Clinical trials: To catch a crook, you might try statistics
Nature Reviews Neurology
A new systematic review detected strong evidence of unreliable results via use of statistical and logical analyses of 33 randomized clinical trials. Our outrage at these rare occurrences of potential fraud could be rooted in our disdain at our failures in peer review, given that this special effort was required to detect long-running potential fraud.
http://onlinelibrary.wiley.com/doi/10.1002/ana.24846/full
Cytokine therapy-mediated neuroprotection in a Friedreich’s ataxia mouse model
Authors
- Kevin C Kemp MSc, PhD, Nadia Cerminara BSc, PhD, Kelly Hares BSc, PhD, Juliana Redondo BSc, PhD, Amelia J Cook, Harry R Haynes BSc, MBChB, Bronwen R Burton BSc, PhD, Mark Pook BSc, PhD, Richard Apps PhD, Neil J Scolding FRCP, PhD, Alastair Wilkins FRCP, PhD
Abstract
Objectives: Friedreich’s ataxia is a devastating neurological disease currently lacking any proven treatment. We studied the neuro-protective effects of the cytokines granulocyte-colony stimulating factor and stem cell factor in a humanised murine model of Friedreich’s ataxia.
Methods: Mice received monthly subcutaneous infusions of cytokines while also being assessed at monthly time points using an extensive range of behavioural motor performance tests. After 6 months of treatment, neurophysiological evaluation of both sensory and motor nerve conduction was performed. Subsequently, mice were sacrificed for mRNA, protein and histological analysis of the dorsal root ganglion, spinal cord and cerebellum.
Results: Cytokine administration resulted in significant reversal of biochemical, neuropathological, neurophysiological and behavioural deficits associated with Friedreich’s ataxia. Both granulocyte-colony stimulating factor and stem cell factor had pronounced effects on frataxin levels (the primary molecular defect in the pathogenesis of the disease), and on regulators of frataxin expression. Sustained improvements in motor coordination and locomotor activity were seen, even after onset of neurological symptoms. Treatment also restored the duration of sensory nerve compound potentials. Improvements in peripheral nerve conduction positively correlated with cytokine-induced increases in frataxin expression, providing a link between increases in frataxin and neurophysiological function. Abrogation of disease-related pathology was also evident, with reductions in inflammation/gliosis and increased neural stem cell numbers in areas of tissue injury.
Interpretation: These experiments show that cytokines already clinically used in other conditions offer the prospect of a novel, rapidly translatable, disease-modifying and neuroprotective treatment for Friedreich’s ataxia.
http://www.pnas.org/content/113/47/E7418.short
Synthetic genome readers target clustered binding sites across diverse chromatin states
- Graham S. Erwina,
- Matthew P. Grieshopa,1,
- Devesh Bhimsariaa,b,1,
- Truman J. Doa,
- José A. Rodríguez-Martíneza,
- Charu Mehtaa,
- Kanika Khannaa,
- Scott A. Swansonc,
- Ron Stewartc,
- James A. Thomsonc,d,
- Parameswaran Ramanathanb, and
- Aseem Z. Ansaria,d,2
Significance
Targeting specific genomic loci with synthetic molecules remains a major goal in chemistry, biology, and precision medicine. Identifying how synthetic genome readers bind the chromatinized genome in cells would facilitate their development, but doing so remains a formidable challenge. We map the genome-wide binding patterns for two structurally distinct synthetic molecules. To achieve this goal, we couple our cross-linking of small molecules to isolate chromatin approach to next-generation sequencing. In addition to binding high-affinity sites, these molecules, surprisingly, bind clustered low-affinity sites. The data also show that these genome readers target sites in both open and closed chromatin. Our findings highlight the importance of genome-guided design for molecules that will serve as precision-targeted therapeutics.
Abstract
Targeting the genome with sequence-specific DNA-binding molecules is a major goal at the interface of chemistry, biology, and precision medicine. Polyamides, composed of N-methylpyrrole and N-methylimidazole monomers, are a class of synthetic molecules that can be rationally designed to “read” specific DNA sequences. However, the impact of different chromatin states on polyamide binding in live cells remains an unresolved question that impedes their deployment in vivo. Here, we use cross-linking of small molecules to isolate chromatin coupled to sequencing to map the binding of two bioactive and structurally distinct polyamides to genomes directly within live H1 human embryonic stem cells. This genome-wide view from live cells reveals that polyamide-based synthetic genome readers bind cognate sites that span a range of binding affinities. Polyamides can access cognate sites within repressive heterochromatin. The occupancy patterns suggest that polyamides could be harnessed to target loci within regions of the genome that are inaccessible to other DNA-targeting molecules.
http://www.nature.com/gt/journal/vaop/naam/pdf/gt201689a.pdf
Deletion of the GAA repeats from the human frataxin gene using the CRISPR-Cas9 system in YG8R-derived cells and mouse models of Friedreich Ataxia
D L Ouellet, K Cherif, J Rousseau and J-P Tremblay
Abstract
The Friedreich ataxia is a monogenic disease due to a hyper-expanded GAA triplet located within the first intron of the frataxin gene that causes transcriptional issues. The resulting frataxin protein deficiency leads to a Fe-S cluster biosynthesis dysfunction in the mitochondria and to oxidative stress and cell death. Here, we use the CRISPR-Cas9 system to remove the mutated GAA expansion and restore the frataxin gene transcriptional activity and protein level. Both YG8R and YG8sR mouse models and cell lines derived from these mice were used to CRISPR-edited successfully the GAA expansion in vitro and in vivo. Nevertheless, our results suggest the YG8sR as a better and more suitable model for the study of the CRISPR-Cas9 edition of the mutated frataxin gene.
