scholarly journals Emerging Therapies for Charcot-Marie-Tooth Inherited Neuropathies

2021 ◽  
Vol 22 (11) ◽  
pp. 6048
Author(s):  
Marina Stavrou ◽  
Irene Sargiannidou ◽  
Elena Georgiou ◽  
Alexia Kagiava ◽  
Kleopas A. Kleopa
Keyword(s):  
Molecular Genetic ◽  
Gene Replacement ◽  
Treatment Approaches ◽  
Charcot Marie Tooth ◽  
Novel Treatments ◽  
Wide Range ◽  
Genetic Mechanisms ◽  
Successful Testing ◽  
Novel Biomarkers ◽  
Inherited Neuropathies

Inherited neuropathies known as Charcot-Marie-Tooth (CMT) disease are genetically heterogeneous disorders affecting the peripheral nerves, causing significant and slowly progressive disability over the lifespan. The discovery of their diverse molecular genetic mechanisms over the past three decades has provided the basis for developing a wide range of therapeutics, leading to an exciting era of finding treatments for this, until now, incurable group of diseases. Many treatment approaches, including gene silencing and gene replacement therapies, as well as small molecule treatments are currently in preclinical testing while several have also reached clinical trial stage. Some of the treatment approaches are disease-specific targeted to the unique disease mechanism of each CMT form, while other therapeutics target common pathways shared by several or all CMT types. As promising treatments reach the stage of clinical translation, optimal outcome measures, novel biomarkers and appropriate trial designs are crucial in order to facilitate successful testing and validation of novel treatments for CMT patients.

scholarly journals PROGRESS IN CLINICAL NEUROSCIENCES: Charcot-Marie-Tooth Disease and Related Inherited Peripheral Neuropathies

2001 ◽  
Vol 28 (3) ◽  
pp. 199-214 ◽  
Author(s):  
Timothy J. Benstead ◽  
Ian A. Grant
Keyword(s):  
Molecular Genetic ◽  
Charcot Marie Tooth ◽  
Hereditary Motor ◽  
Charcot Marie Tooth Disease ◽  
Inherited Neuropathy ◽  
Molecular Aspects ◽  
The Many ◽  
Inherited Neuropathies ◽  
Tooth Disease

The classification of Charcot-Marie-Tooth disease and related hereditary motor and sensory neuropathies has evolved to incorporate clinical, electrophysiological and burgeoning molecular genetic information that characterize the many disorders. For several inherited neuropathies, the gene product abnormality is known and for others, candidate genes have been identified. Genetic testing can pinpoint a specific inherited neuropathy for many patients. However, clinical and electrophysiological assessments continue to be essential tools for diagnosis and management of this disease group. This article reviews clinical, electrophysiological, pathological and molecular aspects of hereditary motor and sensory neuropathies.

Recent Updates in the Alzheimer’s Disease Etiopathology and Possible Treatment Approaches: A Narrative Review of Current Clinical Trials

2020 ◽  
Vol 13 (4) ◽  
pp. 273-294 ◽  
Author(s):  
Elahe Zarini-Gakiye ◽  
Javad Amini ◽  
Nima Sanadgol ◽  
Gholamhassan Vaezi ◽  
Kazem Parivar
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Small Molecules ◽  
Clinical Trial Design ◽  
Treatment Approaches ◽  
Drug Candidates ◽  
Novel Treatments ◽  
Approved Drugs ◽  
Tau Aggregation

