Using the shared genetics of dystonia and ataxia to unravel their pathogenesis

Esther A.R. Nibbeling, Cathérine C.S. Delnooz, Tom J. de Koning, Richard J. Sinke, Hyder A. Jinnah, Marina A.J. Tijssen, Dineke S. Verbeek, Neuroscience & Biobehavioral Reviews, Available online 28 January 2017, ISSN 0149-7634, doi:10.1016/j.neubiorev.2017.01.033.

In this review we explore the similarities between spinocerebellar ataxias and dystonias, and suggest potentially shared molecular pathways using a gene co-expression network approach. Many patients show a combination of cerebellar ataxia and dystonia. Dystonia is frequently seen in SCA2 (14%), SCA3 (24%) and SCA17 (53%), and regularly seen in SCA types 1, 6, 12, 14, 15/16 and 20, in ataxia telangiectasia, in Friedreich’s ataxia, and in ataxia with oculomotor apraxia. Taken into account the clinical and etiological heterogeneity, the exact pathophysiological mechanisms of SCA and dystonia are not exactly clear. For SCA, several etiological roles have been identified that lead to neurotransmission deficits and result in PC death, including transcriptional dysregulation, autophagy, mitochondrial defects and alterations in calcium homeostasis.In dystonia, the basal ganglia have classically been attributed a key role.

miRNAs as biomarkers of neurodegenerative disorders

Vijitha Viswambharan, Ismail Thanseem, Mahesh M Vasu, Suresh A Poovathinal, and Ayyappan Anitha; Biomarkers in Medicine, February 2017 ,Vol. 11, No. 2 , Pages 151-167 doi: 10.2217/bmm-2016-0242

The potential role of epigenetic changes associated with FRDA including miRNA-based regulatory mechanisms is being studied now. Genetic variations that create miRNA target sites in the 3′-UTR of FXN have been found to affect frataxin expression in FRDA. For example, miRNA-145 has been found to directly bind to the 3′-UTR region of FXN, negatively regulating its expression.

Targeting Class I Histone Deacetylases in a “Complex” Environment

Christopher J. Millard, Peter J. Watson, Louise Fairall, John W.R. Schwabe, Trends in Pharmacological Sciences, Available online 28 January 2017, ISSN 0165-6147, doi:10.1016/j.tips.2016.12.006.

Histone deacetylase (HDAC) inhibitors are proven anticancer therapeutics and have potential in the treatment of many other diseases including HIV infection, Alzheimer’s disease, and Friedreich’s ataxia. A problem with the currently available HDAC inhibitors is that they have limited specificity and target multiple deacetylases. Due to their nonselective nature, many patients experience significant side effects.
The focus within the field is turning to the development of isoform-selective HDAC inhibitors to reduce off-target effects experienced by patients.

New Techniques for Ancient Proteins: Direct Coupling Analysis Applied on Proteins involved in Iron Sulfur Cluster Biogenesis

Marco Fantini, Duccio Malinverni, Paolo De Los Rios, Annalisa Pastore, bioRxiv 103283; doi:10.1101/103283

We have used DCA to analyse three proteins of the iron-sulfur biogenesis machine, an essential metabolic pathway conserved in all organisms. We show that, although based on a relatively small number of sequences due to its distribution in genomes, we can correctly recapitulate all the features of the fold of the CyaY/frataxin family, a protein involved in the human disease Friedreich's ataxia.

Influence of substituent heteroatoms on the cytoprotective properties of pyrimidinol antioxidants

Arnaud Chevalier, Omar M. Khdour, Margaret Schmierer, Indrajit Bandyopadhyay, Sidney M. Hecht, Bioorganic & Medicinal Chemistry, Available online 23 January 2017, ISSN 0968-0896, doi:10.1016/j.bmc.2017.01.030.