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http://www.thelancet.com/journals/laneur/article/PIIS1474-4422(16)30350-7/abstract
DNA repair in the trinucleotide repeat disorders
Prof Lesley Jones, PhD Prof Henry Houlden, MD, Prof Sarah J Tabrizi, PhD
Background
Inherited diseases caused by unstable repeated DNA sequences are rare, but together represent a substantial cause of morbidity. Trinucleotide repeat disorders are severe, usually life-shortening, neurological disorders caused by nucleotide expansions, and most have no disease-modifying treatments. Longer repeat expansions are associated with genetic anticipation (ie, earlier disease onset in successive generations), although the differences in age at onset are not entirely accounted for by repeat length. Such phenotypic variation within disorders implies the existence of additional modifying factors in pathways that can potentially be modulated to treat disease.
Recent developments
A genome-wide association study detected genetic modifiers of age at onset in Huntington’s disease. Similar findings were seen in the spinocerebellar ataxias, indicating an association between DNA damage-response and repair pathways and the age at onset of disease. These studies also suggest that a common genetic mechanism modulates age at onset across polyglutamine diseases and could extend to other repeat expansion disorders. Genetic defects in DNA repair underlie other neurodegenerative disorders (eg, ataxia-telangiectasia), and DNA double-strand breaks are crucial to the modulation of early gene expression, which provides a mechanistic link between DNA repair and neurodegeneration. Mismatch and base-excision repair are important in the somatic expansion of repeated sequences in mouse models of trinucleotide repeat disorders, and somatic expansion of the expanded CAG tract in HTT correlates with age at onset of Huntington’s disease and other trinucleotide repeat disorders.
Where next?
To understand the common genetic architecture of trinucleotide repeat disorders and any further genetic susceptibilities in individual disorders, genetic analysis with increased numbers of variants and sample sizes is needed, followed by sequencing approaches to define the phenotype-modifying variants. The findings must then be translated into cell biology analyses to elucidate the mechanisms through which the genetic variants operate. Genes that have roles in the DNA damage response could underpin a common DNA repeat-based mechanism and provide new therapeutic targets (and hence therapeutics) in multiple trinucleotide repeat disorders.
Mitochondrial capacity, muscle endurance & low energy in friedreich ataxia
- M. Bossie M.S.,
- Bradley. Willingham M.S.,
- A. Van Schoick M.S.,
- J. O’Connor Ph.D. and
- K. McCully Ph.D.
Abstract
INTRODUCTION: We noninvasively evaluated skeletal muscle mitochondrial capacity, muscle-specific endurance, and energy/fatigue feelings in persons with Friedreich ataxia (FRDA) and able-bodied controls (AB). METHODS: Forearm mitochondrial capacity was measured in FRDA (n=16) and AB (n=10) using the rate of recovery of oxygen consumption after electrical stimulation with near-infrared spectroscopy. Mechanomyography (MMG) assessed muscle endurance after electrical stimulation for 3-minutes at 2Hz, 4Hz, and 6Hz. Validated scales assessed disease severity and energy/fatigue feelings. RESULTS: Groups did not differ in mitochondrial capacity (FRDA and AB: 1.8 ± 0.3 1/min). The difference in muscle endurance at 6 Hz was lower by 19.2% in the FRDA (group affect: P < 0.001). Feelings of physical energy were 34% lower in FRDA. In FDRA muscle, endurance was positively related to mitochondrial capacity (r=0.59, P=0.03), and disease severity was negatively related to mitochondrial capacity (r=-0.55, P=0.04) and muscle endurance (r=-0.60, P=0.01). DISCUSSION: Non-invasive measures of skeletal muscle mitochondrial capacity and muscle specific endurance are useful in monitoring FRDA. This article is protected by copyright. All rights reserved.
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0164681
Profitability and Market Value of Orphan Drug Companies: A Retrospective, Propensity-Matched Case-Control Study
- Dyfrig A. Hughes,
- Jannine Poletti-Hughes
Abstract
Background
Concerns about the high cost of orphan drugs has led to questions being asked about the generosity of the incentives for development, and associated company profits.
Methods
We conducted a retrospective, propensity score matched study of publicly-listed orphan companies. Cases were defined as holders of orphan drug market authorisation in Europe or the USA between 2000–12. Control companies were selected based on their propensity for being orphan drug market authorisation holders. We applied system General Method of Moments to test whether companies with orphan drug market authorization are valued higher, as measured by the Tobin’s Q and market to book value ratios, and are more profitable based on return on assets, than non-orphan drug companies.
Results
86 companies with orphan drug approvals in European (4), USA (61) or both (21) markets were matched with 258 controls. Following adjustment, orphan drug market authorization holders have a 9.6% (95% confidence interval, 0.6% to 18.7%) higher return on assets than non-orphan drug companies; Tobin’s Q was higher by 9.9% (1.0% to 19.7%); market to book value by 15.7% (3.1% to 30.0%) and operating profit by 516% (CI 19.8% to 1011%). For each additional orphan drug sold, return on assets increased by 11.1% (0.6% to 21.3%), Tobin’s Q by 2.7% (0.2% to 5.2%), and market to book value ratio by 5.8% (0.7% to 10.9%).
Conclusions
Publicly listed pharmaceutical companies that are orphan drug market authorization holders are associated with higher market value and greater profits than companies not producing treatments for rare diseases.