Background: Alzheimer’s disease (AD) is the most frequent subtype of incurable neurodegenerative dementias and its etiopathology is still not clearly elucidated. Objective: Outline the ongoing clinical trials (CTs) in the field of AD, in order to find novel master regulators. Methods: We strictly reviewed all scientific reports from Clinicaltrials.gov and PubMed databases from January 2010 to January 2019. The search terms were “Alzheimer's disease” or “dementia” and “medicine” or “drug” or “treatment” and “clinical trials” and “interventions”. Manuscripts that met the objective of this study were included for further evaluations. Results: Drug candidates have been categorized into two main groups including antibodies, peptides or hormones (such as Ponezumab, Interferon β-1a, Solanezumab, Filgrastim, Levemir, Apidra, and Estrogen), and naturally-derived ingredients or small molecules (such as Paracetamol, Ginkgo, Escitalopram, Simvastatin, Cilostazo, and Ritalin-SR). The majority of natural candidates acted as anti-inflammatory or/and anti-oxidant and antibodies exert their actions via increasing amyloid-beta (Aβ) clearance or decreasing Tau aggregation. Among small molecules, most of them that are present in the last phases act as specific antagonists (Suvorexant, Idalopirdine, Intepirdine, Trazodone, Carvedilol, and Risperidone) or agonists (Dextromethorphan, Resveratrol, Brexpiprazole) and frequently ameliorate cognitive dysfunctions. Conclusion: The presences of a small number of candidates in the last phase suggest that a large number of candidates have had an undesirable side effect or were unable to pass essential eligibility for future phases. Among successful treatment approaches, clearance of Aβ, recovery of cognitive deficits, and control of acute neuroinflammation are widely chosen. It is predicted that some FDA-approved drugs, such as Paracetamol, Risperidone, Escitalopram, Simvastatin, Cilostazoand, and Ritalin-SR, could also be used in off-label ways for AD. This review improves our ability to recognize novel treatments for AD and suggests approaches for the clinical trial design for this devastating disease in the near future.

Epigenetics and Applied Anthropology

2021 ◽  
Author(s):  
Charles H. Klein
Keyword(s):  
Social Inequalities ◽  
Homo Sapiens ◽  
Single Gene ◽  
Molecular Genetic ◽  
Healthcare Providers ◽  
Basic Research ◽  
Sufficient Information ◽  
Theoretical Frameworks ◽  
Noncoding Dna ◽  
Wide Range

Since Francis Crick and James D. Watson’s discovery of DNA in 1953, researchers, policymakers, and the general public have sought to understand the ways in which genetics shapes human lives. A milestone in these efforts was the completion of the Human Genome Project’s (HGP) sequencing of Homo sapiens’ nearly three million base pairs in 2003. Yet, despite the excitement surrounding the HGP and the discovery of the structural genetic underpinnings of several debilitating diseases, the vast majority of human health outcomes have not been linked to a single gene. Moreover, even when genes have been associated with particular diseases (e.g., breast and colon cancer), it is not well understood why certain genetically predisposed individuals become ill and others do not. Nor has the HGP’s map provided sufficient information to understand the actual functioning of the human genetic code, including the role of noncoding DNA (“junk DNA”) in regulating molecular genetic processes. In response, a growing number of scientists have shifted their attention from structural genetics to epigenetics, the study of how genes express themselves in particular situations and environments. Anthropologists play roles in these applications of epigenetics to real-world settings. Their new theoretical frameworks unsettle the nature-versus-nurture binary and support biocultural anthropological research demonstrating how race becomes biology and embodies social inequalities and health disparities across generations. Ethnographically grounded case studies further highlight the diverse epigenetic logics held by healthcare providers, researchers, and patient communities and how these translations of scientific knowledge shape medical practice and basic research. The growing field of environmental epigenetics also offers a wide range of options for students and practitioners interested in applying the anthropological toolkit in epigenetics-related work.

scholarly journals A murine model of Charcot-Marie-Tooth disease 4F reveals a role for the C-terminus of periaxin in the formation and stabilization of Cajal bands

2018 ◽  
Vol 3 ◽  
pp. 20 ◽  
Author(s):  
Diane L. Sherman ◽  
Peter J. Brophy
Keyword(s):  
Plasma Membrane ◽  
Schwann Cell ◽  
Laminin Receptor ◽  
Cell Plasma Membrane ◽  
Charcot Marie Tooth ◽  
Charcot Marie Tooth Disease ◽  
C Terminus ◽  
Cell Plasma ◽  
Inherited Neuropathies ◽  
Tooth Disease

