scholarly journals Current progress in the therapeutic options for mitochondrial disorders.

2020 ◽  
pp. 967-994
Author(s):  
E Koňaříková ◽  
A Marković ◽  
Z Korandová ◽  
J Houštěk ◽  
T Mráček
Keyword(s):  
Energy Production ◽  
Treatment Options ◽  
Mitochondrial Diseases ◽  
Mitochondrial Disorders ◽  
Symptomatic Therapy ◽  
Therapeutic Approaches ◽  
Preclinical Research ◽  
Respiratory Chain Activity ◽  
The Moment ◽  
Generation Sequencing

Mitochondrial disorders manifest enormous genetic and clinical heterogeneity - they can appear at any age, present with various phenotypes affecting any organ, and display any mode of inheritance. What mitochondrial diseases do have in common, is impairment of respiratory chain activity, which is responsible for more than 90% of energy production within cells. While diagnostics of mitochondrial disorders has been accelerated by introducing Next-Generation Sequencing techniques in recent years, the treatment options are still very limited. For many patients only a supportive or symptomatic therapy is available at the moment. However, decades of basic and preclinical research have uncovered potential target points and numerous compounds or interventions are now subjects of clinical trials. In this review, we focus on current and emerging therapeutic approaches towards the treatment of mitochondrial disorders. We focus on small compounds, metabolic interference, such as endurance training or ketogenic diet and also on genomic approaches.

scholarly journals Nitric Oxide Deficiency in Mitochondrial Disorders: The Utility of Arginine and Citrulline

2021 ◽  
Vol 14 ◽  
Author(s):  
Mohammed Almannai ◽  
Ayman W. El-Hattab
Keyword(s):  
Nitric Oxide ◽  
Treatment Options ◽  
Mitochondrial Diseases ◽  
Symptomatic Improvement ◽  
Mitochondrial Disorders ◽  
Treatment Modalities ◽  
Acute Administration ◽  
Randomized Controlled Studies ◽  
Number Of Patients ◽  
Nitric Oxide Deficiency

Mitochondrial diseases represent a growing list of clinically heterogeneous disorders that are associated with dysfunctional mitochondria and multisystemic manifestations. In spite of a better understanding of the underlying pathophysiological basis of mitochondrial disorders, treatment options remain limited. Over the past two decades, there is growing evidence that patients with mitochondrial disorders have nitric oxide (NO) deficiency due to the limited availability of NO substrates, arginine and citrulline; decreased activity of nitric oxide synthase (NOS); and NO sequestration. Studies evaluating the use of arginine in patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) presenting with stroke-like episodes showed symptomatic improvement after acute administration as well as a reduction in the frequency and severity of stroke-like episodes following chronic use. Citrulline, another NO precursor, was shown through stable isotope studies to result in a greater increase in NO synthesis. Recent studies showed a positive response of arginine and citrulline in other mitochondrial disorders besides MELAS. Randomized-controlled studies with a larger number of patients are warranted to better understand the role of NO deficiency in mitochondrial disorders and the efficacy of NO precursors as treatment modalities in these disorders.

Mitochondrial disorders in the Arab Middle East population: the impact of next generation sequencing on the genetic diagnosis.

2019 ◽  
pp. 54-64
Author(s):  
Ahmad Alahmad ◽  
Hebatallah Muhammad ◽  
Angela Pyle ◽  
Buthaina Albash ◽  
Robert McFarland ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Middle East ◽  
Genetic Diagnosis ◽  
Mitochondrial Disorders ◽  
Next Generation ◽  
The Impact ◽  
Generation Sequencing ◽  
Arab Middle East

scholarly journals Neuronal Dopamine D3 Receptors: Translational Implications for Preclinical Research and CNS Disorders