Evaluation of oligonucleotides for therapy of Friedreich ataxia
Funding body
Project description
The aim of this project is firstly to characterise a novel transgenic mouse model of the multi-system autosomal inherited genetic disorder, Friedreich ataxia (FRDA). This mouse model, designated YG8LR, contains the human frataxin transgene together with an inserted 410 GAA repeat expansion mutation. Our studies aim to characterise the FRDA mouse model at molecular, biochemical, histopathological and behavioural levels. Once characterised, the FRDA mouse model will then be used in preclinical studies to investigate the potential of specific frataxin oligonucleotides generated by RaNA Therapeutics to stabilize frataxin mRNA and hence increase frataxin expression.
Impact statement – The generation and characterisation of a mouse model for Friedreich ataxia will be a most useful tool that will be deposited in the Jackson Laboratory for distribution to Friedreich ataxia research investigators throughout the world. The identification of oligonucleotides that have the ability to increase frataxin expression in a FRDA mouse model will provide important evidence for potential future clinical trials of Friedreich ataxia. This is a lethal devastating genetic disorder for which there is currently no effective therapy. Therefore, successful preclinical and clinical trials will have a major impact on the wellbeing of individuals who suffer with this disease. Furthermore, the technique of oligonucleotide therapy may have impact upon similar therapeutic strategies for other diseases caused by protein deficiency.
Principal Investigator: Dr Mark Pook
Co-Investigators: Paula Lewis, Chi-Sung Chiu, RaNA Therapeutics
http://www.tandfonline.com/doi/full/10.1080/01616412.2016.1251711
Oxidative stress and mitochondrial dysfunction-linked neurodegenerative disorders
- Abstract
Reactive species play an important role in physiological functions. Overproduction of reactive species, notably reactive oxygen (ROS) and nitrogen (RNS) species along with the failure of balance by the body’s antioxidant enzyme systems results in destruction of cellular structures, lipids, proteins, and genetic materials such as DNA and RNA. Moreover, the effects of reactive species on mitochondria and their metabolic processes eventually cause a rise in ROS/RNS levels, leading to oxidation of mitochondrial proteins, lipids, and DNA. Oxidative stress has been considered to be linked to the etiology of many diseases, including neurodegenerative diseases (NDDs) such as Alzheimer diseases, Amyotrophic lateral sclerosis, Friedreich’s ataxia, Huntington’s disease, Multiple sclerosis, and Parkinson’s diseases. In addition, oxidative stress causing protein misfold may turn to other NDDs include Creutzfeldt-Jakob disease, Bovine Spongiform Encephalopathy, Kuru, Gerstmann-Straussler-Scheinker syndrome, and Fatal Familial Insomnia. An overview of the oxidative stress and mitochondrial dysfunction-linked NDDs has been summarized in this review.
http://www.sciencedirect.com/science/article/pii/S0167488916303275
Iron mediated toxicity and programmed cell death: A review and a re-examination of existing paradigms
Abstract
Iron is an essential micronutrient that is problematic for biological systems since it is toxic as it generates free radicals by interconverting between ferrous (Fe2 +) and ferric (Fe3 +) forms. Additionally, even though iron is abundant, it is largely insoluble so cells must treat biologically available iron as a valuable commodity. Thus elaborate mechanisms have evolved to absorb, re-cycle and store iron while minimizing toxicity. Focusing on rarely encountered situations, most of the existing literature suggests that iron toxicity is common. A more nuanced examination clearly demonstrates that existing regulatory processes are more than adequate to limit the toxicity of iron even in response to iron overload. Only under pathological or artificially harsh situations of exposure to excess iron does it become problematic. Here we review iron metabolism and its toxicity as well as the literature demonstrating that intracellular iron is not toxic but a stress responsive programmed cell death-inducing second messenger.
Abbreviations
- Fe3 +, Ferric ion;
- Fe+ 2,ferrous ion;
- GI,gastrointestinal tract;
- LIP,Labile Iron Pool (LIP);
- NBIA,neurodegeneration with brain iron accumulation;
- NTBI,Non-Transferrin Bound Iron;
- PCD,programmed cell death;
- RBC,red blood cell;
- RCD,Regulated cell death;
- ROS,reactive oxygen species;
- Tf,transferrin (Tf)
http://www.sciencedirect.com/science/article/pii/S0028393216304481
Dissociating oral motor capabilities: Evidence from patients with movement disorders
Abstract
Abnormal articulation rate is a frequent symptom in neurogenic speech disorders. Performance rates in speech-like or nonspeech tasks involving the vocal motor apparatus are commonly accepted predictors of speech motor function in general and of articulation rate in particular. However, theoretical arguments and behavioral observations in populations with disordered speech indicate that different oral motor behaviors may be governed by distinct mechanisms. The objective of the present study was to expand our knowledge of the relationship between speech movements, on the one hand, and speech-like and nonspeech oral motor behaviors, on the other, by using a rate paradigm. 130 patients with neurological movement disorders of different origins and 130 neurologically healthy subjects participated in the study. Rate data was collected in a speech task (oral reading/repetition), in speech-like tasks (rapid syllable repetitions), and in nonspeech tasks (rapid single articulator movements of the tongue/lips). The main analyses involved a multiple single-case method, by which we tested for differences among each patient’s performance rates on the three task types. The results disclosed statistically significant (classical and strong) dissociations between movement rates obtained from the speech task and those obtained from speech-like and nonspeech oral motor tasks in a number of patients. The findings can be interpreted as reflecting major differences in task demands and underlying control mechanisms. The validity of diagnostic indices for speech obtained from speech-like or nonspeech tasks must thus be called into question.
http://jnnp.bmj.com/content/87/12/e1.117.abstract
UNDERLYING GENETIC CAUSE IN CEREBELLAR ATAXIAS: EVALUATION OF AN IRISH COHORT
+Author Affiliations
1. 1 National Ataxia Clinic, Department of Neurology, Adelaide & Meath Hospital Dublin incorporating the National Children’s Hospital, Tallaght, Dublin 24, Ireland 2. 2 Academic Unit of Neurology, Trinity College Dublin, Ireland
Abstract
Inherited ataxias are a group of genetically heterogeneous neurodegenerative disorders. The chances of obtaining a diagnosis in individuals with rare ataxias increase with evaluation at dedicated Ataxia clinics with comprehensive neurological assessment.