Defects in mitochondrial function are linked to numerous neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and Friedreich’s ataxia, and are the hallmarks of a number of genetic mitochondrial disorders whose manifestations range from muscle weakness to organ failure. In this context, improvements in mitochondrial function and cellular bioenergetics represent potential targets for therapeutic intervention in mitochondrial diseases.
These compounds are able to quench ROS and lipid peroxidation, maintain mitochondrial membrane potential and confer cytoprotection to cultured cells under conditions of induced oxidative stress. These properties are related to their ability to quench reactive oxygen radicals; therefore, the compounds have been denoted multifunctional radical quenchers (MRQs).
The ability of these compounds to quench lipid peroxidation induced by depletion of glutathione with diethyl maleate (DEM) was evaluated in Friedreich’s ataxia (FRDA) lymphocytes.

Sex Differences in Redox Biology: A Mandatory New Point of View Approaching Human Inflammatory Diseases

Straface Elisabetta, Malorni Walter, and Pietraforte Donatella. Antioxidants & Redox Signaling. January 2017, 26(1): 44-45. doi:10.1089/ars.2016.6931.

Cells from females and males respond differently to chemical and microbial stressors. “Male neurons” are more sensitive to stress induced by oxidants and excitatory neurotransmitters, whereas “female neurons” are more susceptible to some stimuli that prompt apoptosis. The growing interest for the redox medicine in human health has recently suggested a reappraisal of the disease-triggering oxidant-generating enzymes as suitable disease-relevant therapeutic targets. In the light of the reported lines of evidence, a sex- and gender perspective should drive future basic research and pre-clinical studies before starting any pharmacological research aimed at the development of new drugs candidates to counteract redox-related human diseases.

What is quality of life and how do we measure it? Relevance to Parkinson's disease and movement disorders

Pablo Martinez-Martin MD, PhD; Movement Disorders, Version of Record online: 2 DEC 2016 DOI: 10.1002/mds.26885

The objective of this review is to present the conceptual framework, the measures, and some of their most relevant applications in the field of Parkinson's disease and movement disorders. Health-related quality of life is a subjective, individual, and multidimensional construct, and its main dimensions are physical, mental, and social, besides global perceptions of health and personal domains. Health-related quality of life measurement is carried out by means of questionnaires or scales, ideally self-applied by patients, and has a diversity of important applications for clinical practice, research, and health policy.

The origins of the quality of life (QoL) concept are ancient and, in some way, controversial from the beginning. Around 4 centuries before Christ, Greek philosophers proposed the “good life” as a vital goal, an ancestry term of the current notion of QoL. Aristippus (435-350 BC) and the hedonists defended the achievement of pleasure as the basis of happiness, a view later nuanced by Aristotle (384-322 BC), who moved the concept of happiness to the pursuit of activities focused on more worthy objectives and values (eudaimonia: well-being, happiness). The controversy between hedonists and eudaimonics, influenced by new theoretical contributions and inspirations, has in some way continued until the present.

In the setting of movement disorders, it is recommended to increase the number of clinical trials focused on HRQoL, with HRQol acting as the mainendpoint of the study. For obtaining more complete information about HRQoL status and change, a combination of generic and specific measures is recommended. The contents of the generic scales may not be relevant for specific conditions, and their responsiveness may be low; however, the specific instruments can overlook important aspects of general health. For example, in the setting of PD, the SF-36 does not include evaluation of self-image or stigma, whereas the PDQ-39 does not include assessment for energy/fatigue. Finally, for the correct use and interpretation of outcomes, it is advisable to keep in mind the potential limitations that HRQoL instruments, their application, or analysis may present.

New Health Technologies Managing Access, Value and Sustainability

OECD Publishing, Paris. DOI:10.1787/9789264266438-en

This report discusses the need for an integrated and cyclical approach to managing health technology in order to mitigate clinical and financial risks, and ensure acceptable value for money.

The proliferation of high-cost drugs and rising drug prices are raising pressure on public health services. Governments need to work with industry and regulators to define a new way of approaching the development and use of new health technologies that encourage innovation while making it more affordable and that justifies better the benefit that it brings.

