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 http://link.springer.com/article/10.1007/s10072-015-2427-3#

GIFT-1, a phase IIa clinical trial to test the safety and efficacy of IFNγ administration in FRDA patients

·        Christian Marcotulli 

·        , Silvia Fortuni

·        , Gaetano Arcuri

·        , Barbara Tomassini

·        , Luca Leonardi

·        ,Francesco Pierelli

·        , Roberto Testi

·        , Carlo Casali

Abstract

Friedreich’s ataxia is an autosomal recessive progressive degenerative disorder caused by deficiency of the protein frataxin. The most common genetic cause is a homozygotic expansion of GAA triplets within intron 1 of the frataxin gene leading to impaired transcription. Preclinical in vivo and in vitro studies have shown that interferon gamma (IFNγ) is able to up-regulate the expression of frataxin gene in multiple cell types. We designed a phase IIa clinical trial, the first in Italy, aimed at assessing both safety and tolerability of IFNγ in Friedreich’s patients and ability to increase frataxin levels in peripheral blood mononuclear cells. Nine patients (6 female and 3 males aged 21–38 years) with genetically confirmed disease were given 3 subcutaneous escalating doses (100, 150 and 200 μg) of IFNγ (human recombinant interferon 1 b gamma, trade name IMUKIN®), over 4 weeks. The primary end-point was the assessment of the safety and tolerability of IFNγ by means of standard clinical and hematological criteria. The secondary end-point was the detection of changes of frataxin levels in peripheral blood mononuclear cells after each single escalating dose of the drug. IFNγ was generally well tolerated, the main adverse event was hyperthermia/fever. Although, increases in frataxin levels could be detected in a minority of patients, these changes were not significant. A large phase III multicenter, randomized clinical trial with IFNγ in Friedreich’s ataxia patients is currently ongoing. This study is expected to conclusively address the clinical efficacy of IFNγ therapy in patients with Friedreich’s ataxia.

 


http://www.sciencedirect.com/science/article

/pii/S0987705315001112?np=y

La phase de double appui : paramètre prédictif de la dégradation de la marche dans l’ataxie de Friedreich ?

·        B. Roche1, 2, , , 

·        R. Martin1, 

·        I. Husson2

Introduction

Ataxie autosomique récessive la plus fréquente, l’ataxie de Friedreich est une maladie neurodégénérative lentement progressive qui touche 1500 personnes en France. Maladie encore incurable, une prise en charge symptomatique et une meilleure compréhension des troubles permettent de mieux cibler les aides techniques et les rééducations à proposer pour compenser les difficultés. L’analyse de la marche s’inscrit dans ce contexte, pour mieux comprendre sa dégradation dans le temps et proposer alors des compensations.

Matériel et méthodes

Trente-et-un jeunes patients ataxiques ont marché sur le tapis de marche GAITRite lors de l’inclusion et 6 mois plus tard. Les paramètres spatiotemporels ont ainsi été obtenus et analysés de façon statistique, et une corrélation de leur évolution recherchée avec l’évolution de l’ICARS, échelle clinique de l’ataxie.

Résultats

Tous les paramètres tendaient à amorcer une dégradation, mais seule la phase de double appui était significativement détériorée (p < 0,05). En 6 mois, le score ICARS moyen ne montrait pas de changement significatif.

Discussion–conclusion

Alors que l’ICARS n’a pas saisi de dégradation significative, le tapis de marche GAITRite a révélé quant à lui une détérioration significative du double appui, paramètre représentatif, quand il augmente, d’une instabilité à la marche. Il semble que la phase de double appui soit le premier marqueur de dégradation de la marche des patients ayant une ataxie de Friedreich et que sa dégradation signe l’évolution de la maladie non nécessairement identifiée par une échelle clinique spécifique et validée.

 


http://www.cbc.ca/news/health/crispr-dna-gene-editing-1.3339346?cmp=rss

CRISPR gene-editing tool has scientists thrilled — but nervous

Scientists gather in unprecedented summit to debate DNA editing implications

By Kelly Crowe, CBC News

 