At the National Ataxia Clinic, Tallaght Hospital, from December 2014–April 2016, 137 patients with inherited ataxias were assessed. In December 2014, 53% of 133 patients had a genetically confirmed diagnosis. The commonest in the autosomal-recessive (AR) group were Friedreich’s ataxia, Ataxia-telangiectasia (AT), Ataxia with oculomotor apraxia 1&2 (AOA1&2) and, in the autosomal-dominant group, SCA2, SCA3 and SCA14.
Over a 16 month-period a number of undiagnosed patients were tested, some with next generation sequencing (NGS) gene panels. As a result, currently 65% of 137 patients have a genetic diagnosis. Interestingly, in the AR group most common non-Friedreich’s ataxias are SPG7 (5 unrelated individuals) and ANO10-associated ataxia in 5 individuals from 2 families.
A commercial panel approach using NGS has increased the rate of positive genetic results where traditional methods were unsuccessful in early and late-onset ataxia patients. These results are likely to change previous assumptions about the prevalence of certain non-Friedreich’s ataxias, as SPG7 and ANO10 now outnumber AOA1&2 and AT in our AR cohort
https://www.ecronicon.com/ecne/pdf/ECNE-03-000052.pdf
Paradoxical Abnormalities of Intra and Postoperative Neuroelectrical Recording of a Scoliotic Child with Friedreich’s Ataxia
Ahmed B. Bayoumi1, Zafer Orkun Toktas1*, Baran Yılmaz1, Orkun Koban1, Murat Sakir Eksi3, Hulya Aydin Gungor2 and Deniz Konya1 1 Department of Neurosurgery, Bahcesehir University, Goztepe Medical Park Hospital, Istnabul, Turkey 2 Department of Neurology, Bahcesehir University, Goztepe Medical Park Hospital, Istnabul, Turkey 3 Department of Neurosurgery, Antalya Ataturk State Hospital, Antalya, Turkey *Corresponding Author: Zafer Orkun Toktas, Department of Neurosurgery, Bahcesehir University, Goztepe Medical Park Hospital, Istnabul, Turkey Citation: Bayoumi AB., et al.
Abstract
Scoliosis is a common skeletal problem in Friedreich’s ataxia. There are both non-operative and operative treatment modalities for scoliosis in these patients. However, success with bracing is very limited. Surgical correction is beneficial, however intra-operative neuromonitoring in these patients could be misleading. We present a patient with Friedreich’s ataxia who presented with severe scoliosis and was treated with posterior spinal instrumentation, in which no MEP recordings were obtainable during the surgery. Case Description A 13-year-old boy presented to our clinic with progressive spinal deformity of three years duration associated with intractable back pain not radiated to the lower limbs. The patient was known to have Friedreich’s ataxia, which was diagnosed 3 years prior to his present illness by DNA testing with no positive family history. He had some neurological deficits beside progressive ataxia. He had a 62 degree of main thoracic curve with a compensatory lumbar curve on A-Pxrays. Posterior spinal instrumentation with transpedicular screws was done. However, no MEP recordings could be obtained during the surgery. Post-operative 3-week follow-up neuromonitoring depicted similar findings. Conclusion Scoliotic patients with Friedrich’s ataxia may show no response during the intra operative neuromonitoring by using MEP or SEP. A wake-up test setting must be planned with anesthesiology team to be done intra operatively for this subset of population to ensure the safety of the spinal procedure. To overcome such circumstances further and to plan the surgery in that fashion, pre-operative baseline neuromonitoring should be obtained in such neuromuscular scoliosis cases.
http://jnnp.bmj.com/content/early/2016/12/13/jnnp-2016-314863
Causes of progressive cerebellar ataxia: prospective evaluation of 1500 patients
- M Hadjivassiliou1,
- J Martindale2,
- P Shanmugarajah1,
- R A Grünewald1,
- P G Sarrigiannis1,
- N Beauchamp2,
- K Garrard2,
- R Warburton2,
- D S Sanders3,
- D Friend1,
- S Duty1,
- J Taylor1,
- N Hoggard4
+Author Affiliations
1. 1Academic Department of Neurosciences, Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Trust, Sheffield, UK 2. 2Sheffield Diagnostic Genetics Service, Sheffield Children’s NHS Foundation Trust, Sheffield, UK 3. 3Department of Gastroenterology, Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Trust, Sheffield, UK 4. 4Department of Neuroradiology, Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Trust, Sheffield, UK
- Correspondence toDr M Hadjivassiliou,hadjivassiliou@sheffield.ac.uk
Abstract
Background Cerebellar ataxias are the result of diverse disease processes that can be genetic or acquired. Establishing a diagnosis requires a methodical approach with expert clinical evaluation and investigations. We describe the causes of ataxia in 1500 patients with cerebellar ataxia.
Methods All patients were referred to the Sheffield Ataxia Centre, UK, and underwent extensive investigations, including, where appropriate genetic testing using next-generation sequencing (NGS). Patients were followed up on a 6-monthly basis for reassessment and further investigations if indicated.