According to the study, "the launch of cancer and rare diseases drugs is rising, sometimes without an assessment of the increased benefits they produce for the health of patients. In this sense, the OECD exemplifies this situation in the case of the United States "where the launch price of cancer drugs per year of life gained has increased fourfold in just 20 years, in constant terms, and already exceeds $ 200,000 ".

Two different genetic diseases in the same patient: Coincident, concomitant, or causally related

Graf, J., Hellenbroich, Y., Veelken, N., Figueroa, K. P., Wolff, S., Pulst, S. and Brüggemann, N. (2016). Mov. Disord., 31: 491–492. doi: 10.1002/mds.26539

A 17-year-old high school student started falling behind his peers and developed cramps at the age of 5 years, diagnosis of myotonic dystrophy was genetically confirmed. He developed progressive ataxia and prominent dysarthria. On examination, besides generalized muscle weakness and myotonic reactions, he showed saccadic pursuit, gaze-evoked nystagmus, dysmetria, gait ataxia, loss of deep-tendon reflexes, and an impaired sense of position and vibration. At the age of 15 years, genetic testing confirmed an additional diagnosis of Friedreich ataxia.
Our findings have several important implications: Although genetic testing is the gold standard for a large number of neurological diseases, it does not replace a detailed neurological examination and careful taking of the family history. In some patients, a broad phenotypic spectrum may be a result of the existence of more than 1 gene defect. Although the occurrence of mutations in 2 genes is most likely coincidental in our patients, the possibility of a potential common predisposition to mutations should also be considered.

Selective antagonism of muscarinic receptors is neuroprotective in peripheral neuropathy

Nigel A. Calcutt, Darrell R. Smith, Katie Frizzi, Mohammad Golam Sabbir, Subir K. Roy Chowdhury, Teresa Mixcoatl-Zecuatl, Ali Saleh, Nabeel Muttalib, Randy Van der Ploeg, Joseline Ochoa, Allison Gopaul, Lori Tessler, Jürgen Wess, Corinne G. Jolivalt, Paul Fernyhough; J Clin Invest. doi:10.1172/JCI88321. Published January 17, 2017

Distal dying-back or degeneration of nerve fibers is observed in many axonopathic diseases, including diabetic neuropathy, chemotherapy-induced peripheral neuropathy (CIPN), Friedreich ataxia, Charcot-Marie-Tooth disease type 2, and HIV-associated distal-symmetric neuropathy. There are no therapies for any of these diseases, all of which display some degree of mitochondrial dysfunction. This is pertinent, as the growth-cone motility required to maintain fields of innervation consumes 50% of ATP supplies in neurons due to high rates of actin treadmilling. Maintenance of plastic innervation therefore requires high consumption of ATP for growth-cone motility and maintenance of terminals and synapses. Unmyelinated axons are also more energetically demanding than myelinated axons, consuming 2.5- to 10-fold more energy per action potential. Mitochondria are known to concentrate in regions of high metabolic demand and sensory terminal boutons are packed with mitochondria.

The blockade of muscarinic receptor–mediated inhibition of mitochondrial activity using antimuscarinic drugs may not represent a specific intervention against any one primary pathogenic mechanism and potentially allows broad therapeutic application to all conditions that show diminished energy capacity under stress. Peripheral neuropathy is a major, and largely untreated, cause of human morbidity, with huge associated health care costs. One particularly encouraging implication of our identification of the endogenous M1R-mediated suppression of sensory neuron metabolism is that drugs that modulate this process are already in widespread clinical use for other indications. Moreover, the safety profile of antimuscarinic drugs is well characterized, with over 20 years of clinical application for a variety of indications in Europe and the safe use of topical pirenzepine applied to the eye to treat myopia in children. The therapeutic application of M1R antagonists suggested by our studies could potentially translate relatively rapidly to clinical use.

Mitochondrial iron-sulfur cluster biogenesis from molecular understanding to clinical disease

Majid Alfadhel, Marwan Nashabat, Qais Abu Ali, Khalid Hundallah; Neurosciences (Riyadh). 2017 Jan;22(1):4-13. doi: 10.17712/nsj.2017.1.20160542.