http://journal.frontiersin.org/article/10.3389/

fnmol.2015.00066/full

Analyzing the Effects of a G137V Mutation in the FXN Gene

http://3b76aaf63d1816bb57bf-a34624e694c43cdf8b40aa048a644ca4.r96.cf2.rackcdn.com/Design/Images/newprofile_default_profileimage_new.jpgNathalie Faggianelli1,  http://3b76aaf63d1816bb57bf-a34624e694c43cdf8b40aa048a644ca4.r96.cf2.rackcdn.com/Design/Images/newprofile_default_profileimage_new.jpgRita Puglisi1,  http://3b76aaf63d1816bb57bf-a34624e694c43cdf8b40aa048a644ca4.r96.cf2.rackcdn.com/Design/Images/newprofile_default_profileimage_new.jpgLiana Veneziano2,  3,  http://3b76aaf63d1816bb57bf-a34624e694c43cdf8b40aa048a644ca4.r96.cf2.rackcdn.com/Design/Images/newprofile_default_profileimage_new.jpgMarina Frontali2, Tommaso Vannocci1,  http://3b76aaf63d1816bb57bf-a34624e694c43cdf8b40aa048a644ca4.r96.cf2.rackcdn.com/Design/Images/newprofile_default_profileimage_new.jpgSilvia Fortuni4,  http://3b76aaf63d1816bb57bf-a34624e694c43cdf8b40aa048a644ca4.r96.cf2.rackcdn.com/Design/Images/newprofile_default_profileimage_new.jpgRoberto Testi4 and Annalisa Pastore1*

·        1Department of Basic and Clinical Neuroscience, Maurice Wohl Institute, King’s College London, London, UK

·        2CNR Institute of Translational Pharmacology, Rome, Italy

·        3Sant’Andrea Hospital, University of Rome La Sapienza, Rome, Italy

·        4Department of Biomedicine and Prevention, University of Rome “Tor Vergata”, Rome, Italy

Reduced levels of frataxin, an essential mitochondrial protein involved in the regulation of iron-sulfur cluster biogenesis, are responsible for the recessive neurodegenerative Friedreich Ataxia (FRDA). Expansion of a GAA triplet in the first intron of the FRDA is essential for disease development which causes partial silencing of frataxin. In the vast majority of cases, patients are homozygotes for the expansion, but a small number of FRDA patients are heterozygotes for expansion and point mutations in the frataxin coding frame. In this study, we analyze the effects of a point mutation G137V. The patient P94–2, with a history of alcohol and drug abuse, showed a FRDA onset at the border between the classic and late onset phenotype. We applied a combination of biophysical and biochemical methods to characterize its effects on the structure, folding and activity of frataxin. Our study reveals no impairment of the structure or activity of the protein but a reduced folding stability. We suggest that the mutation causes misfolding of the native chain with consequent reduction of the protein concentration in the patient and discuss the possible mechanism of disease.

 


http://www.futuremedicine.com/doi/abs/

10.2217/nmt.15.52?journalCode=nmt&

Drug Evaluation

IFN-γ for Friedreich ataxia: present evidence

McKenzie Wells1,2, Lauren Seyer1,2, Kimberly Schadt1,2 & David R Lynch*,1,2

*Author for correspondence: lynchd@mail.med.upenn.edu

IFN-γ-1b is currently US FDA approved as an orphan drug for the treatment of chronic granulomatous disease and severe malignant osteopetrosis. It is administered via subcutaneous injection and is a potential therapy for Friedreich ataxia (FRDA), a rare degenerative neurological condition. Ongoing Phase II and III trials in both adults and children with FRDA were preceded by a small Phase I, open-label trial in children that showed that IFN-γ-1b was reasonably well-tolerated and improved overall neurological function as measured by the Friedreich Ataxia Rating Scale after 12 weeks of treatment, though the primary outcome measure of frataxin level showed no improvement. Although there is an established dose of IFN-γ-1b prescribed for the current indications, the efficacy and tolerability of these dose levels in the FRDA population remains the subject of ongoing investigation.

 


 

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4650310/

Systematic review and clinical recommendations for dosage of supported home-based standing programs for adults with stroke, spinal cord injury and other neurological conditions

Ginny Paleg corresponding author and Roslyn Livingstone


 

http://www.nature.com/nature/journal/v528/

n7580_supp/full/528S10a.html

Medicine: Expanding possibilities

·        Virginia Gewin

 

The first therapeutics based on genome-editing tools will treat diseases caused by single genes, but many other factors dictate what is currently possible.

 


http://friedreichscientificnews.blogspot.com.es

/2015/12/epigenetic-biomarkers-and-diagnostics.html

Epigenetic Biomarkers and Diagnostics

Edited by: José Luis García-Giménez (Center for Biomedical Network Research on Rare Diseases (CIBERER), Madrid, Spain; Medicine and Dentistry School; Biomedical Research Institute INCLIVA, University of Valencia, Spain). Academic Press, Boston, 2016, doi:10.1016/B978-0-12-801899-6.01001-9, Available online 8 December 2015

Chapter 3 - Epigenetic Mechanisms as Key Regulators in Disease: Clinical Implications, Abdelhalim Boukaba, Fabian Sanchis-Gomar and José Luis García-Giménez, doi:10.1016/B978-0-12-801899-6.00003-6
Alterations in the epigenetic machineries deregulate different epigenetic substrates, which in turn might be implemented as clinical epigenetic biomarkers for diagnosis, prognosis, and monitoring a wide variety of pathological conditions.

Chapter 20 – DNA Methylation in Neurodegenerative Diseases, Sahar Al-Mahdawi, Sara Anjomani Virmouni and Mark A. Pook, Pages doi:10.1016/B978-0-12-801899-6.00020-6.
This review focuses on our current understanding of the role of DNA methylation and its potential as a biomarker in neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, Huntington’s disease, fragile X-associated tremor/ataxia syndrome, Friedreich ataxia, and spinocerebellar ataxia type 7

Chapter 21 - The Histone Code and Disease: Posttranslational Modifications as Potential Prognostic Factors for Clinical Diagnosis, Nicolas G. Simonet, George Rasti and Alejandro Vaquero, 417-445, doi:10.1016/B978-0-12-801899-6.00021-8.
In this chapter, we summarize the current knowledge on the implications of histone PTMs in diverse human pathologies. We focus on the identified changes in histone modifications and associated enzymes in human diseases, as well as on their potential role in clinical diagnosis.

 


http://www.sciencedirect.com/science/article

/pii/S1568786415301075

Disease-Associated Repeat Instability and Mismatch Repair

·        Monika H.M. Schmidta, b, 

·        Christopher E. Pearsona, b, , 

 

 Abstract

Expanded tandem repeat sequences in DNA are associated with at least 40 human genetic neurological, neurodegenerative, and neuromuscular diseases. Repeat expansion can occur during parent-to-offspring transmission, and arise at variable rates in specific tissues throughout the life of an affected individual. Since the ongoing somatic repeat expansions can affect disease age-of-onset, severity, and progression, targeting somatic expansion holds potential as a therapeutic target. Thus, understanding the factors that regulate this mutation is crucial. DNA repair, in particular mismatch repair (MMR), is the major driving force of disease-associated repeat expansions. In contrast to its anti-mutagenic roles, mammalian MMR curiously drives the expansion mutations of disease-associated (CAG)•(CTG) repeats. Recent advances have broadened our knowledge of both the MMR proteins involved in disease repeat expansions, including: MSH2, MSH3, MLH1, PMS2, and MLH3, as well as the types of repeats affected by MMR, now including; (CAG)•(CTG), (CGG)•(CCG), and (GAA)•(TTC) repeats. Mutagenic slipped-DNA structures have been detected in patient tissues, and the size of the slip-out and their junction conformation can determine the involvement of MMR. Furthermore, the formation of other unusual DNA and R-loop structures is proposed to play a key role in MMR-mediated instability. A complex correlation is emerging between tissues showing varying amounts of repeat instability and MMR expression levels. Notably, naturally occurring polymorphic variants of DNA repair genes can have dramatic effects upon the levels of repeat instability, which may explain the variation in disease age-of-onset, progression and severity. An increasing grasp of these factors holds prognostic and therapeutic potential.

Abbreviations

  • MMR, mismatch repair; 
  • MSH, mut S homolog; 
  • MLH, mut L homolog; 
  • BER, base excision repair; 
  • NER, nucleotide excision repair; 
  • TNR, trinucleotide repeat; 
  • DM1,myotonic dystrophy type I; 
  • HD, huntington's disease; 
  • FRDA, friedreich's Ataxia; 
  • FXD,fragile X disease; 
  • FXS, fragile X syndrome; 
  • FRAXA, fragile X type Al; 
  • hESC, human embryonic stem cell(s); 
  • MSN, medium-spiny striatal neurons; 
  • B6, C57BL/6J mouse background; 
  • CBy, BALB/cByJ mouse background; 
  • Polβ, polymerase beta; 
  • Polδ,polymerase delta

 


http://www.nature.com/ejhg/journal/v24/n1

/abs/ejhg201559a.html?WT.ec_id=EJHG-201601&spMailingID=50219241&spUserID=

NDQwOTM2MDQ1OQS2&spJobID=

821512190&spReportId=ODIxNTEyMTkwS0

Regulating biobanking with children’s tissue: a legal analysis and the experts’ view

Elcke J Kranendonk1, M Corrette Ploem1 and Raoul C M Hennekam2

1.   1Department of Public Health, AMC, University of Amsterdam, Amsterdam, The Netherlands

2.   2Departments of Paediatrics and Translational Genetics, AMC, University of Amsterdam, Amsterdam, The Netherlands

Correspondence: EJ Kranendonk, Department of Public Health, AMC, University of Amsterdam, Room J2–210, PO Box 22660, Amsterdam 1100 DD, The Netherlands. Tel: +31 20 5668462; Fax: +31 20 6972316; E-mail: e.j.kranendonk@amc.uva.nl

Received 26 September 2014; Revised 20 February 2015; Accepted 24 February 2015
Advance online publication 15 April 2015

Top

Abstract

Many current paediatric studies concern relationships between genes and environment and discuss aetiology, treatment and prevention of Mendelian and multifactorial diseases. Many of these studies depend on collection and long-term storage of data and biological material from affected children in biobanks. Stored material is a source of personal information of the donor and his family and could be used in an undesirable context, potentially leading to discrimination and interfering with a child’s right to an open future. Here, we address the normative framework regarding biobanking with residual tissue of children, protecting the privacy interests of young biobank donors (0–12 years). We analyse relevant legal documents concerning storage and use of children’s material for research purposes. We explore the views of 17 Dutch experts involved in paediatric biobank research and focus on informed consent for donation of leftover tissue as well as disclosure of individual research findings resulting from biobank research. The results of this analysis show that experts have no clear consensus about the appropriate rules for storage of and research with children’s material in biobanks. Development of a framework that provides a fair balance between fundamental paediatric research and privacy protection is necessary.

 


http://europepmc.org/articles/PMC4657516

Antioxidants in Translational Medicine

Harald H.H.W. Schmidt,1 Roland Stocker,2,,3 Claudia Vollbracht,4 Gøran Paulsen,5 Dennis Riley,6Andreas Daiber, corresponding author7,* and Antonio Cuadrado corresponding author8,,9,,10,,11,*


http://europepmc.org/articles/PMC4657508

;jsessionid=pdaKpsHRnPFAteI7oEJ0.0

Pharmacology and Clinical Drug Candidates in Redox Medicine

V. Thao-Vi Dao, corresponding author1 Ana I. Casas,1 Ghassan J. Maghzal,2 Tamara Seredenina,3 Nina Kaludercic,4 Natalia Robledinos-Anton,5,,6,,7,,8 Fabio Di Lisa,4,,9 Roland Stocker,2 Pietro Ghezzi,10 Vincent Jaquet,3 Antonio Cuadrado,5,,6,,7,,8 and Harald H.H.W. Schmidt corresponding author1

 


http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0143600

Pyrroloquinoline Quinone Resists Denervation-Induced Skeletal Muscle Atrophy by Activating PGC-1α and Integrating Mitochondrial Electron Transport Chain Complexes

·        Yung-Ting Kuo,

·        Ping-Hsiao Shih,

·        Shu-Huei Kao,

·        Geng-Chang Yeh,

·        Horng-Mo LeeAbstract

Denervation-mediated skeletal muscle atrophy results from the loss of electric stimulation and leads to protein degradation, which is critically regulated by the well-confirmed transcriptional co-activator peroxisome proliferator co-activator 1 alpha (PGC-1α). No adequate treatments of muscle wasting are available. Pyrroloquinoline quinone (PQQ), a naturally occurring antioxidant component with multiple functions including mitochondrial modulation, demonstrates the ability to protect against muscle dysfunction. However, it remains unclear whether PQQ enhances PGC-1α activation and resists skeletal muscle atrophy in mice subjected to a denervation operation. This work investigates the expression of PGC-1α and mitochondrial function in the skeletal muscle of denervated mice administered PQQ. The C57BL6/J mouse was subjected to a hindlimb sciatic axotomy. A PQQ-containing ALZET® osmotic pump (equivalent to 4.5 mg/day/kg b.w.) was implanted subcutaneously into the right lower abdomen of the mouse. In the time course study, the mouse was sacrificed and the gastrocnemius muscle was prepared for further myopathological staining, energy metabolism analysis, western blotting, and real-time quantitative PCR studies. We observed that PQQ administration abolished the denervation-induced decrease in muscle mass and reduced mitochondrial activities, as evidenced by the reduced fiber size and the decreased expression of cytochrome c oxidase and NADH-tetrazolium reductase. Bioenergetic analysis demonstrated that PQQ reprogrammed the denervation-induced increase in the mitochondrial oxygen consumption rate (OCR) and led to an increase in the extracellular acidification rate (ECAR), a measurement of the glycolytic metabolism. The protein levels of PGC-1α and the electron transport chain (ETC) complexes were also increased by treatment with PQQ. Furthermore, PQQ administration highly enhanced the expression of oxidative fibers and maintained the type II glycolytic fibers. This pre-clinical in vivo study suggests that PQQ may provide a potent therapeutic benefit for the treatment of denervation-induced atrophy by activating PGC-1α and maintaining the mitochondrial ETC complex in skeletal muscles.