Biomolecules ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 104
Author(s):  
Béla Kiss ◽  
István Laszlovszky ◽  
Balázs Krámos ◽  
András Visegrády ◽  
Amrita Bobok ◽  
...  
Keyword(s):  
Emotional Regulation ◽  
Drug Research ◽  
Treatment Options ◽  
Movement Control ◽  
Preclinical Research ◽  
High Affinity ◽  
Partial Agonists ◽  
Promising Target ◽  
The Status ◽  
Dopamine D3

Dopamine (DA), as one of the major neurotransmitters in the central nervous system (CNS) and periphery, exerts its actions through five types of receptors which belong to two major subfamilies such as D1-like (i.e., D1 and D5 receptors) and D2-like (i.e., D2, D3 and D4) receptors. Dopamine D3 receptor (D3R) was cloned 30 years ago, and its distribution in the CNS and in the periphery, molecular structure, cellular signaling mechanisms have been largely explored. Involvement of D3Rs has been recognized in several CNS functions such as movement control, cognition, learning, reward, emotional regulation and social behavior. D3Rs have become a promising target of drug research and great efforts have been made to obtain high affinity ligands (selective agonists, partial agonists and antagonists) in order to elucidate D3R functions. There has been a strong drive behind the efforts to find drug-like compounds with high affinity and selectivity and various functionality for D3Rs in the hope that they would have potential treatment options in CNS diseases such as schizophrenia, drug abuse, Parkinson’s disease, depression, and restless leg syndrome. In this review, we provide an overview and update of the major aspects of research related to D3Rs: distribution in the CNS and periphery, signaling and molecular properties, the status of ligands available for D3R research (agonists, antagonists and partial agonists), behavioral functions of D3Rs, the role in neural networks, and we provide a summary on how the D3R-related drug research has been translated to human therapy.

scholarly journals Mitochondrial Syndromes Revisited

2021 ◽  
Vol 10 (6) ◽  
pp. 1249
Author(s):  
Daniele Orsucci ◽  
Elena Caldarazzo Ienco ◽  
Andrea Rossi ◽  
Gabriele Siciliano ◽  
Michelangelo Mancuso
Keyword(s):  
Clinical Trials ◽  
Genetic Basis ◽  
Phenotypic Variability ◽  
Mitochondrial Diseases ◽  
Genetic Alterations ◽  
Mitochondrial Disorders ◽  
Single Mutation ◽  
Multicenter Studies ◽  
Future Studies ◽  
Clinical Syndromes

In the last ten years, the knowledge of the genetic basis of mitochondrial diseases has significantly advanced. However, the vast phenotypic variability linked to mitochondrial disorders and the peculiar characteristics of their genetics make mitochondrial disorders a complex group of disorders. Although specific genetic alterations have been associated with some syndromic presentations, the genotype–phenotype relationship in mitochondrial disorders is complex (a single mutation can cause several clinical syndromes, while different genetic alterations can cause similar phenotypes). This review will revisit the most common syndromic pictures of mitochondrial disorders, from a clinical rather than a molecular perspective. We believe that the new phenotype definitions implemented by recent large multicenter studies, and revised here, may contribute to a more homogeneous patient categorization, which will be useful in future studies on natural history and clinical trials.

scholarly journals Epilepsy in Mitochondrial Diseases—Current State of Knowledge on Aetiology and Treatment

Children ◽  
2021 ◽  
Vol 8 (7) ◽  
pp. 532
Author(s):  
Dorota Wesół-Kucharska ◽  
Dariusz Rokicki ◽  
Aleksandra Jezela-Stanek
Keyword(s):  
Oxidative Phosphorylation ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Disease ◽  
Clinical Picture ◽  
Poor Prognosis ◽  
Treatment Options ◽  
Mitochondrial Diseases ◽  
Energy Deficit ◽  
Atp Production ◽  
Current State

Mitochondrial diseases are a heterogeneous group of diseases resulting from energy deficit and reduced adenosine triphosphate (ATP) production due to impaired oxidative phosphorylation. The manifestation of mitochondrial disease is usually multi-organ. Epilepsy is one of the most common manifestations of diseases resulting from mitochondrial dysfunction, especially in children. The onset of epilepsy is associated with poor prognosis, while its treatment is very challenging, which further adversely affects the course of these disorders. Fortunately, our knowledge of mitochondrial diseases is still growing, which gives hope for patients to improve their condition in the future. The paper presents the pathophysiology, clinical picture and treatment options for epilepsy in patients with mitochondrial disease.