Iron-sulfur assembly defects which include 5 disorders: Friedreich ataxia due to FXN gene defect, combined oxidative phosphorylation deficiency 19 due to LYRM4 gene defect, infantile complex II/III deficiency (IMC23D) due to NFS1 gene defect, hereditary myopathy with lactic acidosis due to ISCU gene defect and mitochondrial muscle myopathy due to Ferredoxin 1-Like protein (FDX1L) gene defect.
In conclusion, the combined clinical and advanced molecular diagnostic efforts will likely identify more disorders linked to the mitochondrial ISC biogenesis pathway, and potentially discover new genes in association with such diseases. Continued studies will help further elucidate mitochondrial iron homeostasis regulation, as understanding of mitochondrial iron overload could potentially yield better therapeutic approaches for such defects.

Team Led By The Ohio State University Researchers Publish Method in JoVE Video Journal to Standardize Protocol for Testing Mitchondrial Function

Cambridge, MA (PRWEB) January 16, 2017; Today, researchers at The Ohio State University in collaboration with scientists at the University of Pennsylvania and the National Institute of Aging published a reproducible method to noninvasively measure in vivo human skeletal muscle mitochondrial function in JoVE Video Journal.
Aberrant mitochondrial impairment is a hallmark of a wide range of metabolic syndromes and genetic diseases, from common conditions such as aging and diabetes to rare disorders such as Friedreich's ataxia.

Health-related quality of life in patients with spinocerebellar ataxia

Health-related quality of life in patients with spinocerebellar ataxia, C.R. Sánchez-López, L. Perestelo-Pérez, A. Escobar, J. López-Bastida, P. Serrano-Aguilar, Neurología (English Edition), Available online 9 January 2017, ISSN 2173-5808, doi:10.1016/j.nrleng.2015.09.002.

Spinocerebellar ataxia (SCA) comprises a group of clinically and genetically heterogeneous diseases characterised by cerebellar degeneration, including up to 17 types of SCA with an autosomal dominant inheritance pattern and 5 type sof SCA with autosomal recessive inheritance. Overall SCA prevalence in Spain is 20.2 cases per 100 000 population.The prevalence of the autosomal dominant types of SCA is 1.2 cases per 100 000; prevalence of Friedreich ataxia,the most frequent autosomal recessive type of SCA, is 4.7 per 100 000 population.
In summary, decreased HRQoL in SCA seems to beexplained, at least partially, by loss of gait-related motorskills and the likely presence of depression and sleepdisorders. Early detection and effective treatment ofthese variables may contribute to improving HRQoL inpatients with SCA. Our findings suggests that making rehabilitation moreaccessible and intensive would delay and limit thephysical deterioration leading to disability and loss of independence for walking and performing daily living activ-ities. Psychotherapy, a supplementary treatment frequentlyrequested by patients with SCA, may also contribute toreducing the impact of the disease on non-motor function. Likewise, using self-administered HRQoL questionnaires inroutine clinical practice may provide useful additional information rarely obtained from conventional clinical assessment. Using SF-36 to measure HRQoL in patients with SCA in our setting would be useful not only for evaluating theresults of studies and clinical trials, but also for assessingthe real needs of these patients and their carers, which will result in better healthcare planning and allocation of resources.

Establishment and Maintenance of Primary Fibroblast Repositories for Rare Diseases—Friedreich's Ataxia Example

Li Yanjie, Polak Urszula, Clark Amanda D., Bhalla Angela D., Chen Yu-Yun, Li Jixue, Farmer Jennifer, Seyer Lauren, Lynch David, Butler Jill S., and Napierala Marek. Biopreservation and Biobanking. August 2016, 14(4): 324-329. doi:10.1089/bio.2015.0117.

Although classified as a neurodegenerative disease, Friedreich’s ataxia presents with a plethora of clinical symptoms, including ataxia, sensory abnormalities, heart dysfunction, diabetes, and auditory and visual loss.The variable number of GAA repeats among FRDA patients contributes to the clinical variability of the disease. Clinicians and scientists studying orphan diseases face the specific challenge of limited access to biospecimens due to the small number of patients suffering from the particular condition. Creating biorepositories of well-characterized patient samples and cell lines available for academic as well as commercial institutions is critical for developing successful therapeutic strategies to combat rare diseases.

Friedreich's Ataxia and Variants

R. Bhidayasiri, Reference Module in Neuroscience and Biobehavioral Psychology, Elsevier, 2017, ISBN 9780128093245, doi:10.1016/B978-0-12-809324-5.00596-4.

Detailed genetic and family studies emphasize the potential heterogeneity in presenting phenotype as well as age of onset of patients with FRDA. The discovery of the frataxin gene has allowed genotype–phenotype correlations and confirmation that the FRDA expansion is responsible for classical FRDA, late-onset FRDA (LOFA), Friedreich's ataxia with retained reflexes (FARR), and Acadian ataxia.
Therapeutic approaches aimed at improving mitochondrial functioning and to increase frataxin expression, which may have lead to new realistic treatments in the future.

Friedreich Ataxia: Hypoplasia of Spinal Cord and Dorsal Root Ganglia

Arnulf H. Koeppen MD, Alyssa B. Becker BA, Jiang Qian MD, PhD, Paul J. Feustel PhD. Journal of Neuropathology & Experimental Neurology, DOI:10.1093/jnen/nlw111, First published online: 12 January 2017

The FA patients included a wide range of disease onset and duration suggesting that the SC undergoes growth arrest early and remains abnormally small throughout life. The results strongly support the conclusion that these neural tissues are small because of hypoplasia rather than atrophy and that their developmental delay occurs independently.
It is of interest that Friedreich had already proposed in 1877 that smallness of the clavae (gracile and cuneate nuclei) was developmental.

New hearts for Friedreich patients

David Pleasure, Journal of the Neurological Sciences, Available online 12 January 2017, ISSN 0022-510X, doi:10.1016/j.jns.2017.01.035.
Editorial

The impact of the transplanted hearts on quality of life was large. The transplanted hearts showed no signs of cardiomyopathy during decades-long post-transplantation followup, providing strong evidence that FRDA cardiomyopathy develops independently of other manifestations of this systemic disease.

Cardiac transplantation in Friedreich ataxia: Extended follow-up

Ashley McCormick, Julianna Shinnick, Kim Schadt, Rose Rodriguez, Linda Addonizio, Michio Hirano, Susan Perlman, Kimberly Y. Lin, David R Lynch, Journal of the Neurological Sciences, Available online 10 January 2017, ISSN 0022-510X, doi:10.1016/j.jns.2017.01.027.

Observations emphasize that the rate and nature of progression to end stage heart failure in ndividuals with FRDA is highly variable and, at least in these unusual individuals, not easily predicted by their neurologic status or GAA triplet repeat length. Our case series demonstrates the safety and efficacy of heart transplantations as a possible treatment option for end-stage heart failure in the setting of neurologic disease in both early-and late-onset individuals.
Diagnosis of FRDA should not be viewed as an absolute contraindication that would negatively impact a patient’s candidacy for heart transplantation or re-transplantation.

Catalent to Develop Softgel Capsules for JOT’s Leading Orphan Disease Candidates

Catalent. Somerset, N.J. (PRWEB) January 09, 2017 . Catalent Pharma Solutions, the leading global provider of advanced delivery technologies and development solutions for drugs, biologics and consumer health products, today announced that it is to evaluate Jupiter Orphan Therapeutics, Inc.’s (JOT) novel formulation of resveratrol, JOTROL, for delivery using Catalent’s R.P. Scherer softgel technology. Under the agreement, Catalent will assess different softgel delivery technologies for JOTROL to determine the optimum oral dosage form, before going on to manufacture doses for human PK studies and Phase II clinical studies.
JOTROL, which is being developed to remedy resveratrol’s poor bioavailability and dose limiting gastrointestinal side effects, is being studied in multiple pre-clinical and clinical trial programs in progress for the treatment of rare diseases linked to single gene deficiencies. These include Friedreich’s Ataxia and Mucopolysaccharide (MPS) diseases, as well as partner programs for treatments in pancreatic cancer, Machado-Joseph and Alzheimer’s disease.

Impact of cerebellar atrophy on cortical gray matter and cerebellar peduncles as assessed by voxel-based morphometry and high angular resolution diffusion imaging

Dayan M., Olivito G., Molinari M., Cercignani M., Bozzali M., Leggio M.,Functional Neurology 2016; 31(3)

Structural and dMRI data of seven patients with cerebellar atrophy (2 with spinocerebellar atrophy type 2, 1 with Friedreich’s ataxia, 4 with idiopathic cerebellar ataxia) and no visible cortical lesions or cortical atrophy were investigated with Freesurfer and voxel-based morphometry (VBM) of gray matter (GM) as well as MCP and SCP FA maps. The significant difference in the MCP and SCP dMRI metrics between patients and controls as well as the significant correlation with ataxia total score and subscores support the use of dMRI metrics as an imaging biomarker for cerebellar degeneration and ataxia.

A new case of complete primary cerebellar agenesis: clinical and imaging findings in a living patient

Feng Yu, Qing-jun Jiang, Xi-yan Sun, Rong-wei Zhang; Brain, Volume 138, Issue 6, 1 June 2015 DOI:10.1093/brain/awu239

DON’T mind the gap. A woman has reached the age of 24 without anyone realising she was missing a large part of her brain. The case highlights just how adaptable the organ is. Woman of 24 found to have no cerebellum in her brain, however, in this woman, the missing cerebellum resulted in only mild to moderate motor deficiency, and mild speech problems such as slightly slurred pronunciation. Her doctors describe these effects as “less than would be expected”, and say her case highlights the remarkable plasticity of the brain.

Cerebellar agenesis is an extremely rare condition implying complete absence of the cerebellum.

Otoneurological Abnormalities in Patients with Friedreich's Ataxia

Zeigelboim BS, Mesti JC, Fonseca VR, Faryniuk JH, Marques JM, Cardoso RC, Teive HA. Int Arch Otorhinolaryngol. 2017 Jan;21(1):79-85. doi: 10.1055/s-0036-1572529.

The most prevalent otoneurological symptoms were incoordination of movement, gait imbalance, and dizziness. Alterations in the vestibular examination occurred in 90% of patients, located mainly in the caloric test, with a predominance of deficient central vestibular system dysfunction.

The study emphasizes the importance of the vestibular evaluation for the topographic diagnosis of neurodegenerative diseases since, in most cases, the otoneurological symptoms present early and such information may aid in the choice of procedures to be performed in clinical and therapeutic monitoring.

Synthetic genome readers target clustered binding sites across diverse chromatin states

Graham S. Erwin, Matthew P. Grieshop, Devesh Bhimsaria, Truman J. Do, José A. Rodríguez-Martínez, Charu Mehta, Kanika Khanna, Scott A. Swanson, Ron Stewart, James A. Thomson, Parameswaran Ramanathan, and Aseem Z. Ansari; PNAS 2016 113 (47) E7418-E7427; published ahead of print November 8, 2016, doi: 10.1073/pnas.1604847113

The linear polyamide (3) studied here was designed to bind to GAA repeats in the first intron of frataxin, a locus that appears to be situated within heterochromatin marked by H3K9me3. Taken together, the ability of polyamides to access heterochromatin (a major barrier to binding to natural and artificial DNA-binding factors) opens unique opportunities to deploy this class of synthetic genome readers to regulate gene networks that direct cellular fate and function. Linear 3, designed to target 5′-AAGAAGAAG-3′, is designed to target a GAA repeat expansion found in patients with Friedreich’s ataxia to alleviate transcriptional repression.
The COSMIC-seq approach that we describe here is a robust and broadly applicable method that can be readily extended to map the genome-wide binding properties of other classes of DNAbinding molecules, including several genome-directed therapeutics. COSMIC-seq will be instrumental in the genome-guided design of molecules that serve as precision-targeted therapeutics.

A wearable proprioceptive stabilizer for rehabilitation of limb and gait ataxia in hereditary cerebellar ataxias: a pilot open-labeled study

Luca Leonardi, Maria Gabriella Aceto, Christian Marcotulli, Giuseppe Arcuria, Mariano Serrao, Francesco Pierelli, Paolo Paone, Alessandro Filla, Alessandro Roca, Carlo Casali. Neurol Sci (2016). First Online: 31 December 2016 doi:10.1007/s10072-016-2800-x

The aim of this pilot study is to test the feasibility and effectiveness of a wearable proprioceptive stabilizer that emits focal mechanical vibrations in patients affected by hereditary cerebellar ataxias. This small open-labeled study shows preliminary evidence that focal mechanical vibration exerted by a wearable proprioceptive stabilizer might improve limb and gait ataxia in patients affected by hereditary cerebellar ataxias.

CN Project OPUS10: “Role of microRNAs in regulation iron metabolism in Friedreich's ataxia”

biotechnologia.pl; Prof. Włodzimierz Krzyżosiak, Institute of Bioorganic Chemistry PAS, Polish Academy of Sciences.(2017-01-02)

The goals of this project are to define changes in the expression and activity of microRNAs in FRDA, and analyze how these abnormalities affect the activity of genes which are responsible for the localization and amount of iron in neuronal and heart cells of patients with Friedreich’s ataxia. We will define relationship between miRNA molecules and iron availability. We will also uncover the pattern of detectable microRNA molecules that is specific to FRDA.

Percutaneous needle tenotomy for the treatment of muscle and tendon contractures in adults with brain damage: results and complications

Flavia Coroian, Claire Jourdan, Jérome Froger, Claire Anquetil, Olivier Choquet, Bertand Coulet, Isabelle Laffont, Archives of Physical Medicine and Rehabilitation, Available online 18 December 2016, ISSN 0003-9993, doi:10.1016/j.apmr.2016.11.014.

In our series, percutaneous needle tenotomy procedures under local or locoregional anesthesia were performed by a PM&R physician trained by an orthopedic surgeon and yielded very few complications. This technique seems relevant for contractures of several superficial tendons for the upper and lower limb alike. Furthermore, this technique gives a satisfactory orthopedic outcome fulfilling non-functional objectives (hygiene, pain, nursing) and even functional ones for a small number of well-selected patients (gait, grip, daily life).
PNT yields good results in the management of superficial muscle and tendon contractures in selected brain-damaged patients. The complications rate is very low and this treatment can be an alternative to conventional surgery in frail neurological patients.

Gene therapy: Gene-editing therapy for neurological disease

Moira A. McMahon & Don W. Cleveland. Nature Reviews Neurology 13, 7–9 (2017) doi:10.1038/nrneurol.2016.190 Published online 16 December 2016.

Guide RNA-mediated CRISPR–Cas nucleases are a powerful technology for the engineering of mammalian genomes. CRISPR–Cas9-dependent editing of mutated genes that cause Huntington disease and fragile X syndrome was recently achieved in cell-based models, heralding the first step towards developing this technology into viable therapeutics for neurological diseases.
The successful translation of these proof‑of‑principle studies to in vivo gene editing is eagerly anticipated, but several challenges remain. One major challenge is delivery of the sgRNA and nuclease to target cells. A final major challenge for extension of gene-editing approaches to applications within the nervous system is the efficiency of gene silencing or correction: can the changes be made in sufficient numbers of cells to alter the disease course?.
What seems certain is that continued development of genome-editing technology to target neurological diseases is likely to provide a greater understanding of the diseases themselves and, hopefully, will one day form the basis of a successful therapy.