Results A total of 1500 patients were assessed over 20 years. Twenty per cent had a family history, the remaining having sporadic ataxia. The commonest cause of sporadic ataxia was gluten ataxia (25%). A genetic cause was identified in 156 (13%) of sporadic cases with other causes being alcohol excess (12%) and cerebellar variant of multiple system atrophy (11%). Using NGS, positive results were obtained in 32% of 146 patients tested. The commonest ataxia identified was EA2. A genetic diagnosis was achieved in 57% of all familial ataxias. The commonest genetic ataxias were Friedreich’s ataxia (22%), SCA6 (14%), EA2 (13%), SPG7 (10%) and mitochondrial disease (10%). The diagnostic yield following attendance at the Sheffield Ataxia Centre was 63%.
Conclusions Immune-mediated ataxias are common. Advances in genetic testing have significantly improved the diagnostic yield of patients suspected of having a genetic ataxia. Making a diagnosis of the cause of ataxia is essential due to potential therapeutic interventions for immune and some genetic ataxias.
http://www.tandfonline.com/doi/full/10.1080/17474086.2016.1268047?scroll=top&needAccess=true&
Mitochondria and Iron: current questions
Bibbin T. Paul, David H. Manz, Frank M. Torti & Suzy V. Torti
- Abstract
Introduction: Mitochondria are cellular organelles that perform numerous bioenergetic, biosynthetic, and regulatory functions and play a central role in iron metabolism. Extracellular iron is taken up by cells and transported to the mitochondria, where it is utilized for synthesis of cofactors essential to the function of enzymes involved in oxidation-reduction reactions, DNA synthesis and repair, and a variety of other cellular processes.
Areas covered: This article reviews the trafficking of iron to the mitochondria and normal mitochondrial iron metabolism, including heme synthesis and iron-sulfur cluster biogenesis. Much of our understanding of mitochondrial iron metabolism has been revealed by pathologies that disrupt normal iron metabolism. These conditions affect not only iron metabolism but mitochondrial function and systemic health. Therefore, this article also discusses these pathologies, including conditions of systemic and mitochondrial iron dysregulation as well as cancer. Literature covering these areas was identified via PubMed searches using keywords: Iron, mitochondria, Heme Synthesis, Iron-sulfur Cluster, and Cancer. References cited by publications retrieved using this search strategy were also consulted.
Expert commentary: While much has been learned about mitochondrial and its iron, key questions remain. Developing a better understanding of mitochondrial iron and its regulation will be paramount in developing therapies for syndromes that affect mitochondrial iron.
http://www.surgeryjournal.co.uk/article/S0263-9319(16)30158-2/abstract
Paediatric spinal conditions
James E. Tomlinson, Nigel W. Gummerson
James E Tomlinson FRCS(Tr&Orth) is a Consultant Orthopaedic Spinal Surgeon at Sheffield Teaching Hospitals NHS Foundation Trust, Northern General Hospital, Sheffield, UK. Conflicts of interest: none declared
Nigel W Gummerson MA FRCS(Tr&Orth) is a Consultant Orthopaedic Spinal Surgeon at Leeds Teaching Hospitals NHS Trust, Leeds General Infirmary, Leeds, UK. Conflicts of interest: none declared
Abstract
Children with spinal problems present to a wide range of healthcare providers. These providers include the emergency department, their GPs, physiotherapy and the paediatric medical and surgical clinics (including orthopaedics). They may present with a variety of symptoms, but the common complaints are: back pain, leg pain or a change in back shape (spinal deformity). Some children may experience a combination of these problems. A systematic approach to the history and examination with knowledge of the common spinal conditions in children will allow you to select the best investigations. This will maximize the chance of making the correct diagnosis and providing appropriate care. This article aims to give an overview, appropriate for surgeons in the early years of their training.
http://www.gaitposture.com/article/S0966-6362(16)30688-9/abstract
Automatic classification of gait in children with early-onset ataxia or developmental coordination disorder and controls using inertial sensors
Andrea Mannini1, Octavio Martinez-Manzanera, Tjitske F. Lawerman, Diana Trojaniello,Ugo Della Croce, Deborah A. Sival, Natasha M. Maurits, Angelo Maria Sabatini
Abstract
Early-Onset Ataxia (EOA) and Developmental Coordination Disorder (DCD) are two conditions that affect coordination in children. Phenotypic identification of impaired coordination plays an important role in their diagnosis. Gait is one of the tests included in rating scales that can be used to assess motor coordination.
A practical problem is that the resemblance between EOA and DCD symptoms can hamper their diagnosis. In this study we employed inertial sensors and a supervised classifier to obtain an automatic classification of the condition of participants. Data from shank and waist mounted inertial measurement units were used to extract features during gait in children diagnosed with EOA or DCD and age-matched controls. We defined a set of features from the recorded signals and we obtained the optimal features for classification using a backward sequential approach. We correctly classified 80.0%, 85.7%, and 70.0% of the control, DCD and EOA children, respectively. Overall, the automatic classifier correctly classified 78.4% of the participants, which is slightly better than the phenotypic assessment of gait by two pediatric neurologists (73.0%). These results demonstrate that automatic classification employing signals from inertial sensors obtained during gait maybe used as a support tool in the differential diagnosis of EOA and DCD. Furthermore, future extension of the classifier’s test domains may help to further improve the diagnostic accuracy of pediatric coordination impairment. In this sense, this study may provide a first step towards incorporating a clinically objective and viable biomarker for identification of EOA and DCD.
http://jamanetwork.com/journals/jamaneurology/article-abstract/2591315
Gradually Progressive Spastic Ataxia in a Young ManSteadily Unsteady
Divyanshu Dubey, MD1; Pravin Khemani, MD1; Eric Remster, MD1; et alJeffrey L. Elliott, MD1
Abstract
A 26-year-old right-handed man presented with progressive gait imbalance over 6 years. His examination was consistent with cerebellar and upper motor neuronal dysfunction. He had no significant family history. Most of the serum and cerebrospinal fluid studies were unremarkable. Neuroimaging was remarkable for mild cerebellar and noticeable thoracic spinal cord atrophy. The initial differential diagnosis for the patient’s presentation was broad, but because of certain clinical characteristics, it was later focused on hereditary ataxias. Detailed analysis of the clinical features in the history, neurologic examination, and neuroimaging studies led to the diagnosis.