Charcot-Marie-Tooth (CMT) disease comprises up to 80 monogenic inherited neuropathies of the peripheral nervous system (PNS) that collectively result in demyelination and axon degeneration. The majority of CMT disease is primarily either dysmyelinating or demyelinating in which mutations affect the ability of Schwann cells to either assemble or stabilize peripheral nerve myelin. CMT4F is a recessive demyelinating form of the disease caused by mutations in the Periaxin (PRX) gene. Periaxin (Prx) interacts with Dystrophin Related Protein 2 (Drp2) in an adhesion complex with the laminin receptor Dystroglycan (Dag). In mice the Prx/Drp2/Dag complex assembles adhesive domains at the interface between the abaxonal surface of the myelin sheath and the cytoplasmic surface of the Schwann cell plasma membrane. Assembly of these appositions causes the formation of cytoplasmic channels called Cajal bands beneath the surface of the Schwann cell plasma membrane. Loss of either Periaxin or Drp2 disrupts the appositions and causes CMT in both mouse and man. In a mouse model of CMT4F, complete loss of Periaxin first prevents normal Schwann cell elongation resulting in abnormally short internodal distances which can reduce nerve conduction velocity, and subsequently precipitates demyelination. Distinct functional domains responsible for Periaxin homodimerization and interaction with Drp2 to form the Prx/Drp2/Dag complex have been identified at the N-terminus of Periaxin. However, CMT4F can also be caused by a mutation that results in the truncation of Periaxin at the extreme C-terminus with the loss of 391 amino acids. By modelling this in mice, we show that loss of the C-terminus of Periaxin results in a surprising reduction in Drp2. This would be predicted to cause the observed instability of both appositions and myelin, and contribute significantly to the clinical phenotype in CMT4F.

scholarly journals Application of the real-time PCR in veterinary practice

2020 ◽  
Vol 2020 (2) ◽  
pp. 5-12
Author(s):  
Maksim Doronin ◽  
Dmitriy Lozovoy ◽  
Aleksey Scherbakov ◽  
Vladimir Makarov
Keyword(s):  
Infectious Diseases ◽  
Real Time ◽  
Quantitative Pcr ◽  
Biological Material ◽  
Molecular Genetic ◽  
The Body ◽  
Suspected Infection ◽  
Virus Content ◽  
Wide Range ◽  
Pathogenic Agents

To date the molecular genetic methods of analysis are widely used for laboratory diagnostic tests in various infectious diseases of animals. This discourse reflects information about the history of the invention of real-time polymerase chain reaction (PCR-RV), the nature of the processes that occur during this reaction, the main stages of the reaction, the preparation of biological material for research in PCR-RV. The spectrum of possibilities of using the PCR-RV method for a qualitative study of biological material in cases of suspected infection of animals with certain viral and bacterial agents, as well as a quantitative assessment of the virus content in tissues, organs or in the body by analogy with conventional methods for titrating infectiousness without direct manipulation with pathogenic agents, is presented. . A quantitative PCR-RV option allows veterinarians to evaluate the pathogenetic dynamics of the development of the disease, monitor the effect of antiviral and antibacterial therapy, and monitor the emergence of pathogen variants with high resistance to the drugs used. Thanks to the development of ARRIAH, the qualitative and quantitative PCR-RV method can now be used in domestic veterinary science and laboratory practice for the diagnosis of a wide range of animal infectious diseases.

scholarly journals The issue of nosocomial infection caused by Klebsiella pneumoniae blaNDM-type

2020 ◽  
Vol 15 (2) ◽  
pp. 124-133
Author(s):  
Olga Mironenko ◽  
◽  
Victoria Selnitseva ◽  
Lidia Soprun ◽  
Elena Shmushkevich ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Nosocomial Infection ◽  
Molecular Genetic ◽  
Mechanisms Of Resistance ◽  
Infectious Process ◽  
Saint Petersburg ◽  
Microbiological Study ◽  
Wide Range ◽  
Almost All ◽  
Emergence Of Resistance

The article presents information about circulating isolates Klebsiella pneumoniae in a hospital megapolis with properties of hypervirulence and simultaneous multiresistance. The resulting K. pneumonia isolates are of particular importance due to the emergence of resistance to almost all β-lactams due to the presence of carbapenemase metal-β-lactamase. Furthermore, the isolated strains producing carbapenemases possess mechanisms of resistance to a wide range of antimicrobial preparations, and the types of infectious process caused by carbapenemazo-producing enterobacteries are characterized by a high lethality level. Microbiological, biochemical, biophysical, molecular-genetic, biological, bioinformational and statistical methods of research were used in the work. A prospective method was used to identify the source of the infections. In the first stage, a microbiological study was carried out on biomaterials obtained from patients treated in a hospital in Saint Petersburg. After a microbiological study, 52 isolates of K. pneumoniae were obtained, 53.8 % of isolates had a hypermucoid phenotype and 98 % had carbapenemases:blaNDM type — 49 (92 %), blaNDM+OXA-48-like — 3 (8 %). Isolates with two new phenotypes have been isolated (no. 2511 and no. 2512). Isolates of no. 2512 LD50 had 10*2 BAC/ml, and plasmids such as Incfib(Mar), Inchi1b, and Incr were also found, with Incr-A plasmid emitted encoding resistance to fluoroquinolone: aac(6’)-Ib-cr and to β-lactam antibiotics: blaTEM-1B. The described data confirm the opinions of the researchers about the possible formation of a new “super pathogen” — instantaneously hypervirulent and plural resistant strain of K. pneumoniae.

scholarly journals Analysis of the mutational spectrum of the SLC26A4 gene and its contribution to the etiology of inherited hearing loss in the indigenous population of Southern Siberia

2020 ◽  
pp. 43-45
Author(s):  
В.Ю. Данильченко ◽  
М.В. Зыцарь ◽  
Е.А. Маслова ◽  
М.С. Бады-Хоо ◽  
И.В. Морозов ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Molecular Genetic ◽  
Molecular Genetic Analysis ◽  
Unknown Etiology ◽  
Southern Siberia ◽  
Pathogenic Variants ◽  
Slc26a4 Gene ◽  
Wide Range ◽  
Polymorphic Variants ◽  
Tyva Republic

Мутации в гене SLC26A4 являются частой причиной потери слуха во многих регионах мира. В работе приводятся результаты молекулярно-генетического анализа (с использованием секвенирования по Сэнгеру) последовательности гена SLC26A4, впервые проведенного в выборке пациентов с потерей слуха неустановленной этиологии (n=232) из Республик Тыва и Алтай. Установлены контрастные различия патогенетического вклада мутаций в гене SLC26A4 в этиологию нарушения слуха у коренных жителей этих географически близких регионов: 28,2% - для тувинцев и 4,3% - для алтайцев. Выявлены как уже известные, так и новые патогенные варианты, а также широкий спектр полиморфных вариантов гена SLC26A4. Mutations in the SLC26A4 gene are a common cause of hearing loss in many regions of the world. This paper presents the results of molecular genetic analysis (by Sanger sequencing) of the SLC26A4 sequence, first performed in the sample of patients with hearing loss of unknown etiology (n=232) from the Tyva Republic and the Altai Republic. Contrast differences of the pathogenic contribution of SLC26A4 mutations to the etiology of hearing impairment were revealed in the indigenous peoples of these geographically close regions: 28.2% for Tuvinians and 4.3% for Altaians. Both known and novel pathogenic variants as well as a wide range of polymorphic variants were found in the SLC26A4 gene sequence.

Sign in / Sign up

Export Citation Format

Share Document