                                                               


http://www.sciencedirect.com/science/article/

pii/S1353802015007920
Otoneurological findings prevalent in hereditary ataxias

·        Bianca Simone Zeigelboim1

·        Helio Afonso Ghizoni Teive2

·        Geslaine Santos3

·        Maria Izabel Severiano3,

·        Vinicius Ribas Fonseca3

·        João Henrique Faryniuk3

 


 

http://www.sciencedirect.com/science/article/pii/

S0966636215001630

Functional and gait assessment in children with Friedreich ataxia: Comparison of quantitative and functional evaluation

·        G. Vasco1, 2

·        M. Petrarca1

·        S. Gazzellini1

·        M.L. Lispi1

·        G. Della Bella1

·        S. Carniel1

·        M. Zazza2

·        E. Castelli1

·        E. Bertini2

 


http://www.sciencedirect.com/science/article/

pii/S0163725815002296

Vitamin E therapy beyond cancer: Tocopherol versus tocotrienol

·        Hong Yong Peha, 

·        W.S. Daniel Tana, 

·        Wupeng Liaoa, 

·        W.S. Fred Wonga, b, , 

 

 

 Abstract

The discovery of vitamin E (α-tocopherol) began in 1922 as a vital component required in reproduction. Today, there are eight naturally occurring vitamin E isoforms, namely α-, β-, γ- and δ-tocopherol and α-, β-, γ- and δ-tocotrienol. Vitamin E is potent antioxidants, capable of neutralizing free radicals directly by donating hydrogen from its chromanol ring. α-Tocopherol is regarded the dominant form in vitamin E as the α-tocopherol transfer protein in the liver binds mainly α-tocopherol, thus preventing its degradation. That contributed to the oversight of tocotrienols and resulted in less than 3% of all vitamin E publications studying tocotrienols. Nevertheless, tocotrienols have been shown to possess superior antioxidant and anti-inflammatory properties over α-tocopherol. In particular, inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A reductase to lower cholesterol, attenuating inflammation via downregulation of transcription factor NF-κB activation, and potent radioprotectant against radiation damage are some properties unique to tocotrienols, not tocopherols. Aside from cancer, vitamin E has also been shown protective in bone, cardiovascular, eye, nephrological and neurological diseases. In light of the different pharmacological properties of tocopherols and tocotrienols, it becomes critical to specify which vitamin E isoform(s) are being studied in any future vitamin E publications. This review provides an update on vitamin E therapeutic potentials, protective effects and modes of action beyond cancer, with comparison of tocopherols against tocotrienols. With the concerted efforts in synthesizing novel vitamin E analogs and clinical pharmacology of vitamin E, it is likely that certain vitamin E isoform(s) will be therapeutic agents against human diseases besides cancer

Abbreviations

·        α-TS, α-tocopherol succinate; 

·        AKT, protein kinase B; 

·        αTTP, α-tocopherol transport protein; 

·        Bcl-2, B-cell lymphoma 2; 

·        C/EBP, CCAAT-enhancer binding protein; 

·        CAT,catalase; 

·        CNS, central nervous system; 

·        COX, cyclooxygenase; 

·        ERK, extracellular-signal-regulated kinase; 

·        G-CSF, granulocyte-colony stimulating factor; 

·        GPx,glutathione peroxidase; 

·        GSH, glutathione; 

·        HDL, high-density lipoprotein; 

·        HMG-CoA, 3-hydroxy-3-methylglutaryl-coenzyme A; 

·        IL, interleukin; 

·        JNK, c-Jun N-terminal kinase;

·        LDL, low-density lipoprotein; 

·        LOX, lipoxygenase; 

·        LT, leukotriene; 

·        MAPK, mitogen-activated protein kinase; 

·        MDA, malondialdehyde; 

·        MPP+, 1-methyl-4-phenylpyridinium ion; 

·        NF-κB, nuclear factor κ-light-chain-enhancer of activated B cells; 

·        NO, nitric oxide;

·        NO2, nitrogen dioxide; 

·        NOS, nitric oxide synthase; 

·        Nrf-2, nuclear factor (erythroid-derived 2)-like 2; 

·        ONOO, peroxynitrite; 

·        PI3K, phosphatidylinositide 3-kinase; 

·        PG,prostaglandin; 

·        PKC, protein kinase C; 

·        PPAR, peroxisome proliferator-activated receptor; 

·        RNS, reactive nitrogen species; 

·        ROS, reactive oxygen species; 

·        SOD,superoxide dismutase; 

·        STAT6, signal transducer and activator of transcription 6; 

·        T3,tocotrienol; 

·        TBARS, thiobarbituric reactive substances; 

·        TGF-β1, transforming growth factor-β1; 

·        TNF-α, tumor necrosis factor-α; 

·        TP, tocopherol; 

·        TRF, tocotrienol rich fraction; 

·        WMLs, white matter lesions

Corresponding author at: Department of Pharmacology, Yong Loo Lin School of Medicine, 16 Medical Drive, Block MD3, #04-01, National University of Singapore, Singapore 117600, Singapore. Tel.: +65 6516 3266; fax: +65 6776 6872.

 


http://www.nature.com/articles/srep18251

Perturbation of cellular proteostasis networks identifies pathways that modulate precursor and intermediate but not mature levels of frataxin

Abstract

Friedreich’s Ataxia is a genetic disease caused by expansion of an intronic trinucleotide repeat in the frataxin (FXN) gene yielding diminished FXN expression and consequently disease. Since increasing FXN protein levels is desirable to ameliorate pathology, we explored the role of major cellular proteostasis pathways and mitochondrial proteases in FXN processing and turnover. We targeted p97/VCP, the ubiquitin proteasome pathway (UPP), and autophagy with chemical inhibitors in cell lines and patient-derived cells. p97 inhibition by DBeQ increased precursor FXN levels, while UPP and autophagic flux modulators had variable effects predominantly on intermediate FXN. Our data suggest that these pathways cannot be modulated to influence mature functional FXN levels. We also targeted known mitochondrial proteases by RNA interference and discovered a novel protease PITRM1 that regulates intermediate FXN levels. Treatment with the aforementioned chemical and genetic modulators did not have a differential effect in patient cells containing lower amounts of FXN. Interestingly, a number of treatments caused a change in total amount of FXN protein, without an effect on mature FXN. Our results imply that regulation of FXN protein levels is complex and that total amounts can be modulated chemically and genetically without altering the absolute amount of mature FXN protein.

 


http://www.ncbi.nlm.nih.gov/pubmed/23338283

Eye movements in patients with neurodegenerative disorders.

Anderson TJ1, MacAskill MR

Abstract

The neural pathways and brain regions involved in eye movements during ocular fixation and gaze control include the cerebrum, brainstem and cerebellum, and abnormal eye movements can indicate the presence of neurodegeneration. In some patients, oculomotor signs are key to making a diagnosis. Careful clinical examination of eye movements in patients with neurodegenerative disorders is, therefore, an invaluable adjunct to neurological and cognitive assessments. Eye movement recordings in the laboratory are generally not necessary for diagnostic purposes, but can be a useful addition to the clinical examination. Laboratory recordings of eye movements can provide valuable information about disease severity, progression or regression in neurodegenerative disease, and hold particular promise for objective evaluation of the efficacy of putative neuroprotective and neurorestorative therapies. For example, aspects of saccade performance can be tested to probe both motor and cognitive aspects of oculomotor behaviour. This Review describes the oculomotor features of the major age-related movement disorders, including Parkinson disease, Huntington disease, dementia and other neurodegenerative disorders. Findings in presymptomatic individuals and changes associated with disease progression are discussed.



 

http://onlinelibrary.wiley.com/doi/10.1002/ana.24595/

abstract

Compound heterozygous FXN mutations and clinical outcome in Friedreich ataxia

1.   Charles A. Galea1,2,†, 

2.   Aamira Huq2,†, 

3.   Paul J. Lockhart2,3, 

4.   Geneieve Tai2, 

5.   Louise A. Corben2,3,4, 

6.   Eppie M. Yiu2,3,5, 

7.   Lyle C. Gurrin6, 

8.   David R. Lynch7, 

9.   Sarah Gelbard7,

10.               Alexandra Durr8,9,10, 

11.               Francoise Pousset11,

12.               Michael Parkinson12, 

13.               Robyn Labrum13,

14.               Paola Giunti12,13, 

15.               Susan L. Perlman14,

16.               Martin B. Delatycki2,3,4,15,* and

17.               Marguerite V. Evans-Galea2,3,*

 

 

 ABSTRACT

Objective: Friedreich ataxia (FRDA) is an inherited neurodegenerative disease characterized by ataxia and cardiomyopathy. Homozygous GAA trinucleotide repeat expansions in the first intron of FXN occur in 96% affected individuals and reduce frataxin expression. Remaining individuals are compound heterozygous for a GAA expansion and a FXN point/insertion/deletion mutation. We examined disease-causing mutations and the impact on frataxin structure/function and clinical outcome in FRDA.