Vestibular findings in autosomal recessive ataxia
Abstract
OBJECTIVE: This study aims to examine vestibular disorders in patients with recessive spinocerebellar ataxia.
DESIGN: A retrospective cross-sectional study was conducted. The patients underwent the following procedures: case history, ENT and vestibular evaluations.
STUDY SAMPLE: The tests were performed in 19 patients ranging from 6 to 63 years of age (mean age of 36.7).
RESULTS: Clinically, the patients commonly had symptoms of dizziness (57.8%), lack of coordination of movement with imbalance when walking (52.6%), and headaches (42.1%). In vestibular testing, alterations were predominantly evident under caloric testing (73.5%), rotational chair testing, and testing for gaze and optokinetic nystagmus (36.8%). The presence of alterations occurred under examination in 89.5% of these patients, 100% occurred in subjects with Friedreich’s ataxia and 84.6% for subjects with indeterminate recessive spinocerebellar ataxia, with the majority occurring in those with central vestibular dysfunction, 57.9% of the examinations.
CONCLUSION: The most evident neurotological symptoms were dizziness, lack of coordination of movement, and imbalance when walking. Alterations in vestibular examinations occurred in 89.5% of patients, mostly in the caloric test, with a predominance of deficient central vestibular system dysfunction. This underscores the importance of the contribution of topodiagnostic labyrinthine evaluations for neurodegenerative diseases.
Author(s): Bianca Simone Zeigelboim Helio Afonso Ghizoni Teive Hugo Amilton Santos de Carvalho Edna Marcia da Silva Abdulmassih Jair Mendes Marques and Rafaella Cristyne Cardoso
http://www.mdpi.com/1422-0067/17/12/2066
Liver Growth Factor (LGF) Upregulates Frataxin Protein Expression and Reduces Oxidative Stress in Friedreich’s Ataxia Transgenic Mice
,Juan José Díaz-Gil 1,‡ andEulalia Bazán 1,*
1
Service of Neurobiology, Ramón y Cajal Institute for Health Research (IRYCIS), 28034 Madrid, Spain
2
Service of Neurology, Ramón y Cajal Hospital, 28034 Madrid, Spain
3
Departamento de Anatomía, Histología y Neurociencia Facultad de Medicina Universidad Autónoma de Madrid, 28400 Madrid, Spain
†
These authors contributed equally to this work.
‡
Deceased on 4 November 2016.
*
Author to whom correspondence should be addressed.
Academic Editor: Katalin Prokai-Tatrai
Abstract
Friedreich’s ataxia (FA) is a severe disorder with autosomal recessive inheritance that is caused by the abnormal expansion of GAA repeat in intron 1 of FRDA gen. This alteration leads to a partial silencing of frataxin transcription, causing a multisystem disorder disease that includes neurological and non-neurological damage. Recent studies have proven the effectiveness of neurotrophic factors in a number of neurodegenerative diseases. Therefore, we intend to determine if liver growth factor (LGF), which has a demonstrated antioxidant and neuroprotective capability, could be a useful therapy for FA. To investigate the potential therapeutic activity of LGF we used transgenic mice of the FXNtm1MknTg (FXN)YG8Pook strain. In these mice, intraperitoneal administration of LGF (1.6 μg/mouse) exerted a neuroprotective effect on neurons of the lumbar spinal cord and improved cardiac hypertrophy. Both events could be the consequence of the increment in frataxin expression induced by LGF in spinal cord (1.34-fold) and heart (1.2-fold). LGF also upregulated by 2.6-fold mitochondrial chain complex IV expression in spinal cord, while in skeletal muscle it reduced the relation oxidized glutathione/reduced glutathione. Since LGF partially restores motor coordination, we propose LGF as a novel factor that may be useful in the treatment of FA.
http://ir.horizon-pharma.com/releasedetail.cfm?ReleaseID=1003338
Horizon Pharma plc Announces Topline Results from Phase 3 Study of ACTIMMUNE® (interferon gamma-1b) in Friedreich’s Ataxia
DUBLIN, Ireland, Dec. 08, 2016 (GLOBE NEWSWIRE) — Horizon Pharma plc (NASDAQ:HZNP), a biopharmaceutical company focused on improving patients’ lives by identifying, developing, acquiring and commercializing differentiated and accessible medicines that address unmet medical needs, today announced that the Phase 3 trial, STEADFAST (Safety, Tolerability and Efficacy of ACTIMMUNE Dose Escalation in Friedreich’s Ataxia study), evaluating ACTIMMUNE® (interferon gamma-1b) for the treatment of Friedreich’s ataxia (FA) did not meet its primary endpoint of a statistically significant change from baseline in the modified Friedreich’s Ataxia Rating Scale (FARS‐mNeuro) at 26 weeks versus treatment with placebo. FARS‐mNeuro is an exam-based rating scale that measures disease progression based on functional parameters such as speech, ability to swallow, upper and lower limb coordination, gait and posture.
In addition, the secondary endpoints did not meet statistical significance. No new safety findings were identified on initial review of data other than those already noted in the ACTIMMUNE prescribing information for approved indications. The Company, in conjunction with the independent Data Safety Monitoring Board, the principal investigator and the Friedreich’s Ataxia Research Alliance (FARA) Collaborative Clinical Research Network (CCRN) in FA, has determined that, based on the trial results, the FA development program will be discontinued, including the 26-week extension study and the long-term safety study.
