·        Reactive oxygen species; 

·        Microsomal stability




Neurobehavioral deficits in the KIKO mouse model of Friedreich’s ataxia

·        Marissa Z. McMackin

·        Chelsea K. Henderson

·        Gino A. Cortopassi


Friedreich’s Ataxia (FA) is a pediatric neurodegenerative disease whose clinical presentation includes ataxia, muscle weakness, and peripheral sensory neuropathy. The KIKO mouse is an animal model of FA with frataxin deficiency first described in 2002, but neurobehavioral deficits have never been described in this model. The identification of robust neurobehavioral deficits in KIKO mice could support the testing of drugs for FA, which currently has no approved therapy. We tested 13 neurobehavioral tasks to identify a robust KIKO phenotype: Open Field, Grip Strength Test(s), Cylinder, Skilled Forelimb Grasp Task(s), Treadmill Endurance, Locotronic Motor Coordination, Inverted Screen, Treadscan, and Von Frey. Of these, Inverted Screen, Treadscan and Von Frey produced significant neurobehavioral deficits at >8 months of age, and relate to the clinically relevant endpoints of muscle strength and endurance, gait ataxia, and peripheral insensitivity. Thus we identify robust phenotypic measures related to Friedreich's ataxia clinical endpoints which could be used to test effectiveness of potential drug therapy.




Blood–brain barrier shuttle peptides: an emerging paradigm for brain delivery

Benjamí Oller-Salvia a, Macarena Sánchez-Navarro a, Ernest Giralt ab and Meritxell Teixidó a  aInstitute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), 08028 Barcelona, Spain. E-mail:;  bDepartment of Organic Chemistry, University of Barcelona, 08028 Barcelona, Spain

Brain delivery is one of the major challenges in drug development because of the high number of patients suffering from neural diseases and the low efficiency of the treatments available. Although the blood–brain barrier (BBB) prevents most drugs from reaching their targets, molecular vectors – known as BBB shuttles – offer great promise to safely overcome this formidable obstacle. In recent years, peptide shuttles have received growing attention because of their lower cost, reduced immunogenicity, and higher chemical versatility than traditional Trojan horse antibodies and other proteins.



Serum versus Imaging Biomarkers in Friedreich Ataxia to Indicate Left Ventricular Remodeling and Outcomes

Nishaki Mehta, MD, Paul Chacko, MD, James Jin, MD, Tam Tran, 

MSN, Thomas W. Prior, PhD, Xin He, PhD, Gunjan Agarwal,PhD, and Subha V. Raman, MD, MSEE

From: Davis Heart and Lung Research Institute (Drs. Agarwal, Chacko, Jin, Mehta, and Raman, and Mr. Tran) and Department of Pathology (Dr. Prior), The Ohio State University, Columbus, Ohio 43210; and Department of Epidemiology and Biostatistics (Dr. He), University of Maryland, College Park, Maryland 20742

Dr. Chacko is now at Metro-Health Heart and Vascular Center, Cleveland, Ohio.

Dr. Raman receives research support from Siemens.

This work was supported in part by the National Institutes of Health (HL095563 to SVR).

Address for reprints: Nishaki Mehta, MD, Division of Cardiology, Brigham and Women's Hospital, Boston, MA 02115,

Patients with Friedreich ataxia typically die of cardiomyopathy, marked by myocardial fibrosis and abnormal left ventricular (LV) geometry. We measured procollagen I carboxyterminal propeptide (PICP), a serum biomarker of collagen production, and characterized genotypes, phenotypes, and outcomes in these patients.

Twenty-nine patients with Friedreich ataxia (mean age, 34.2 ± 2.2 yr) and 29 healthy subjects (mean age, 32.5 ± 1.1 yr) underwent serum PICP measurements. Patients underwent cardiac magnetic resonance imaging and outcome evaluations at baseline and 12 months.

Baseline PICP values were significantly higher in the patients than in the control group (1,048 ± 77 vs 614 ± 23 ng/mL; P<0.001); severity of genetic abnormality did not indicate severity of PICP elevation. Higher PICP levels corresponded to greater LV concentric remodeling only at baseline (r=0.37, P <0.05). Higher baseline PICP strongly indicated subsequent increases in LV end-diastolic volume (r=0.52, P=0.02). The PICP levels did not distinguish between 14 patients with evident myocardial fibrosis identified through positive late gadolinium enhancement and 15 who had no enhancement (1,067 ± 125 vs 1,030 ± 98 ng/mL; P=0.82). At 12 months, cardiac events had occurred in 3 of 14 fibrosis-positive and none of 15 fibrosis-negative patients (P=0.1); their baseline PICP levels were similar.

We conclude that PICP, a serum marker of collagen synthesis, is elevated in Friedreich ataxia and indicates baseline abnormal LV geometry and subsequent dilation. Cardiac magnetic resonance and PICP warrant consideration as complementary biomarkers in therapeutic trials of Friedreich ataxia cardiomyopathy.






Drug screening: Drug repositioning needs a rethink

·        Xianting Ding

Subject terms:

·        Drug discovery

·        Diseases

Repurposing drugs to treat illnesses for which they were not originally intended can be faster and cheaper than developing new ones (see Nature 534, 314–316; 2016). I suggest that greater improvements would come from testing different drug combinations, rather than relying only on high-throughput screening of generic or failed drugs.

Disease is often an integration of multiple pathologies (see, for example, J. N. Weinstein et al.Nature 507, 315–322; 2014), so these are potentially treatable with different drug combinations that act in synergy. Such combinations often show better efficacy than single treatments, have fewer side effects and are less likely to result in drug resistance (see F. Klein et al. Nature 492,118–122; 2012).

For commercial reasons, pharmaceutical firms tend to dismiss reposition testing of drugs that are off patent. I therefore suggest that governments step in to fund the repurposing of established drugs to broaden the search.