Understanding relevant immune mechanisms in gastrointestinal oncology

2021 ◽  
pp. 107815522199286
Author(s):  
Bulent Cetin ◽  
Ozge Gumusay
Keyword(s):  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Checkpoint Inhibition ◽  
Immune Checkpoint Inhibition ◽  
Gastrointestinal Cancers ◽  
Therapeutic Approaches ◽  
Cancer Treatments ◽  
Multiple Treatment ◽  
Gi Cancers ◽  
The Many

Rapid and successful drug development has resulted in multiple treatment options for gastrointestinal cancer, requiring careful decision making for individual patients. The general theme in modern immunology is that the field is moving beyond establishing the fundamental principles of immune response mechanisms to applying these propositions to understand human diseases and develop new therapies. Immunotherapy has contributed enormously to cancer treatments with a virtual explosion in novel therapeutics including checkpoint inhibitors and other recently developed immunomodulators and the development of novel therapeutic approaches. Although the majority of gastrointestinal (GI) cancers are generally considered poorly immunogenic, clinical trials have revealed that some of the patients with various gastrointestinal cancers are highly responsive to immune checkpoint inhibition-based therapies. We paid special attention to the clinical relevance of immunology and emphasized how newly developed therapies work, including what their strengths and pitfalls are. This review aims to enhance the interest of practitioners in the many specialties and subspecialties that the discipline influences and to assist them in understanding this increasing complexity.

Educational Session: Managing Chronic Myeloid Leukemia as a Chronic Disease

Hematology ◽  
2011 ◽  
Vol 2011 (1) ◽  
pp. 128-135 ◽  
Author(s):  
Andreas Hochhaus
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Blast Crisis ◽  
Treatment Options ◽  
Age Groups ◽  
Continuous Treatment ◽  
Symptomatic Therapy ◽  
Therapeutic Success

Abstract Elucidation of the pathogenesis of chronic myeloid leukemia (CML) and the introduction of tyrosine kinase inhibitors (TKIs) has transformed this disease from being invariably fatal to being the type of leukemia with the best prognosis. Median survival associated with CML is estimated at > 20 years. Nevertheless, blast crisis occurs at an incidence of 1%-2% per year, and once this has occurred, treatment options are limited and survival is short. Due to the overall therapeutic success, the prevalence of CML is gradually increasing. The optimal management of this disease includes access to modern therapies and standardized surveillance methods for all patients, which will certainly create challenges. Furthermore, all available TKIs show mild but frequent side effects that may require symptomatic therapy. Adherence to therapy is the key prerequisite for efficacy of the drugs and for long-term success. Comprehensive information on the nature of the disease and the need for the continuous treatment using the appropriate dosages and timely information on efficacy data are key factors for optimal compliance. Standardized laboratory methods are required to provide optimal surveillance according to current recommendations. CML occurs in all age groups. Despite a median age of 55-60 years, particular challenges are the management of the disease in children, young women with the wish to get pregnant, and older patients. The main challenges in the long-term management of CML patients are discussed in this review.

Risk factors of postthrombotic syndrome before and after deep venous thrombosis treatment

2016 ◽  
Vol 32 (6) ◽  
pp. 384-389 ◽  
Author(s):  
Rob HW Strijkers ◽  
Mark AF de Wolf ◽  
Cees HA Wittens
Keyword(s):  
Risk Factors ◽  
Venous Thrombosis ◽  
Deep Venous Thrombosis ◽  
Treatment Options ◽  
Postthrombotic Syndrome ◽  
Factor X ◽  
Catheter Directed Thrombolysis ◽  
Before And After ◽  
Patient Selection Criteria ◽  
The Moment

Postthrombotic syndrome is the most common complication after deep venous thrombosis. Postthrombotic syndrome is a debilitating disease and associated with decreased quality of life and high healthcare costs. Postthrombotic syndrome is a chronic disease, and causative treatment options are limited. Prevention of postthrombotic syndrome is therefore very important. Not all patients develop postthrombotic syndrome. Risk factors have been identified to try to predict the risk of developing postthrombotic syndrome. Age, gender, and recurrent deep venous thrombosis are factors that cannot be changed. Deep venous thrombosis location and extent seem to predict severity of postthrombotic syndrome and are potentially suitable as patient selection criteria. Residual thrombosis and reflux are known to increase the incidence of postthrombotic syndrome, but are of limited use. More recently developed treatment options for deep venous thrombosis, such as new oral factor X inhibitors and catheter-directed thrombolysis, are available at the moment. Catheter-directed thrombolysis shows promising results in reducing the incidence of postthrombotic syndrome after deep venous thrombosis. The role of new oral factor X inhibitors in preventing postthrombotic syndrome is still to be determined.

PCR-based targeted enrichment and next-generation sequencing of 101 nuclear genes for the diagnosis of mitochondrial disorders

Mitochondrion ◽  
2012 ◽  
Vol 12 (5) ◽  
pp. 589
Author(s):  
Renkui Bai ◽  
Jaimie Higgs ◽  
Sharon Suchy ◽  
Federica Gibellini ◽  
Melanie Knight ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Mitochondrial Disorders ◽  
Nuclear Genes ◽  
Next Generation ◽  
Generation Sequencing ◽  
Targeted Enrichment

A novel mitochondrial m.14430A>G (MT-ND6, p.W82R) variant causes complex I deficiency and mitochondrial Leigh syndrome

2020 ◽  
Vol 58 (11) ◽  
pp. 1809-1817
Author(s):  
Miaomiao Du ◽  
Xiujuan Wei ◽  
Pu Xu ◽  
Anran Xie ◽  
Xiyue Zhou ◽  
...  
Keyword(s):  
Mitochondrial Respiration ◽  
Complex I ◽  
Clinical Symptoms ◽  
Lactate Production ◽  
Mitochondrial Diseases ◽  
Leigh Syndrome ◽  
Extracellular Lactate ◽  
Next Generation Sequencing Ngs ◽  
Mutant Cells ◽  
Generation Sequencing

AbstractObjectivesLeigh syndrome (LS) is one of the most common mitochondrial diseases and has variable clinical symptoms. However, the genetic variant spectrum of this disease is incomplete.MethodsNext-generation sequencing (NGS) was used to identify the m.14430A > G (p.W82R) variant in a patient with LS. The pathogenesis of this novel complex I (CI) variant was verified by determining the mitochondrial respiration, assembly of CI, ATP, MMP and lactate production, and cell growth rate in cybrids with and without this variant.ResultsA novel m.14430A > G (p.W82R) variant in the NADH dehydrogenase 6 (ND6) gene was identified in the patient; the mutant loads of m.14430A > G (p.W82R) in the patient were much higher than those in his mother. Although the transmitochondrial cybrid-based study showed that mitochondrial CI assembly remains unaffected in cells with the m.14430G variant, control cells had significantly higher endogenous and CI-dependent mitochondrial respiration than mutant cells. Accordingly, mutant cells had a lower ATP, MMP and higher extracellular lactate production than control cells. Notably, mutant cells had impaired growth in a galactose-containing medium when compared to wild-type cells.ConclusionsA novel m.14430A > G (p.W82R) variant in the ND6 gene was identified from a patient suspected to have LS, and this variant impaired mitochondrial respiration by decreasing the activity of mitochondrial CI.

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