Patients participating in the ongoing extension studies should contact their study site coordinator for further information and next steps.
The Company will continue to work with FARA and the principal investigator to further analyze the data to help inform future research efforts as well as future data presentation or publication.
«A well-designed, rigorous study like STEADFAST would not have been possible without the extraordinary drive of the FA community, particularly the people who enrolled in the study, the clinical trial investigators and the Friedreich’s Ataxia Research Alliance,» said Timothy P. Walbert, chairman, president and chief executive officer, Horizon Pharma plc. «While the results were not what we hoped for, this is the very reason why research and development is important – to find answers that may help inform future research.»
«FARA’s mission is to drive research to develop therapies that will treat and cure Friedreich’s ataxia and we remain passionately committed to that mission so that one day soon patients and caregivers impacted by this devastating disease will have effective treatment options,» said Ronald J. Bartek, co-founder and founding president, FARA. «We want to extend our sincere appreciation to all of the patients, patient families and investigators who were a part of this study as well as Horizon for collaborating with us so impressively on this important research.»
http://phys.org/news/2016-12-uncover-source-genetic-error-multiple.html
Researchers uncover possible source of genetic error causing multiple diseases
December 5, 2016
Sergei Mirkin, Ph.D., is the White Family Chair in Biology at Tufts University’s School of Arts and Sciences. Credit: Melody Ko/Tufts University
Tufts University researchers have discovered a possible explanation for the occurrence of a genetic error that causes over a dozen neuromuscular and neurodegenerative disorders, including Huntington’s disease, myotonic dystrophy and forms of spinocerebellar ataxia.
The error occurs as copies of three-letter sequences of DNA—known as CAG and CTG triplets—expand and repeat themselves hundreds or even thousands of times, disrupting normal gene sequences.
Genetic analyses in baker’s yeast now reveal that these large-scale expansions are controlled by genes that have been implicated in a process for repairing DNA breaks, leading the researchers to surmise that the expansions occur while breaks are being healed. Baker’s yeast, known as Saccharomyces cerevisiae, is frequently used in scientific research.
The findings are published in Nature Structural & Molecular Biology.
«We think these large-scale repeat expansions could occur in a single step,» said Sergei Mirkin, Ph.D., White Family Chair in Biology at Tufts School of Arts and Sciences and corresponding author on the paper. «The DNA replication machinery stalls within those repeats, which ultimately results in the formation of DNA breaks. To heal those breaks, cells seem to involve a special path of repair, called break-induced replication, which sacrifices the fidelity of DNA synthesis for the sake of a quick fix. As a result, large numbers of extra repeats can be added while the break is healed.»
Previous studies have identified certain mutations in DNA replication machinery that account for small-scale repeat expansions in which only a few extra repeats are added, but the cause of rapid accumulation of hundreds of repeats has remained unclear until now.
To detect and analyze large-scale expansions of CAG and CTG repeats, Mirkin and his colleagues developed an experimental system in yeast that observed simultaneous additions of more than 100 triplets, a first for such systems. This observation is similar to what happens in human disease.
Jane Kim, Ph.D., who was a research assistant professor in Mirkin’s lab when the research was conducted and who is the paper’s first author, said the model suggests answers to two questions that have puzzled researchers.
«Not only does this model explain how additions of hundreds of repeats can occur in human diseases, but it can also account for a bias towards expansions observed in human pedigrees,» said Kim, now an assistant professor at California State University San Marcos.
The authors note that the timing of expansion in human cases is still unclear and presents an important area of future investigation.
Read more at: http://phys.org/news/2016-12-uncover-source-genetic-error-multiple.html#jCp
Protective role of frataxin against myocardial ischemia reperfusion injury
Global Summit on Heart Diseases and Therapeutics
October 20-21, 2016 Chicago, USA
| Abdullah Al Asmari |
| Auburn University, USA |
| Abstract |
| Oxygen free radicals associated with ischemia-reperfusion (IR) injury in cardiomyocytes is known to cause mitochondrial damage. However, the exact mechanism of how the oxygen free radicals develop in the mitochondria due to IR stress is currently unclear. In the current study, we focus upon understanding the role of frataxin (FXN) in regulating mitochondrial damage associated with IR injury. FXN, a nuclear encoded mitochondrial matrix protein, has been observed to regulate mitochondrial iron homeostasis and thus mitochondrial energy regulation. Loss of FXN, in Friedreich’s ataxia, is associated with mitochondrial iron overload and increased ROS formation and cellular damage. In this study, we hypothesized that FXN protects cardiomyocytes against IR injury by preventing the dysregulation of myocardial bioenergetics. We identified that FXN expression is increased in response to IR injury and that increase is mediated by hypoxia inducible factor (HIF-1α) which results in regulation of mitochondrial iron homeostasis and the ensuing mitochondrial ROS formation. Most surprisingly, we observed that enhanced FXN expression displayed elevated levels of glutathione (GSH) and superoxide dismutase (SOD). Furthermore, these findings were supported in our FXN over-expressing and knock down cells under the same IR condition. Together, these results demonstrate that increased expression of FXN is cardioprotective against IR injury through its anti-oxidant effect and by improving mitochondrial energetics. |
https://lens.elifesciences.org/20732/index.html#info
Loss of Frataxin activates the iron/sphingolipid/PDK1/Mef2 pathway in mammals
Kuchuan Chen, Tammy Szu-Yu Ho, Guang Lin, Kai Li Tan, Matthew N Rasband, Hugo J Bellen, PDF Source XML Lens JSON
Abstract
Friedreich’s ataxia (FRDA) is an autosomal recessive neurodegenerative disease caused by mutations in Frataxin (FXN). Loss of FXN causes impaired mitochondrial function and iron homeostasis. An elevated production of reactive oxygen species (ROS) was previously proposed to contribute to the pathogenesis of FRDA. We recently showed that loss of frataxin homolog (fh), a Drosophila homolog of FXN, causes a ROS independent neurodegeneration in flies (Chen et al., 2016). In fh mutants, iron accumulation in the nervous system enhances the synthesis of sphingolipids, which in turn activates 3-phosphoinositide dependent protein kinase-1 (Pdk1) and myocyte enhancer factor-2 (Mef2) to trigger neurodegeneration of adult photoreceptors. Here, we show that loss of Fxn in the nervous system in mice also activates an iron/sphingolipid/PDK1/Mef2 pathway, indicating that the mechanism is evolutionarily conserved. Furthermore, sphingolipid levels and PDK1 activity are also increased in hearts of FRDA patients, suggesting that a similar pathway is affected in FRDA.