Author information


1.  Shanghai Jiao Tong University, Shanghai, China.

·        Xianting Ding




Characterization of novel small-molecule NRF2 activators: Structural and biochemical validation of stereospecific KEAP1 binding

·        Carlos Huertaab

·        Xin Jiangc

·        Isaac Trevinoa

·        Christopher F. Benderc

·        Deborah A. Fergusona

·        Brandon Probsta

·        Kerren K. Swingerd1

·        Vincent S. Stolld

·        Philip J. Thomasb

·        Irina Dulubovaa

·        Melean Visnickc, , , 

·        W. Christian Wigleya, , 

·         Abstract


Semi-synthetic oleanane triterpenoid antioxidant inflammation modulators (tpAIMs) are small molecules that interact with KEAP1 cysteine residue 151 (C151) and activate NRF2. Exploration of the structure-activity relationship between the tpAIMs and KEAP1 is limited by the predominantly hydrocarbon nature of the oleanane triterpenoid pentacyclic ring structure. Therefore, we used novel, chemically-tractable, synthetic antioxidant inflammation modulators (sAIMs) to probe the stereoselectivity of the ligand-protein interaction.


We measured several parameters of NRF2 activation to assess the potency of sAIM enantiomers with natural (tpAIM-like) 4(S),5(S),10(R) or unnatural 4(R),5(R),10(S) configurations. Additionally, we determined the crystal structure of the KEAP1 BTB domain in complex with two different sAIMs.


We found that the potencies of sAIM enantiomers in the natural configuration were similar to those of the tpAIM, RTA 405. Strikingly, sAIM enantiomers in the unnatural configuration were 10- to 40-fold less potent than their natural counterparts. Crystallographic studies of sAIMs in complex with the KEAP1 BTB domain demonstrated that these ligands form a covalent bond with C151 and revealed the presence of additional hydrogen bonds, Van der Waals interactions, and pi-stacking interactions.


Although KEAP1 C151 is required for NRF2 activation by tpAIMs and sAIMs, interactions with other KEAP1 residues are critical for the stereospecific recognition and potency of these ligands.

General significance

This work demonstrates that reversible cyanoenone Michael acceptors, such as the tpAIMs and sAIMs, can be specifically tuned to regulate redox sensitive cysteine residues on key signaling molecules, an approach with significant promise for innovative drug development.

Graphical abstract




Synthetic Nucleic Acids and Treatment of Neurological Diseases 

David R. Corey, PhD1,2



Importance  The ability to control gene expression with antisense oligonucleotides (ASOs) could provide a new treatment strategy for disease.

Objective  To review the use of ASOs for the treatment of neurological disorders.

Evidence Review  Articles were identified through a search of PubMed references from 2000 to 2016 for articles describing the use of ASOs to treat disease, with specific attention to neurological disease. We concentrated our review on articles pertaining to activation of frataxin expression (Friedreich’s ataxia) and production of active survival motor neuron 2 (SMN2, spinal muscular atrophy).

Findings  Many neurological diseases are caused by inappropriate expression of a protein. Mutations may reduce expression of a wild-type protein, and strategies to activate expression may provide therapeutic benefit. For other diseases, a mutant protein may be expressed too highly and methods that reduce mutant protein expression might form the basis for drug development. Synthetic ASOs can recognize cellular RNA and control gene expression. Antisense oligonucleotides are not a new concept, but successful clinical development has proceeded at a slow pace. Advances in ASO chemistry, biological understanding, and clinical design are making successful applications more likely.

Conclusions and Relevance  Both laboratory and clinical studies are demonstrating the potential of ASOs as a source of drugs to treat neurological disease.





Variable sensory nerve conduction parameters in late onset Friedreich ataxia


·        James J.P. Alix PhD, MRCP,

               Taimour Alam MRCP,

               Kate Garrard BSc,

               Joanne Martindale MRCPath,

               Priya Shanmugarajah MD, MRCP,

               D. Ganesh Rao DM, FRCP,

               Marios Hadjivassiliou MD, FRCP



Long-Axis Left Ventricular and Left Atrial Dysfunction in Friedreich Ataxia with Normal Ejection Fraction – Global Longitudinal Strain Versus Tissue Doppler Imaging Velocities

D. Jackson Press enter key for correspondence information

R. Hassam

L. Donelan

R. Peverill

Monash Cardiovascular Research Centre, MonashHeart and Department of Medicine (School of Clinical Sciences at Monash Medical Centre), Monash University and Monash Health, Melbourne, Australia

·        Abstract

Friedreich ataxia (FRDA) is a progressive neurological disease due to a GAA expansion in both alleles of the frataxin gene, and is commonly also accompanied by a cardiomyopathy. Abnormalities of left ventricular (LV) and left atrial long-axis function can be evident in FRDA before there is any reduction of ejection fraction (EF), with reductions reported in tissue Doppler imaging (TDI) measures of systolic (s‘), early diastolic (e‘) and atrial contraction (a‘) mitral annular velocities and also in global longitudinal strain (GLS).




Translating HDAC inhibitors in Friedreich’s ataxia

Elisabetta Soragni & Joel M. Gottesfeld


Introduction: Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disease caused by expansion of a GAA·TCC triplet in the first intron of the FXN gene, encoding the essential mitochondrial protein frataxin. Repeat expansion results in transcriptional silencing through an epigenetic mechanism, resulting in significant decreases in frataxin protein in affected individuals.

Areas covered: We review the evidence that histone postsynthetic modifications and heterochromatin formation are responsible for FXN gene silencing in FRDA, along with efforts to reverse silencing with drugs that target histone modifying enzymes. Chemical and pharmacological properties of histone deacetylase (HDAC) inhibitors, which reverse silencing, together with enzyme target profiles and kinetics of inhibition, are discussed. Two HDAC inhibitors have been studied in human clinical trials and the properties of these compounds are compared and contrasted.

Expert opinion: 2-aminobenzamide class I HDAC inhibitors are attractive therapeutic small molecules for FRDA. These molecules increase FXN gene expression in human neuronal cells derived from patient induced pluripotent stem cells, and in two mouse models for the disease, as well as in circulating lymphocytes in patients treated in a phase Ib clinical trial. Medicinal chemistry efforts have identified compounds with improved brain penetration, metabolic stability and efficacy in the human neuronal cell model. A clinical candidate will soon be identified for further human testing.

KEYWORDS: Friedreich ataxiahistone deacetylase inhibitorheterochromatinepigeneticsneurodegenerative disease



Voice in Friedreich Ataxia

·        Adam P. Vogel*, , 1, , 

·        Mayumi I. Wardrop*

·        Joanne E. Folker§

·        Matthis Synofzik

·        Louise A. Corben#

·        Martin B. Delatycki**

·        Shaheen N. Awan††


·        1Summary


Friedreich Ataxia (FRDA) is the most common hereditary ataxia, with dysarthria as one of its key clinical signs.


To describe the voice profile of individuals with FRDA to inform outcome marker development and goals of speech therapy.


Thirty-six individuals with FRDA and 30 age-matched controls provided sustained vowel and connected speech samples. Speech and voice samples were analyzed acoustically using the Analysis of Dysphonia in Speech and Voice program and perceptually using the Consensus Auditory-Perceptual Evaluation of Voice form. Correlations between dysphonia and overall dysarthria severity, demographic, clinical, and genetic information were explored.


Individuals with FRDA presented with mild dysphonia characterized by hoarseness (combined roughness and breathiness), increased strain, and altered pitch variability (increased in vowel productions; slightly decreased on reading samples). Acoustically, individuals with FRDA had significantly higher scores on the Cepstral Spectral Index of Dysphonia during vowel production. A combination of perceptual and acoustic measures of dysphonia used in this study was quite effective in categorizing the FRDA versus control participants, with >80% overall accuracy.


Although dysphonia severity in FRDA did not correlate significantly with overall disease severity, speaking rate and syllabic duration significantly correlated with age at disease onset and disease duration, and also have an effect on listener perception of dysphonia. The relationship between dysphonia and dysarthria in FRDA suggests that reducing overall dysphonia severity via therapeutic techniques that improve phonatory stability and increase speaking rate is a viable target for speech therapy.




The Pediatric Cerebellum in Inherited Neurodegenerative Disorders : A Pattern-recognition Approach

·        Susan I. Blaser, MDa, , , 

·        Maja Steinlin, MDb

·        Almundher Al-Maawali, MDc

·        Grace Yoon, MDd

·        a Division of Paediatric Neuroradiology, The Hospital for Sick Children, University of Toronto, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada

·        b Division of Neuropaediatrics, Development and Rehabilitation, University Children’s Hospital Inselspital, University of Bern, Freiburgstrasse 4, Bern 3010, Switzerland

·        c Department of Genetics, Sultan Qaboos University Hospital, Al Khoudh, Muscat 123, Oman

·        d Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, University of Toronto, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada


Long-term treatment with thiamine as possible medical therapy for Friedreich ataxia

·        Antonio Costantini

·        Tiziana Laureti

·        Maria Immacolata Pala

·        Marco Colangeli

·        Simona Cavalieri

·        Elisa Pozzi

·        Alfredo Brusco

·        Sandro Salvarani

·        Carlo Serrati


Thiamine (vitamin B1) is a cofactor of fundamental enzymes of cell energetic metabolism; its deficiency causes disorders affecting both the peripheral and central nervous system. Previous studies reported low thiamine levels in cerebrospinal fluid and pyruvate dehydrogenase dysfunction in Friedreich ataxia (FRDA). We investigated the effect of long-term treatment with thiamine in FRDA, evaluating changes in neurological symptoms, echocardiographic parameters, and plasma FXN mRNA levels. Thirty-four consecutive FRDA patients have been continuously treated with intramuscular thiamine 100 mg twice a week and have been assessed with the Scale for the Assessment and Rating of Ataxia (SARA) at baseline, after 1 month, and then every 3 months during treatment. Thiamine administration ranged from 80 to 930 days and was effective in improving total SARA scores from 26.6 ± 7.7 to 21.5 ± 6.2 (p < 0.02). Moreover, deep tendon reflexes reappeared in 57 % of patients with areflexia at baseline, and swallowing improved in 63 % of dysphagic patients. Clinical improvement was stable in all patients, who did not show worsening even after 2 years of treatment. In a subgroup of 13 patients who performed echocardiogram before and during treatment, interventricular septum thickness reduced significantly (p < 0.02). Frataxin mRNA blood levels were modestly increased in one-half of treated patients. We suppose that a focal thiamine deficiency may contribute to a selective neuronal damage in the areas involved in FRDA. Further studies are mandatory to evaluate thiamine role on FXN regulation, to exclude placebo effect, to verify our clinical results, and to confirm restorative and neuroprotective action of thiamine in FRDA.



Agilis Biotherapeutics Announces FDA Orphan Drug Designation for the Treatment of Friedreich’s Ataxia (FA)

First Gene Therapy Candidate to Receive Designation for FA

August 02, 2016 08:30 AM Eastern Daylight Time

CAMBRIDGE, Mass.--(BUSINESS WIRE)--Agilis Biotherapeutics, LLC (Agilis), a biotechnology company advancing innovative DNA therapeutics for rare genetic diseases that affect the central nervous system (CNS), announced today that the United States Food and Drug Administration (FDA) has granted Orphan Drug Designation to Agilis’ gene therapy product candidate, AGIL-FA, being developed for the treatment of Friedreich’s ataxia (FA), an inherited degenerative neuromuscular disorder resulting in loss of motor coordination and strength, hearing, vision, speech and often premature death. Agilis is the first company to receive orphan designation from the FDA for a gene therapy to treat FA and it is the fourth time this year that Agilis has been granted orphan designation in the US and Europe for its gene therapies. The Company’s gene therapies for AADC deficiency and Angelman syndrome have previously received orphan status.

Agilis Receives First Orphan Designation for Gene Therapy Candidate for Friedreich's Ataxia

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“Having the first gene therapy product candidate to receive orphan drug designation from the FDA for the treatment of FA is an honor,” said Mark Pykett, President and CEO of Agilis. “The orphan designation is another step on our path to bringing this important new therapy to patients who currently lack treatment options.” AGIL-FA is a gene-therapy product consisting of a unique gene construct developed in partnership with Intrexon Corporation (NYSE: XON) delivered with adeno-associated virus technology.

“We are extremely pleased to receive this landmark designation, as we move our FA development program forward,” said Christopher Silber, MD, Agilis Chief Medical Officer. “With each of our IND and clinical stage pipeline candidates having now received Orphan Designation, this achievement highlights our efforts to advance innovative therapeutics for patients with rare genetic diseases affecting the CNS.”

Friedreich’s ataxia (FA) is a rare and life-shortening neurodegenerative disease caused by a defect in the FXN gene that reduces production of the frataxin protein. Agilis’ FA gene therapy program is focused on delivering corrective DNA to specific CNS cells to restore frataxin protein levels. Agilis has worked closely with the Friedreich’s Ataxia Research Alliance (FARA) to focus the development program on patient needs. “FARA is delighted to continue our support of Agilis and their innovative approach to the treatment of FA,” said Jennifer Farmer, MS, Executive Director of FARA. “We look forward to continuing our partnership to advance this important potential therapy, as well as supporting research to identify biomarkers and clinical outcome measures, which will advance the development of the product candidate into clinical trials.”

FDA Orphan Drug Designation is evaluated for drugs from all classes (e.g. small molecules, proteins, and gene or cell therapies) that are intended for the treatment of rare diseases, defined as diseases affecting fewer than 200,000 people in the United States. The designation provides sponsors with development and commercial incentives, including seven years of market exclusivity in the US, prioritized consultation by FDA on clinical studies, and certain exemptions from or reductions in regulatory fees.

About Friedreich’s ataxia

Friedreich’s ataxia (FA) is an inherited neuromuscular disorder most commonly caused by a single genetic defect in the FXN gene that leads to reduced production of frataxin, a mitochondrial protein that is important for cellular metabolism and energy production. FA results in a physically debilitating, life-shortening condition and is the most common hereditary ataxia, with an estimated 5,000 to 10,000 patients in the US (i.e., one in every 50,000 people). Both male and female children can inherit the disorder. Symptoms of FA include progressive loss of coordination and muscle strength, which lead to the full-time use of a wheelchair; scoliosis (which often requires surgical intervention); diabetes mellitus; hearing and vision impairment; serious heart conditions; and premature death. Current FA therapies are primarily focused on symptomatic relief, and there are no FDA-approved drugs to treat the cause of FA. Visit for more information.

About Agilis Biotherapeutics

Agilis is advancing innovative gene therapies designed to provide long-term efficacy for patients with debilitating, often fatal, rare genetic diseases that affect the central nervous system. Our therapies are engineered to impart sustainable clinical benefits, and potentially a functional cure, by inducing persistent expression of a therapeutic gene. The Company’s technology is aimed at the precise targeting and restoration of a lost gene function, while avoiding unintended off-target effects. Our integrated strategy increases the efficiency of developing DNA therapeutics into safe, targeted gene therapies that achieve long-term efficacy and enable patients to remain asymptomatic without continuous invasive treatment. Agilis’ rare disease programs are focused on gene therapy for AADC deficiency, Friedreich’s ataxia, and Angelman syndrome, rare genetic diseases that include severe neurological deficits and result in physically debilitating conditions.

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

·        Martina Stevanoni ,

·        Elisa Palumbo ,

·        Antonella Russo 


It is well known that DNA replication affects the stability of several trinucleotide repeats, but whether replication profiles of human loci carrying an expanded repeat differ from those of normal alleles is poorly understood in the endogenous context. We investigated this issue using cell lines from Friedreich’s ataxia patients, homozygous for a GAA-repeat expansion in intron 1 of the Frataxin gene. By interphase, FISH we found that in comparison to the normalFrataxin sequence the replication of expanded alleles is slowed or delayed. According to molecular combing, origins never fired within the normal Frataxin allele. In contrast, in mutant alleles dormant origins are recruited within the gene, causing a switch of the prevalent fork direction through the expanded repeat. Furthermore, a global modification of the replication profile, involving origin choice and a differential distribution of unidirectional forks, was observed in the surrounding 850 kb region. These data provide a wide-view of the interplay of events occurring during replication of genes carrying an expanded repeat.


Progression of Friedreich ataxia: quantitative characterization over 5 years


·        Maya Patel,


·        Charles J. Isaacs,


·        Lauren Seyer,


·        Karlla Brigatti,


·        Sarah Gelbard,


·        Cassandra Strawser,


·        Debbie Foerster,


·        Julianna Shinnick,


·        Kimberly Schadt,


·        Eppie M. Yiu,


·        Martin B. Delatycki,


·        Susan Perlman,


·        George R. Wilmot,


·        Theresa Zesiewicz,


·        Katherine Mathews,


·        Christopher M. Gomez,


·        Grace Yoon,


·        Sub H. Subramony,


·        Alicia Brocht,


·        Jennifer Farmer,


·        David R. Lynch



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.


Eight hundred and twelve subjects in a natural history study were evaluated annually across 12 sites using the Friedreich Ataxia Rating Scale (FARS), 9-Hole Peg Test, Timed 25-Foot Walk, visual acuity tests, self-reported surveys and disability scales. Cross-sectional outcomes were assessed from recent visits, and longitudinal changes were gaged over 5 years from baseline.


Cross-sectional outcomes correlated with measures of disease severity. Age, genetic severity (guanine-adenine-adenine [GAA] repeat length), and testing site predicted performance. Serial progression was relatively linear using FARS and composite measures of performance, while individual performance outcomes were nonlinear over time. Age strongly predicted change from baseline until removing the effects of baseline FARS scores, when GAA becomes a more important factor. Progression is fastest in younger subjects and subjects with longer GAA repeats. Improved coefficients of variation show that progression results are more reproducible over longer assessment durations.


While age predicted progression speed in simple analyses and may provide an effective way to stratify cohorts, separating the effects of age and genetic severity is difficult. Controlling for baseline severity, GAA is the major determinant of progression rate in FRDA. Clinical trials will benefit from enrollment of younger subjects, and sample size requirements will shrink with longer assessment periods. These findings should prove useful in devising gene therapy trials in the near future.


Non-coding RNAs as drug targets

·        Masayuki Matsui

·        & David R. Corey



Most of the human genome encodes RNAs that do not code for proteins. These non-coding RNAs (ncRNAs) may affect normal gene expression and disease progression, making them a new class of targets for drug discovery. Because their mechanisms of action are often novel, developing drugs to target ncRNAs will involve equally novel challenges. However, many potential problems may already have been solved during the development of technologies to target mRNA. Here, we discuss the growing field of ncRNA — including microRNA, intronic RNA, repetitive RNA and long non-coding RNA — and assess the potential and challenges in their therapeutic exploitation.


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

This study is currently recruiting participants. (see Contacts and Locations)

Verified July 2016 by Annapurna Therapeutics


Annapurna Therapeutics


Adverum Biotechnologies

Weill Medical College of Cornell University

Information provided by (Responsible Party):

Annapurna Therapeutics Identifier:


First received: July 19, 2016

Last updated: July 21, 2016

Last verified: July 2016

History of Changes

·        Full Text View

·        Tabular View

·        No Study Results Posted

·        Disclaimer

·        How to Read a Study Record


Friedreich's ataxia (FA) is an autosomal recessive disease with an incidence of 1/50,000 in the Caucasian population. The main manifestations of FA are progressive sensory and cerebellar ataxia and cardiomyopathy (CM). It is the most common form of inherited ataxia. A severe CM affects ~60% of FA patients, mostly young adults, and leads to cardiac failure then death. Currently, no therapy can change the course of this severe cardiomyopathy.

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.




Friedreich's Ataxia

Procedure: Cardiac magnetic resonance imaging (CMR) Procedure: Exercise-stress test Procedure: Echocardiography (ECHO) Procedure: Cardiac-related blood studies


Study Type:


Study Design:

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

Official Title:

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


Resource links provided by NLM:


Genetics Home Reference related topics: Friedreich ataxia VLDLR-associated cerebellar hypoplasia ataxia neuropathy spectrumautosomal 

recessive cerebellar ataxia type 1 childhood myocerebrohepatopathy

spectrum deoxyguanosine kinase deficiencymitochondrial 

neurogastrointestinal encephalopathy disease myoclonic epilepsy

myopathy sensory ataxia

MedlinePlus related topics: Friedreich's Ataxia MRI Scans

Genetic and Rare Diseases Information Center resources: Friedreich Ataxia Spinocerebellar Ataxia

U.S. FDA Resources 


Further study details as provided by Annapurna Therapeutics:


Primary Outcome Measures:

·        Exercise-stress test [ Time Frame: 2 hours ] [ Designated as safety issue: No ]

·        Cardiac magnetic resonance imaging (CMR) [ Time Frame: 2 hours ] [ Designated as safety issue: No ]

·        Echocardiogram [ Time Frame: 2 hours ] [ Designated as safety issue: No ]

·        Level of cardiac biomarkers in serum [ Time Frame: 30 minutes ] [ Designated as safety issue: No ]

·        Fatigue Severity Scale [ Time Frame: 30 minutes ] [ Designated as safety issue: No ]


Estimated Enrollment:


Study Start Date:

July 2016

Estimated Primary Completion Date:

June 2018 (Final data collection date for primary outcome measure)



Assigned Interventions

Friedreich's Ataxia

Procedure: Cardiac magnetic resonance imaging (CMR) Procedure: Exercise-stress test Procedure: Echocardiography (ECHO) Procedure: Cardiac-related blood studies

Healthy Volunteers (Controls)

Procedure: Cardiac magnetic resonance imaging (CMR) Procedure: Exercise-stress test Procedure: Echocardiography (ECHO) Procedure: Cardiac-related blood studies


Ages Eligible for Study:  

18 Years and older   (Adult, Senior)

Genders Eligible for Study:  


Accepts Healthy Volunteers:  



Inclusion Criteria (Friedreich's Ataxia):

·        Males and females;

·        ≥ 18 years old;

·        Willing and able to provide informed consent;

·        Definitive diagnosis of FA, based on clinical phenotype and genotype;

·        With a hypertrophic cardiomyopathy;

·        Ability to complete study assessments

Exclusion Criteria (Friedreich's Ataxia):

·        Symptoms of cardiac failure;

·        Moderate to severe atrial or ventricular arrhythmias;

·        History of angina pectoris;

·        Inability to undergo cardiac MRI;

·        Glycated hemoglobin HbA1c > 8%;

·        Abnormal kidney function;

·        Females who are pregnant or nursing;

·        Receipt of an investigational drug within 30 days or 5 half-lives, or active enrollment in an investigational medication or device study;

·        Inability to sit with back support;

·        Inability to undergo exercise test;

·        Inability to comply with all study requirements;

·        Unaffiliated to any French health insurance or equivalent.

Inclusion Criteria (Healthy Volunteers):

·        Healthy males and females;

·        ≥ 18 years old;

·        Willing and able to provide informed consent;

·        Age and gender matched to the Friedreich's Ataxia group

·        Ability to complete study assessments

Exclusion Criteria (Healthy Volunteers):

·        Inability to undergo cardiac MRI;

·        Abnormal kidney function;

·        Females who are pregnant or nursing;

·        Receipt of an investigational drug within 30 days or 5 half-lives, or active enrollment in an investigational medication or device study;

·        Inability to undergo exercise test;

·        Inability to comply with all study requirements;

·        Unaffiliated to any French health insurance or equivalent.

  Contacts and Locations

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.  Please refer to this study by its identifier: NCT02840669


Contact: Carla Fiankan

+1 (650) 665-7025



Hôpital Pitié-Salpêtrière, AP-HP


Paris, France, 75013

Contact: Alexandra Durr         

Principal Investigator: Alexandra Durr, MD, PhD         

Sub-Investigator: Françoise Pousset, MD         

Sub-Investigator: Alban Redheuil, MD, PhD         

Sub-Investigator: Stéphane Hatem, MD, PhD         

Sponsors and Collaborators

Annapurna Therapeutics

Adverum Biotechnologies

Weill Medical College of Cornell University


Principal Investigator:

Alexandra Durr, MD, PhD

Groupe hospitalier Pitié Salpêtrière, APHP

  More Information


Responsible Party:

Annapurna Therapeutics Identifier:

NCT02840669     History of Changes

Other Study ID Numbers:


Study First Received:

July 19, 2016

Last Updated:

July 21, 2016

Health Authority:

France: Agence Nationale de Sécurité du Médicament et des produits de santé France: Ethics Committee

Keywords provided by Annapurna Therapeutics:


Additional relevant MeSH terms:


Friedreich Ataxia Ataxia Cerebellar Ataxia Dyskinesias Neurologic Manifestations Nervous System Diseases Signs and Symptoms Cerebellar Diseases Brain Diseases

Central Nervous System Diseases Spinocerebellar Degenerations Spinal Cord Diseases Heredodegenerative Disorders, Nervous System Neurodegenerative Diseases Genetic Diseases, Inborn Mitochondrial Diseases Metabolic Diseases processed this record on September 08, 2016




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

Paul A. Lindahl*†‡ and Michael J. Moore

† Department of Chemistry, Texas A&M University, College Station, Texas 77843-3255, United States

‡ Department of Biochemistry and Biophysics, Texas A&M University, College Station, Texas 77843-2128, United States


Iron, copper, zinc, manganese, cobalt, and molybdenum play important roles in mitochondrial biochemistry, serving to help catalyze reactions in numerous metalloenzymes. These metals are also found in labile “pools” within mitochondria. Although the composition and cellular function of these pools are largely unknown, they are thought to be comprised of nonproteinaceous low-molecular-mass (LMM) metal complexes. Many problems must be solved before these pools can be fully defined, especially problems stemming from the lability of such complexes. This lability arises from inherently weak coordinate bonds between ligands and metals. This is an advantage for catalysis and trafficking, but it makes characterization difficult. The most popular strategy for investigating such pools is to detect them using chelator probes with fluorescent properties that change upon metal coordination. Characterization is limited because of the inevitable destruction of the complexes during their detection. Moreover, probes likely react with more than one type of metal complex, confusing analyses. An alternative approach is to use liquid chromatography (LC) coupled with inductively coupled plasma mass spectrometry (ICP-MS). With help from a previous lab member, the authors recently developed an LC–ICP-MS approach to analyze LMM extracts from yeast and mammalian mitochondria. They detected several metal complexes, including Fe580, Fe1100, Fe1500, Cu5000, Zn1200, Zn1500, Mn1100, Mn2000, Co1200, Co1500, and Mo780 (numbers refer to approximate masses in daltons). Many of these may be used to metalate apo-metalloproteins as they fold inside the organelle. The LC-based approach also has challenges, e.g., in distinguishing artifactual metal complexes from endogenous ones, due to the fact that cells must be disrupted to form extracts before they are passed through chromatography columns prior to analysis. Ultimately, both approaches will be needed to characterize these intriguing complexes and to elucidate their roles in mitochondrial biochemistry.


Metal Homeostasis Regulators Suppress FRDA Phenotypes in aDrosophila Model of the Disease

·        Sirena Soriano,

·        Pablo Calap-Quintana,

·        José Vicente Llorens,

·        Ismael Al-Ramahi,

·        Lucía Gutiérrez,

·        María José Martínez-Sebastián,

·        Juan Botas,

·        María Dolores Moltó 



Friedreich’s ataxia (FRDA), the most commonly inherited ataxia in populations of European origin, is a neurodegenerative disorder caused by a decrease in frataxin levels. One of the hallmarks of the disease is the accumulation of iron in several tissues including the brain, and frataxin has been proposed to play a key role in iron homeostasis. We found that the levels of zinc, copper, manganese and aluminum were also increased in a Drosophila model of FRDA, and that copper and zinc chelation improve their impaired motor performance. By means of a candidate genetic screen, we identified that genes implicated in iron, zinc and copper transport and metal detoxification can restore frataxin deficiency-induced phenotypes. Taken together, these results demonstrate that the metal dysregulation in FRDA includes other metals besides iron, therefore providing a new set of potential therapeutic targets.




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

Václav Marcián1,2, Pavel Filip1, Martin Bareš1,3,4 & Milan Brázdil1,3,*

1First Department of Neurology, St. Anne’s University Hospital and Medical Faculty of Masaryk University, Brno, Czech Republic, 2Department of Neurology, University Hospital Ostrava, Czech Republic, 3Behavioral and Social Neuroscience Research Group, CEITEC (Central European Institute of Technology), Masaryk University, Brno, Czech Republic,4Department of Neurology, School of Medicine, University of Minnesota, Minneapolis, MN, USA


Basic epilepsy teachings assert that seizures arise from the cerebral cortex, glossing over infratentorial structures such as the cerebellum that are believed to modulate rather than generate seizures. Nonetheless, ataxia and other clinical findings in epileptic patients are slowly but inevitably drawing attention to this neural node. Tracing the evolution of this line of inquiry from the observed coincidence of cerebellar atrophy and cerebellar dysfunction (most apparently manifested as ataxia) in epilepsy to their close association, this review considers converging clinical, physiological, histological, and neuroimaging evidence that support incorporating the cerebellum into epilepsy pathology. We examine reports of still controversial cerebellar epilepsy, studies of cerebellar stimulation alleviating paroxysmal epileptic activity, studies and case reports of cerebellar lesions directly associated with seizures, and conditions in which ataxia is accompanied by epileptic seizures. Finally, the review substantiates the role of this complex brain structure in epilepsy whether by coincidence, as a consequence of deleterious cortical epileptic activity or antiepileptic drugs, or the very cause of the disease.

Keywords: Ataxia, epilepsy, seizures, atrophy, stimulation



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


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. It was proposed that formation of unusual DNA structures such as R-loops over repeat regions may play a role, but their molecular function has not been investigated in vivo. R-loops are three-stranded structures, which occur when RNA hybridises to a complementary DNA strand. This leads to formation of an RNA/DNA hybrid and results in displacement of the other DNA strand.

In the first part of this thesis, I show that RNA/DNA hybrids are formed in patient cells on expanded repeats of FXN and FMR1 genes, mutated in Friedreich ataxia and fragile X syndrome. These RNA/DNA hybrids are stable, colocalise with repressive chromatin marks and impede FXN gene transcription in patient cells. Furthermore, I studied the relationship between repressive chromatin and RNA/DNA hybrids. I found that increasing RNA/DNA hybrid levels triggers heterochromatin formation and leads to transcriptional repression of the FXN gene, providing a direct molecular link between RNA/DNA hybrids and the pathology of expansion diseases.

The current understanding of R-loop biology in health and disease is limited by the small number of proteins known to bind RNA/DNA hybrids or R-loops in vivo. In the second part of this thesis I therefore established an affinity purification approach, employing the RNA/DNA hybrid-specific S9.6 antibody followed by mass spectrometry to identify RNA/DNA hybrid-binding proteins in HeLa cells. Using this approach, 469 proteins were identified that constitute the RNA/DNA hybrid interactome by stringent biochemical and statistical criteria. Identified proteins include known R-loop factors senataxin, SRSF1 and topoisomerase I and yet uncharacterised interactors, such as RNA- and DNA-binding proteins, DNA repair and chromatin factors, and helicases. To demonstrate the biological relevance of the RNA/DNA hybrid interactome, I show that the top candidate DHX9 helicase promotes RNA/DNA hybrid resolution in vivo. Furthermore, DHX9 and other RNA/DNA hybrid interactome helicases are overexpressed in cancer, revealing a strong link between R-loop-mediated genome instability and human disease.

About The Authors and Contributors

Matthias Groh




Dr Natalia Gromak





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

Article type: Research Article

Authors: Luis,* | Costa, | Muñoz, E.d | de Carvalho, M.a | Carmona, S.e | Schneider, E.f |Gordon, | Valls-Solé, J.d

Affiliations: [a] Clinical Translational Physiology Unit, Institute of Molecular Medicine, Faculty of Medicine, University of Lisbon, Lisbon, Portugal | [b] Department of Surgical Specialties and Anesthesia, Otolaryngology Unit, Hospital de Cascais, Portugal | [c] Institute of Health Sciences, Portuguese Catholic University, Lisbon, Portugal | [d] Department of Neurology, EMG and Motor Control Unit, Hospital Clínic, Universitat de Barcelona, IDIBAPS, Spain | [e] Department of Neuro-otology and Pain and Headache, Instituto de Neurociencias de Buenos Aires INEBA, Buenos Aires, Argentina | [f] Institute of Medical Technology, Brandenburg University of Technology Cottbus – Senftenberg, Germany | [g] Department of Neurology, Meir Medical Center, Kfar Saba, Tel Aviv University, Tel Aviv, Israel | [h] Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

Correspondence: [*] Corresponding author: Leonel Luis, MD, PhD, Clinical Translational Physiology Unit, IMM, Faculty of Medicine,University of Lisbon, Av. Prof. Egas Moniz, 1649-028 Lisbon, Portugal. Tel.: +351 217 999 41; E-mail:

Abstract: OBJECTIVE: 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. METHODS: We explored the vestibulo-ocular reflex (VOR) with the video Head Impulse Test in patients diagnosed with spinocerebellar ataxia (SCA) type 3 (n = 15), type 1 (n = 4) and type 2 (n = 4), Friedreich’s ataxia (FA) (n = 9) and healthy controls (n = 40). We estimated the latency, regression (VORr) and instantaneous VOR gain at 40, 60 and 80 ms (VOR40, VOR60 and VOR80), and determined the latency, peak-velocity and occurrence rate of catch-up saccades triggered with head-impulses. RESULTS: VOR latency was higher in FA (p < 0.001) and SCA3 (p = 0.02) as compared to controls, discriminating FA from other ataxic patients with an overall diagnostic accuracy of 88%. VORr, VOR40 and VOR60 were significantly lower in FA and SCA3 (p < 0.01). VOR80 was only significantly lower than controls in SCA3 (p < 0.01), discriminating these from other ataxic patients with an overall diagnostic accuracy of 78%. Covert saccades were only triggered in SCA3 but with low occurrence rate and peak velocity (11.1 ± 28.5% and 77.50 ± 15.30°/s) whereas overt saccades were present in all groups. VORr gain showed a negative correlation with disease severity evaluated with SARA (Spearman r = –0.46, p = 0.01). CONCLUSIONS: vHIT provides phenotypic information that differentiates these autosomal ataxias and can serve as a strategy to orient genetic diagnosis. A correlation between VOR and SARA raises the possibility of using VOR gain as a neurophysiologic biomarker for disease severity.

Keywords: Neuro-otology, vestibulo-ocular reflex (VOR), vestibular function tests, spinocerebellar ataxia, Friedreich ataxia



Friedreich’s ataxia and advanced heart failure: An ethical conundrum in decision-making

Peter Ivak, MD

Alena Zumrová, MD

Ivan Netuka, MD, PhD



Friedreich’s ataxia (FA) is a neurodegenerative disorder with an autosomal recessive pattern of inheritance, resulting from amplified intronic GAA repeats in FXN domain1 on chromosome 9q13–q21.1. The defect disrupts production of frataxin, which regulates iron transfer in the mitochondria and results in excessive free radical generation with subsequent neuronal degeneration. FA is a common (1:50,000) inherited ataxia and presents with progressive neurologic symptoms (spinocerebellar ataxia, arreflexia, pyramidal signs, dysarthria and nystagmus).


Deuterium switcheroo breathes life into old drugs

Drugmakers juggle isotopes in hopes of achieving novelty, stability, and success

By Bethany Halford

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.

In particular, deuterium can be far more difficult to pluck from a carbon atom than hydrogen. That property has long intrigued drugmakers: Metabolic enzymes often begin to break down drugs by stripping them of their hydrogen atoms. If . . .


Genetic testing in neurology

·        Henrietta Lefroy

·        Victoria Harrison

·        Andrea H. Németh


Genetic testing is now an integral part of most areas of medicine, including neurological disorders. This article provides clinicians with guidance on the issues and pathways for genetic testing, including ethical dilemmas that can arise in the care of families with a confirmed or suspected genetic condition. As genetics moves more into the mainstream, it is increasingly important for non-geneticists to be aware of these issues, the potential pitfalls and when to seek specialist advice. We explain patterns of inheritance, their complexities and the important distinctions between pre-symptomatic, diagnostic and carrier testing. We explain the ethical framework for testing, including confidentiality and consent, and testing in children and in at-risk relatives. We outline core technologies for genetic testing and the importance of close liaison with clinical genetics services and medical genetics laboratories to remain updated with the type, availability and appropriateness of any genetic test. We also summarise new genetic sequencing technologies that are transforming clinical practice.


·        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 MuellerEmail authorView ORCID ID profile,

·        Andreas Jerrentrup,

·        Max Jakob Bauer,

·        Hans Walter Fritsch and

·        Juergen Rolf Schaefer



Little is known about the characteristics of patients seeking help from dedicated centers for undiagnosed and rare diseases. However, information about their demographics, symptoms, prior diagnoses and medical specialty is crucial to optimize these centers’ processes and infrastructure.


Using a questionnaire, structured information from 522 adult patients contacting a center for undiagnosed and rare diseases was obtained. The information included basic sociodemographic data (age, gender, insurance status), previous hospital admissions, primary symptoms of complaint and previously determined diagnosis.


The majority of patients completing the questionnaire were female, 300 (57 %) vs. 222 men (43 %). The median age was 52 years (range 18–92). More than half, 309 (59 %), of our patients had never been admitted to a university hospital. Common diagnoses included other soft tissue disorders, not classified elsewhere (ICD M79, n = 63, 15.3 %), somatoform disorders (ICD F45, n = 51, 12.3 %) and other polyneuropathies (ICD G62,n=36, 8.7 %). The most frequent symptoms were general weakness (n = 180, 36.6 %) followed by arthralgia (n = 124, 25.2 %) and abdominal discomfort (n = 113, 23.0 %). The majority of patients had either internal medicine (81.3 %) and/or neurologic (37.6 %) health problems.


Pain-associated diagnoses and the typical “unexplained” medical conditions (chronic fatigue syndrome, fibromyalgia, irritable bowel syndrome) are frequent among people contacting a center dedicated to undiagnosed diseases. The chief symptoms are mostly unspecific. An interdisciplinary organizational approach involving mainly internal medicine, neurology and psychiatry/psychosomatic care is needed.




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

·        Delia Yuberoa

·        Raquel Monteroab

·        Miguel A. Martínbc

·        Julio Montoyabd

·        Antonia Ribesbe

·        Manuela Grazinaf

·        Eva Trevissong

·        Juan Carlos Rodriguez-Aguilerabh

·        Iain P. Hargreavesi

·        Leonardo Salviatig,

·        Plácido Navasbh

·        Rafael Artuchab, , , 


o   CoQ deficiency study group 

·        Cristina Jouab

·        Cecilia Jimenez-Mallebreraab

·        Andres Nascimentoab

·        Belén Pérez-Dueñasab

·        Carlos Orteza

·        Federico Ramosa

·        Jaume Colomera

·        Mar O’Callaghanab

·        Mercè Pinedaa

·        Angels García-Cazorlaab

·        Carmina Espinósj,



We evaluated the coenzyme Q₁₀ (CoQ) levels in patients who were diagnosed with mitochondrial oxidative phosphorylation (OXPHOS) and non-OXPHOS disorders (n = 72). Data from the 72 cases in this study revealed that 44.4% of patients showed low CoQ concentrations in either their skeletal muscle or skin fibroblasts. Our findings suggest that secondary CoQ deficiency is a common finding in OXPHOS and non-OXPHOS disorders. We hypothesize that cases of CoQ deficiency associated with OXPHOS defects could be an adaptive mechanism to maintain a balanced OXPHOS, although the mechanisms explaining these deficiencies and the pathophysiological role of secondary CoQ deficiency deserves further investigation.


·        CoQ, Coenzyme Q10; 

·        OXPHOS, Mitochondrial oxidative phosphorylation; 

·        mtDNA,mitochondrial DNA; 

·        nDNA, nuclear DNA; 

·        CS, citrate synthase; 

·        MRC, mitochondrial respiratory chain enzymes





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

·        Alessandro Rimessia1

·        Maurizio Previatib1

·        Federica Nigroa

·        Mariusz R. Wieckowskic, , 2, , 

·        Paolo Pintona, , 2


Over the last few decades, many different groups have been engaged in studies of new roles for mitochondria, particularly the coupling of alterations in the redox pathway with the inflammatory responses involved in different diseases, including Alzheimer’s disease, Parkinson's disease, atherosclerosis, cerebral cavernous malformations, cystic fibrosis and cancer. Mitochondrial dysfunction is important in these pathological conditions, suggesting a pivotal role for mitochondria in the coordination of pro-inflammatory signaling from the cytosol and signaling from other subcellular organelles. In this regard, mitochondrial reactive oxygen species are emerging as perfect liaisons that can trigger the assembly and successive activation of large caspase-1- activating complexes known as inflammasomes. This review offers a glimpse into the mechanisms by which inflammasomes are activated by mitochondrial mechanisms, including reactive oxygen species production and mitochondrial Ca2+ uptake, and the roles they can play in several inflammatory pathologies.




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

·        Vegard Bruun Wyllerab, , , 

·        Kristine Jacobsenbc

·        Mai Britt Dahlcd

·        Hilde Nilsencd

·        Simone Proskeb,

·        Thorsten Horterb

·        Henrik Brune




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

·        Noëlia Sancheza, , 

·        Pierre Chapdelainea, , 

·        Joël Rousseaua, , 

·        Frédéric Raymondb, , 

·        Jacques Corbeilb, , 

·        Jacques P. Tremblaya, , 


Friedreich's ataxia is an autosomal recessive neurodegenerative disorder associated with an unstable GAA trinucleotide repeat expansion in the first intron of the frataxin gene. This mutation leads to a decrease and partial loss of function of frataxin, a mitochondrial protein involved in heme biosynthesis and cellular iron homeostasis. Since no effective therapy exists for Friedreich's ataxia, new insights into frataxin regulated genes and associated cellular pathways will provide a better understanding of the molecular mechanisms underlying this debilitating condition. In this study, we demonstrate that frataxin regulates the expression of genes involved in interferon-induced apoptosis, DNA damage and blood clotting regulation. This work provides valuable insight into the regulatory network of frataxin and may open new avenues for gene therapy of Friedreich's ataxia.



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