Methods: We compared clinical information from 111 compound heterozygotes and 131 individuals with homozygous expansions. Frataxin mutations were examined using structural modeling, stability analyses and systematic literature review, and categorized into four groups: (i) homozygous expansions, and three compound heterozygote groups; (ii) null (no frataxin produced); (iii) moderate/strong impact, and; (iv) minimal impact. Mean age of onset and the presence of cardiomyopathy and diabetes mellitus were compared using regression analyses.

Results: Mutations in the hydrophobic core of frataxin affected stability while surface residue mutations affected interactions with iron sulfur cluster assembly and heme biosynthetic proteins. The null group of compound heterozygotes had significantly earlier age of onset and increased diabetes mellitus compared to the homozygous expansion group. There were no significant differences in mean age of onset between homozygotes and the minimal and moderate/strong impact groups.

Interpretation: In compound heterozygotes, expression of partially functional mutant frataxin delays age of onset and reduces diabetes mellitus, compared to those with no frataxin expression from the non-expanded allele. This integrated analysis of categorized frataxin mutations and their correlation with clinical outcome provides a definitive resource for investigating disease pathogenesis in FRDA.

 


 

http://www.nature.com/news/european-medical-research-escapes-stifling-privacy-laws-1.19054

European medical research escapes stifling privacy laws

Proposed legislation had threatened the use of genomic and clinical data in medical studies.

·        Alison Abbott

16 December 2015

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A threat to medical research projects in Europe has been averted. European Union politicians and officials agreed on 15 December to exempt research from some of the strict provisions in planned data-protection legislation.

“This is very positive for us – the biggest threats are over,” says Michaela Mayrhofer, senior project manager at the European Union's Biobanking and Biomolecular Research Infrastructure, which is building collections of billions of biological samples across Europe and is headquartered in Vienna, Austria.

The legislation, first proposed three years ago, is primarily intended to protect people from having their digital information exploited for commercial, or other, purposes. At first medical researchers viewed the proposed rules positively because they clarified procedures for sharing clinical and genomic data across European Union (EU) member states.

 


 

http://onlinelibrary.wiley.com/doi/10.1002/mds.26436

/abstract

Longitudinal magnetic resonance imaging study shows progressive pyramidal and callosal damage in Friedreich's ataxia

1.   Thiago J.R. Rezende Msc1,†, 

2.   Cynthia B. Silva MD, PhD1,†, 

3.   Clarissa L. Yassuda MD, PhD1, 

4.   Brunno M. Campos Msc1, 

5.   Anelyssa D'Abreu MD, PhD1, 

6.   Fernando Cendes MD, PhD1, 

7.   Iscia Lopes-Cendes MD PhD2and

8.   Marcondes C. França Jr. MD, PhD1

 

 

ABSTRACT

Introduction

Spinal cord and peripheral nerves are classically known to be damaged in Friedreich's ataxia, but the extent of cerebral involvement in the disease and its progression over time are not yet characterized. The aim of this study was to evaluate longitudinally cerebral damage in Friedreich's ataxia

Methods

We enrolled 31 patients and 40 controls, which were evaluated at baseline and after 1 and 2 years. To assess gray matter, we employed voxel-based morphometry and cortical thickness measurements. White matter was evaluated using diffusion tensor imaging. Statistical analyses were both cross-sectional and longitudinal (corrected for multiple comparisons).

Results

Group comparison between patients and controls revealed widespread macrostructural differences at baseline: gray matter atrophy in the dentate nuclei, brainstem, and precentral gyri; and white matter atrophy in the cerebellum and superior cerebellar peduncles, brainstem, and periventricular areas. We did not identify any longitudinal volumetric change over time. There were extensive microstructural alterations, including superior cerebellar peduncles, corpus callosum, and pyramidal tracts. Longitudinal analyses identified progressive microstructural abnormalities at the corpus callosum, pyramidal tracts, and superior cerebellar peduncles after 1 year of follow-up.

Conclusion

Patients with Friedreich's ataxia present more widespread gray and white matter damage than previously reported, including not only infratentorial areas, but also supratentorial structures. Furthermore, patients with Friedreich's ataxia have progressive microstructural abnormalities amenable to detection in a short-term follow-up

 


 

http://www.nature.com/articles/srep18375

Identification of potential mitochondrial CLPXP protease interactors and substrates suggests its central role in energy metabolism

Abstract

Maintenance of mitochondria is achieved by several mechanisms, including the regulation of mitochondrial proteostasis. The matrix protease CLPXP, involved in protein quality control, has been implicated in ageing and disease. However, particularly due to the lack of knowledge of CLPXP’s substrate spectrum, only little is known about the pathways and mechanisms controlled by this protease. Here we report the first comprehensive identification of potential mitochondrial CLPXP in vivo interaction partners and substrates using a combination of tandem affinity purification and differential proteomics. This analysis reveals that CLPXP in the fungal ageing model Podospora anserina is mainly associated with metabolic pathways in mitochondria, e.g. components of the pyruvate dehydrogenase complex and the tricarboxylic acid cycle as well as subunits of electron transport chain complex I. These data suggest a possible function of mitochondrial CLPXP in the control and/or maintenance of energy metabolism. Since bioenergetic alterations are a common feature of neurodegenerative diseases, cancer, and ageing, our data comprise an important resource for specific studies addressing the role of CLPXP in these adverse processes.


 

http://www.mynewsdesk.com/us/persistence-market-research-2/pressreleases/treatments-for-syndromes-of-progressive-ataxia-and-weakness-disorders-pmr-market-insight-report-to-2020-1278323
Treatments for Syndromes of Progressive Ataxia and Weakness Disorders - PMR Market Insight Report to 2020

Ataxia is a neurological condition, characterized by lack of voluntary coordination of muscle movement. Ataxia causes head trauma, stroke, Transient Ischemic Attack (TIA), tumor and toxic reaction. Progressive ataxia and weakness disorders are related to damage, degeneration or loss of neurons of the brain which leads to muscle coordination disability.

The global market for treatments of syndromes of progressive ataxia and weakness disorders is categorized based on various drugs used for treatment of progressive ataxia syndromes, drugs for progressive weakness syndromes and by technology. The progressive ataxia syndrome segment is further sub-segmented into major diseases, such as Friedreich's ataxia, Gertsman-Straussler-Scheinker disease and Machado-Joseph disease. The progressive weakness syndrome segment includes amyotrophic lateral sclerosis, hereditary spastic paraplegia, hereditary neuropathies, progressive bulbar palsy and multiple sclerosis. The technology segment is further sub-segmented into small molecules based therapies and monoclonal antibody.

In terms of geography, the U.S. and Canada holds major market share of treatments for syndromes of progressive ataxia and weakness disorders market in North America. In Europe, Germany, France and the U.K are major markets for treatments of syndromes of progressive ataxia and weakness disorders.

Globally, treatments for syndromes of progressive ataxia and weakness disorders market are growing due to novel drug development and rapid technological advancement for treatment of progressive ataxia and weakness disorders. Some of the major technological advancement involved in growth of the market are protein mis-folding, gene mutation and stem cell therapy. In addition, increased collaborations between industry players for development of new therapies is a key trend for the market.

However, patent expiries of major drugs hampers growth of the treatments for syndromes of progressive ataxia and weakness disorders market. Moreover, stringent regulations and standard requires for approval process of new drugs impede growth of the treatments for syndromes of progressive ataxia and weakness disorders market. Several government agencies, such as FDA and European Medicines Agency, are responsible for the approval of every drug. In addition, the approval process takes a very long time to approve a specific drug.

Request to view TOC: http://www.persistencemarketresearch.com/toc/2834

Some of the major companies operating in the treatment for syndromes of progressive ataxia and weakness disorders market are Abbott Laboratories, Acorda Therapeutics Inc., American Regent Inc., Baxter International Inc., Biogen Idec., Bristol-Myers Squibb, Cadila Healthcare Ltd., Eli Lilly and Company, Glaxosmilthkline Plc., Sanofi, Roche Holding Ltd., Pfizer Inc. and Novartis AG.

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/2834


 

http://www.prd-journal.com/article/S1353-8020(15)00796-8/abstract

Burden of mitochondrial DNA variations in Friedreich's Ataxia (FRDA) patients and sharing of mitochondrial lineage with Caucasians

Inder singh

,

 Sunil Sakhya

,

 Madhuri Behari

,

 M.V. Padma Srivastava

,

 Garima Shukla

,

 Vinay Goyal

,

 Achal Kumar Srivastava

,

 Mohd. Faruq

Introduction: Friedreich's ataxia (FRDA) is an autosomal recessive disorder caused by GAA repeat expansions (<66) in FXN gene. The protein product frataxin role in implicated in MT as biogenesis of iron-sulphur cluster (ISC).

 



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