http://www.sciencedirect.com/science/article/pii/S1098301516327383
PSY57 – A Cost of Illness Study Evaluating The Healthcare And Societal Burden of Friedreich’s Ataxia In The United Kingdom
http://www.nature.com/articles/ncomms13272#ref-link-section-95
Contracting CAG/CTG repeats using the CRISPR-Cas9 nickase
Abstract
CAG/CTG repeat expansions cause over 13 neurological diseases that remain without a cure. Because longer tracts cause more severe phenotypes, contracting them may provide a therapeutic avenue. No currently known agent can specifically generate contractions. Using a GFP-based chromosomal reporter that monitors expansions and contractions in the same cell population, here we find that inducing double-strand breaks within the repeat tract causes instability in both directions. In contrast, the CRISPR-Cas9 D10A nickase induces mainly contractions independently of single-strand break repair. Nickase-induced contractions depend on the DNA damage response kinase ATM, whereas ATR inhibition increases both expansions and contractions in a MSH2- and XPA-dependent manner. We propose that DNA gaps lead to contractions and that the type of DNA damage present within the repeat tract dictates the levels and the direction of CAG repeat instability. Our study paves the way towards deliberate induction of CAG/CTG repeat contractions in vivo.
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Launches of First Therapies Approved for Spinal Muscular Atrophy and Friedreich’s Ataxia Will Revolutionize Treatment and Drive Growth of These Rare Disease Markets
05:01 EDT 25 Oct 2016 | PR Newswire
Home » Topics » Drug Discovery » Latest News » Launches of First Therapies Approved for Spinal Muscular Atrophy and Friedreich’s Ataxia Will Revolutionize Treatment and Drive Growth of These Rare Disease Markets
BURLINGTON, Mass., Oct. 25, 2016 /PRNewswire/ — Decision Resources Group finds that the anticipated launches of the first therapies for the treatment of spinal muscular atrophy (SMA) or Friedreich’s ataxia (FA) will transform treatment of these diseases and lead to their markets expanding dramatically. Medical practice in SMA and FA is currently dominated by supportive care or symptomatic treatment. However, the complete lack of efficacious treatment options translates into high unmet need and represents an as-yet untapped and lucrative market opportunity for drug developers.
Related Biotechnology, Pharmaceutical and Healthcare News
- [Comment] Dawn of a new therapeutic era for spinal muscular atrophy
- Success for Biogen, Ionis as spinal muscular atrophy drug performs in Phase III
- FDA Approves Spinraza (nusinersen) for Spinal Muscular Atrophy
- Trial offers hope of a treatment for spinal muscular atrophy
- Biogen wins a pioneering drug approval for a rare and deadly disease
Ionis/Biogen’s antisense oligonucleotide nusinersen, which targets the underlying cause of SMA, will be the first agent ever approved for this disease. Based on efficacy data from clinical trials, interviewed pediatric neurologists expect rapid and widespread use of nusinersen. Assuming high-premium pricing, the launch of nusinersen, expected in 2017, will be a key driver of market expansion.
Following the anticipated label expansion of Horizon Pharma’s Actimmune (interferon gamma-1b), the FA market is forecasted to grow significantly over the next ten years. However, interviewed neurologists’ perceived limitations of Actimmune, including its unclear mechanism of action, variable effect on frataxin protein levels, and modest preservation of neurological function, could constrain its uptake and allow competitors to challenge Actimmune’s position.
Other key findings from the Niche & Rare Disease Landscape & Forecast reports entitled Spinal Muscular Atrophy and Friedreich’s Ataxia:
- In both SMA and FA, first-to-market therapies will likely benefit patients, but commercial opportunity remains for novel therapies that can offer improvements in efficacy, safety, and delivery. Further, physicians expect new therapies with different targets and mechanisms of action would be used in combination with existing agents.
- During the second half of the 2015-2025 study period, nusinersen may face competition from AveXis’s investigational gene therapy AVXS-101, which has shown tremendous promise in an ongoing clinical trial. AVXS-101 could potentially be delivered in a single intravenous administration, in contrast to nusinersen’s triannual intrathecal administration, and may be curative.
- According to interviewed experts, gene therapy will also transform the FA treatment landscape, possibly negating the need for drug treatment. However, gene therapies being developed by Agilis Biotherapeutics, Pfizer, and RaNA Therapeutics are in preclinical testing and unlikely to launch during the study period.
Comments from Decision Resources Group Analysts, Ian Love, Ph.D., and Tara M. Stewart, M.A., Ph.D., respectively:
