6 research outputs found
Distinctive gastrointestinal motor dysfunction in patients with MNGIE
Intestinal manometry; Intestinal pseudo-obstruction; Small bowel motilityManometria intestinal; Pseudo-obstrucció intestinal; Motilitat de l'intestí primManometría intestinal; Pseudo-obstrucción intestinal; Motilidad del intestino delgadoBackground
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare mitochondrial disease caused by mutations in TYMP, encoding thymidine phosphorylase. Clinically it is characterized by severe gastrointestinal dysmotility associated with cachexia and a demyelinating sensorimotor polyneuropathy. Even though digestive manifestations are progressive and invariably lead to death, the features of gastrointestinal motor dysfunction have not been systematically evaluated. The objective of this study was to describe gastrointestinal motor dysfunction in MNGIE using state-of-the art techniques and to evaluate the relationship between motor abnormalities and symptoms.
Methods
Prospective study evaluating gastrointestinal motor function and digestive symptoms in all patients with MNGIE attended at a national referral center in Spain between January 2018 and July 2022.
Key Results
In this period, five patients diagnosed of MNGIE (age range 16–46 years, four men) were evaluated. Esophageal motility by high-resolution manometry was abnormal in four patients (two hypoperistalsis, two aperistalsis). Gastric emptying by scintigraphy was mildly delayed in four and indicative of gastroparesis in one. In all patients, small bowel high-resolution manometry exhibited a common, distinctive dysmotility pattern, characterized by repetitive bursts of spasmodic contractions, without traces of normal fasting and postprandial motility patterns. Interestingly, objective motor dysfunctions were detected in the absence of severe digestive symptoms.
Conclusions and Inferences
MNGIE patients exhibit a characteristic motor dysfunction, particularly of the small bowel, even in patients with mild digestive symptoms and in the absence of morphological signs of intestinal failure. Since symptoms are not predictive of objective findings, early investigation is indicated.This work was supported by the Instituto de Salud Carlos III and co-financed by the European Union (FEDER/FSE) [PI17/01794]; Spanish Ministry of Science and Innovation (Dirección General de Investigación Científica y Técnica, PID2021-122295OB-I00); Ciberehd is funded by the Instituto de Salud Carlos III. LA was supported by scholarship from the Instituto de Salud Carlos III (CM20/00182)
Biofluid Biomarkers in the Prognosis of Amyotrophic Lateral Sclerosis: Recent Developments and Therapeutic Applications
Amyotrophic lateral sclerosis; Biomarker; PrognosisEsclerosi lateral amiotròfica; Biomarcador; PronòsticEsclerosis lateral amiotrófica; Biomarcador; PronósticoAmyotrophic lateral sclerosis is a neurodegenerative disease characterized by the degeneration of motor neurons for which effective therapies are lacking. One of the most explored areas of research in ALS is the discovery and validation of biomarkers that can be applied to clinical practice and incorporated into the development of innovative therapies. The study of biomarkers requires an adequate theoretical and operational framework, highlighting the “fit-for-purpose” concept and distinguishing different types of biomarkers based on common terminology. In this review, we aim to discuss the current status of fluid-based prognostic and predictive biomarkers in ALS, with particular emphasis on those that are the most promising ones for clinical trial design and routine clinical practice. Neurofilaments in cerebrospinal fluid and blood are the main prognostic and pharmacodynamic biomarkers. Furthermore, several candidates exist covering various pathological aspects of the disease, such as immune, metabolic and muscle damage markers. Urine has been studied less often and should be explored for its possible advantages. New advances in the knowledge of cryptic exons introduce the possibility of discovering new biomarkers. Collaborative efforts, prospective studies and standardized procedures are needed to validate candidate biomarkers. A combined biomarkers panel can provide a more detailed disease status.This study has been funded by Instituto de Salud Carlos III through the project “PI19/0593” (co-funded by European Regional Development Fund: “A way to make Europe “)
New Targeted Agents in Myasthenia Gravis and Future Therapeutic Strategies
Myasthenia gravis (MG) is a chronic autoimmune disease for which multiple immunomodulatory therapies are available. Nevertheless, MG has a significant impact on patient quality of life. In recent years, experts’ main efforts have focused on optimizing treatment strategies, since disease burden is considerably affected by their safety and tolerability profiles, especially in patients with refractory phenotypes. This article aims to offer neurologists caring for MG patients an overview of the most innovative targeted drugs specifically designed for this disease and summarizes the recent literature and more recent evidence on agents targeting B cells and plasmablasts, complement inhibitors, and neonatal fragment crystallizable receptor (FcRn) antagonists. Positive clinical trial results have been reported, and other studies are ongoing. Finally, we briefly discuss how the introduction of these novel targeted immunological therapies in a changing management paradigm would affect not only clinical outcomes, disease burden, safety, and tolerability, but also health spending in a condition that is increasingly managed based on a patient-centred model
Distinctive gastrointestinal motor dysfunction in patients with MNGIE
This work was supported by the Instituto de Salud Carlos III and co-financed by the European Union (FEDER/FSE) [PI17/01794]; Spanish Ministry of Science and Innovation (Dirección General de Investigación Científica y Técnica, PID2021-122295OB-I00); Ciberehd is funded by the Instituto de Salud Carlos III. LA was supported by scholarship from the Instituto de Salud Carlos III (CM20/00182).Background: Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare mitochondrial disease caused by mutations in TYMP, encoding thymidine phosphorylase. Clinically it is characterized by severe gastrointestinal dysmotility associated with cachexia and a demyelinating sensorimotor polyneuropathy. Even though digestive manifestations are progressive and invariably lead to death, the features of gastrointestinal motor dysfunction have not been systematically evaluated. The objective of this study was to describe gastrointestinal motor dysfunction in MNGIE using state-of-the art techniques and to evaluate the relationship between motor abnormalities and symptoms. Methods: Prospective study evaluating gastrointestinal motor function and digestive symptoms in all patients with MNGIE attended at a national referral center in Spain between January 2018 and July 2022. Key Results: In this period, five patients diagnosed of MNGIE (age range 16-46 years, four men) were evaluated. Esophageal motility by high-resolution manometry was abnormal in four patients (two hypoperistalsis, two aperistalsis). Gastric emptying by scintigraphy was mildly delayed in four and indicative of gastroparesis in one. In all patients, small bowel high-resolution manometry exhibited a common, distinctive dysmotility pattern, characterized by repetitive bursts of spasmodic contractions, without traces of normal fasting and postprandial motility patterns. Interestingly, objective motor dysfunctions were detected in the absence of severe digestive symptoms. Conclusions and Inferences: MNGIE patients exhibit a characteristic motor dysfunction, particularly of the small bowel, even in patients with mild digestive symptoms and in the absence of morphological signs of intestinal failure. Since symptoms are not predictive of objective findings, early investigation is indicated
Remibrutinib inhibits hives effector cells stimulated by serum from chronic urticaria patients independently of FcεR1 expression level and omalizumab clinical response
Background: Despite advances in the treatment of chronic urticaria, in a significant
percentage of the patients symptoms are not fully controlled with conventional
approaches. New strategies under development include blocking intracellular mediators
of mast cell and basophil activation.
Objective: We aim to investigate the effects of the Bruton's tyrosine kinase (BTK)
inhibitor remibrutinib on human blood basophils and CD34+‐derived mast cells
activation induced by serum obtained from chronic urticaria patients.
Methods: Twenty‐two patients with chronic spontaneous urticaria (mean age
52 years, 27% women) and 22 patients with chronic inducible urticaria (46 years,
27% women) were included in the study together with a sex‐matched control group.
Patients were classified as responders or non‐responders to anti‐IgE therapy on the
basis of their clinical data, FcεR1a expression on blood basophils and total IgE levels.
Changes on CD63 expression—as an activation marker‐, were used to evaluate in
vitro the response of basophils and mast cells to serum exposure and the inhibitory
effects of remibrutinib.
Results: Remibrutinib inhibits degranulation induced by IgE cross‐linking in mast
cells and basophils and also the activation triggered by factors present in the sera of
spontaneous and inducible chronic urticaria patients. Patient's serum induces a
greater degranulation of effector cells than controls. Activation of mast cells and
basophils by patient sera and remibrutinib effects were not related to omalizumab
responsiveness.
Conclusion: Remibrutinib inhibits activation of human basophils and mast cells
induced in vitro by exposure to the serum of chronic urticaria patients independently
of their response to omalizumab
An Atypical Presentation of Upper Motor Neuron Predominant Juvenile Amyotrophic Lateral Sclerosis Associated with TARDBP Gene : A Case Report and Review of the Literature
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that can rarely affect young individuals. Juvenile ALS (JALS) is defined for individuals with an onset of the disease before the age of 25. The contribution of genetics to ALS pathology is a field of growing interest. One of the differences between adult-onset ALS and JALS is their genetic background, with a higher contribution of genetic causes in JALS. We report a patient with JALS and a pathogenic variant in the TARDBP gene (c.1035C > G; p.Asn345Lys), previously reported only in adult-onset ALS, and with an atypical phenotype of marked upper motor neuron predominance. In addition, the proband presented an additional variant in the NEK1 gene, c.2961C > G (p.Phe987Leu), which is classified as a variant of unknown significance. Segregation studies showed a paternal origin of the TARDBP variant, while the variant in NEK1 was inherited from the mother. We hypothesize that the NEK1 variant acts as a disease modifier and suggests the possibility of a functional interaction between both genes in our case. This hypothesis could explain the peculiarities of the phenotype, penetrance, and the age of onset. This report highlights the heterogeneity of the phenotypic presentation of ALS associated with diverse pathogenic genetic variants