scholarly journals Charcot-Marie-Tooth: From Molecules to Therapy

2019 ◽  
Vol 20 (14) ◽  
pp. 3419 ◽  
Author(s):  
Jonathan Morena ◽  
Anirudh Gupta ◽  
J. Chad Hoyle
Keyword(s):  
Diagnostic Yield ◽  
Treatment Options ◽  
Research Attention ◽  
Charcot Marie Tooth ◽  
Inherited Neuropathy ◽  
Clinical Background ◽  
Disease Modifying ◽  
Therapeutic Research ◽  
Next Generation Sequencing Ngs ◽  
Disease Modifying Treatment

Charcot-Marie-Tooth (CMT) is the most prevalent category of inherited neuropathy. The most common inheritance pattern is autosomal dominant, though there also are X-linked and autosomal recessive subtypes. In addition to a variety of inheritance patterns, there are a myriad of genes associated with CMT, reflecting the heterogeneity of this disorder. Next generation sequencing (NGS) has expanded and simplified the diagnostic yield of genes/molecules underlying and/or associated with CMT, which is of paramount importance in providing a substrate for current and future targeted disease-modifying treatment options. Considerable research attention for disease-modifying therapy has been geared towards the most commonly encountered genetic mutations (PMP22, GJB1, MPZ, and MFN2). In this review, we highlight the clinical background, molecular understanding, and therapeutic investigations of these CMT subtypes, while also discussing therapeutic research pertinent to the remaining less common CMT subtypes.

scholarly journals Tocilizumab Treatment of Patients with Systemic Sclerosis: Clinical Data

2017 ◽  
Vol 2 (2_suppl) ◽  
pp. S29-S35 ◽  
Author(s):  
Dinesh Khanna ◽  
Angelika Jahreis ◽  
Daniel E. Furst
Keyword(s):  
Systemic Sclerosis ◽  
Treatment Options ◽  
Current Treatment ◽  
Phase 2 Trial ◽  
Immune Mediated ◽  
Interleukin 6 Receptor ◽  
Organ Specific ◽  
Pharmacologic Management ◽  
Disease Modifying ◽  
Disease Modifying Treatment

Systemic sclerosis (SSc) is an immune-mediated disease characterized by progressive, and often severe, inflammation and fibrosis of the skin and internal organs, such as the lungs, heart, kidneys, and gastrointestinal tract. There is an unmet medical need to treat patients with SSc given the high SSc-related mortality rate. Furthermore, disease-modifying therapies are lacking, and current treatment options focus on the management of individual organ-specific complications associated with the disease. Immunosuppressive therapies are the mainstay of pharmacologic management of major SSc-associated complications, such as skin and lung manifestations, but their overall effectiveness is limited and toxicity issues are common. Advances in understanding of the pathological processes involved in the immunologic and fibrotic mechanisms of SSc have led to clinical research focusing on targeted immunotherapies, in an effort to develop much needed disease-modifying treatment options. The interleukin-6 receptor-alpha antagonist tocilizumab has demonstrated promising efficacy in a phase 2 trial and is being investigated in a phase 3 trial. This article provides an overview of current pharmacologic treatment options for the management of SSc-related complications and discusses tocilizumab for the treatment of SSc in clinical trials.

scholarly journals One in seven pathogenic variants can be challenging to detect by NGS: an analysis of 450,000 patients with implications for clinical sensitivity and genetic test implementation

2021 ◽  
Author(s):  
Stephen E. Lincoln ◽  
Tina Hambuch ◽  
Justin M. Zook ◽  
Sara L. Bristow ◽  
Kathryn Hatchell ◽  
...  
Keyword(s):  
Diagnostic Yield ◽  
Copy Number Variants ◽  
Low Complexity ◽  
Clinical Genetic ◽  
Clinical Sensitivity ◽  
Pathogenic Variants ◽  
Wide Range ◽  
Large Indels ◽  
Next Generation Sequencing Ngs ◽  
The Impact

Abstract Purpose To evaluate the impact of technically challenging variants on the implementation, validation, and diagnostic yield of commonly used clinical genetic tests. Such variants include large indels, small copy-number variants (CNVs), complex alterations, and variants in low-complexity or segmentally duplicated regions. Methods An interlaboratory pilot study used synthetic specimens to assess detection of challenging variant types by various next-generation sequencing (NGS)–based workflows. One well-performing workflow was further validated and used in clinician-ordered testing of more than 450,000 patients. Results In the interlaboratory study, only 2 of 13 challenging variants were detected by all 10 workflows, and just 3 workflows detected all 13. Limitations were also observed among 11 less-challenging indels. In clinical testing, 21.6% of patients carried one or more pathogenic variants, of which 13.8% (17,561) were classified as technically challenging. These variants were of diverse types, affecting 556 of 1,217 genes across hereditary cancer, cardiovascular, neurological, pediatric, reproductive carrier screening, and other indicated tests. Conclusion The analytic and clinical sensitivity of NGS workflows can vary considerably, particularly for prevalent, technically challenging variants. This can have important implications for the design and validation of tests (by laboratories) and the selection of tests (by clinicians) for a wide range of clinical indications.

scholarly journals Relapse recovery in multiple sclerosis: Effect of treatment and contribution to long-term disability

2021 ◽  
Vol 7 (2) ◽  
pp. 205521732110155
Author(s):  
Marinos G Sotiropoulos ◽  
Hrishikesh Lokhande ◽  
Brian C Healy ◽  
Mariann Polgar-Turcsanyi ◽  
Bonnie I Glanz ◽  
...  
Keyword(s):  
Functional System ◽  
Older Age ◽  
Lesion Volume ◽  
Clinical Predictors ◽  
Disability Status ◽  
Bladder Symptoms ◽  
Disease Modifying ◽  
Disease Modifying Treatment ◽  
Baseline Bmi

Background Although recovery from relapses in MS appears to contribute to disability, it has largely been ignored as a treatment endpoint and disability predictor. Objective To identify demographic and clinical predictors of relapse recovery in the first 3 years and examine its contribution to 10-year disability and MRI outcomes. Methods Relapse recovery was retrospectively assessed in 360 patients with MS using the return of the Expanded Disability Status Scale (EDSS), Functional System Scale and neurologic signs to baseline at least 6 months after onset. Univariate and multivariable models were used to associate recovery with demographic and clinical factors and predict 10-year outcomes. Results Recovery from relapses in the first 3 years was better in patients who were younger, on disease-modifying treatment, with a longer disease duration and without bowel or bladder symptoms. For every incomplete recovery, 10-year EDSS increased by 0.6 and 10-year timed 25-foot walk increased by 0.5 s. These outcomes were also higher with older age and higher baseline BMI. Ten-year MRI brain atrophy was associated only with older age, and MRI lesion volume was only associated with smoking. Conclusions Early initiation of disease-modifying treatment in MS was associated with improved relapse recovery, which in turn prevented long-term disability.

Planning and approach to allergen-specific immunotherapy in polyallergic patients

Immunotherapy ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 577-585
Author(s):  
Nerin N Bahceciler ◽  
Ozel Yuruker
Keyword(s):  
Clinical Management ◽  
Respiratory Diseases ◽  
Specific Immunotherapy ◽  
Clinical Symptoms ◽  
Allergen Specific Immunotherapy ◽  
Stepwise Approach ◽  
Future Studies ◽  
Disease Modifying ◽  
Management Recommendations ◽  
Disease Modifying Treatment

Allergy immunotherapy (AIT) is currently the only disease-modifying treatment for allergic-respiratory diseases. Polysensitization may increase the severity of current disease resulting in subsequent asthma development in patients with allergic rhinitis. Due to the absence of general recommendations for the practical approach to polysensitized patients, clinical management is not standardized. The correlation between sensitizations and clinical symptoms, elimination of possible pollen cross-reactivities and principles of homologous allergen groups will guide the allergists to deduce the most relevant allergens for AIT. In the highlight of the previously proposed approach strategies to polyallergic patients, hereby we propose a revised practical stepwise approach based on the current European Medicine Agency (EMA) guidelines. However, more supporting data from well-designed, controlled, future studies are needed to improve clinical management recommendations for AIT in polyallergic patients.

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