Cardiac Defects and Genetic Syndromes: Old Uncertainties and New Insights.
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ABSTRACT:
SUBMITTER: Calcagni G
PROVIDER: S-EPMC8307133 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Calcium ions (Ca2+) play a major role in the cardiac excitation-contraction coupling. Intracellular Ca2+ concentration increases during systole and falls in diastole thereby determining cardiac contraction and relaxation. Normal cardiac function also requires perfect organization of the ion currents at the cellular level to drive action potentials and to maintain action potential propagation and electrical homogeneity at the tissue level. Any imbalance in Ca2+ homeostasis of a cardiac myocyte can lead to electrical disturbances. This review aims to discuss cardiac physiology and pathophysiology from the elementary membrane processes that can cause the electrical instability of the ventricular myocytes through intracellular Ca2+ handling maladies to inherited and acquired arrhythmias. Finally, the paper will discuss the current therapeutic approaches targeting cardiac arrhythmias.
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Project description:BackgroundNumerous genetic syndromes associated with heart disease and ocular manifestations have been described. However, a compilation and a summarization of these syndromes for better consultation and comparison have not been performed yet.ObjectiveThe objective of this work is to systematize available evidence in the literature on different syndromes that may cause congenital heart diseases associated with ocular changes, focusing on the types of anatomical and functional changes.MethodA systematic search was performed on Medline electronic databases (PubMed, Embase, Cochrane, Lilacs) of articles published until January 2016. Eligibility criteria were case reports or review articles that evaluated the association of ophthalmic and cardiac abnormalities in genetic syndrome patients younger than 18 years.ResultsThe most frequent genetic syndromes were: Down Syndrome, Velo-cardio-facial / DiGeorge Syndrome, Charge Syndrome and Noonan Syndrome. The most associated cardiac malformations with ocular findings were interatrial communication (77.4%), interventricular communication (51.6%), patent ductus arteriosus (35.4%), pulmonary artery stenosis (25.8%) and tetralogy of Fallot (22.5%).ConclusionDue to their clinical variability, congenital cardiac malformations may progress asymptomatically to heart defects associated with high morbidity and mortality. For this reason, the identification of extra-cardiac characteristics that may somehow contribute to the diagnosis of the disease or reveal its severity is of great relevance.
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Project description:After the first proposed model of the red blood cell membrane skeleton 36 years ago, several additional proteins have been discovered during the intervening years, and their relationship with the pathogenesis of the related disorders have been somewhat defined. The knowledge of erythrocyte membrane structure is important because it represents the model for spectrin-based membrane skeletons in all cells and because defects in its structure underlie multiple hemolytic anemias. This review summarizes the main features of erythrocyte membrane disorders, dividing them into structural and altered permeability defects, focusing particularly on the most recent advances. New proteins involved in alterations of the red blood cell membrane permeability were recently described. The mechanoreceptor PIEZO1 is the largest ion channel identified to date, the fundamental regulator of erythrocyte volume homeostasis. Missense, gain-of-function mutations in the PIEZO1 gene have been identified in several families as causative of dehydrated hereditary stomatocytosis or xerocytosis. Similarly, the KCNN4 gene, codifying the so called Gardos channel, has been recently identified as a second causative gene of hereditary xerocytosis. Finally, ABCB6 missense mutations were identified in different pedigrees of familial pseudohyperkalemia. New genomic technologies have improved the quality and reduced the time of diagnosis of these diseases. Moreover, they are essential for the identification of the new causative genes. However, many questions remain to solve, and are currently objects of intensive studies.
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Project description:The stomach is the most frequent site of extranodal lymphoma. Gastric lymphoma originating from mucosa-associated lymphoid tissue (MALT) is typically a low-grade, B-cell neoplasia strongly associated with Helicobacter pylori (H. pylori) infection. Only certain H. pylori strains in some predisposed patients determine lymphoma development in the stomach, according to a strain-host-organ specific process. The clinical presentation is poorly specific, symptoms ranging from vague dyspepsia to alarm symptoms. Similarly, different endoscopy patterns have been described for gastric lymphoma. H. pylori eradication is advised as first-line therapy in early stage disease, and complete lymphoma remission is achieved in 75% of cases. Neoplasia stage, depth of infiltration in the gastric wall, presence of the API2-MALT1 translocation, localization in the stomach, and patient ethnicity have been identified as predictors of remission. Recent data suggests that H. pylori eradication therapy may be successful for gastric lymphoma treatment also in a small subgroup (15%) of H. pylori-negative patients. The overall 5-year survival and disease-free survival rates are as high as 90% and 75%, respectively. Management of patients who failed to achieve lymphoma remission following H. pylori eradication include radiotherapy, chemotherapy and, in selected cases, surgery.
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Project description:The neuroendocrine control of reproduction in mammals is governed by a neural hypothalamic network of nearly 1500 gonadotropin-releasing hormone (GnRH) secreting neurons that modulate the activity of the reproductive axis across life. Congenital hypogonadotropic hypogonadism (HH) is a clinical syndrome that is characterized by partial or complete pubertal failure. HH may result from inadequate hypothalamic GnRH axis activation, or a failure of pituitary gonadotropin secretion/effects. In man, several genes that participate in olfactory and GnRH neuronal migration are thought to interact during the embryonic life. A growing number of mutations in different genes are responsible for congenital HH. Based on the presence or absence of olfaction dysfunction, HH is divided in two syndromes: HH with olfactory alterations [Kallmann syndrome (KS)] and idiopathic hypogonadotropic hypogonadism (IHH) with normal smell (normosmic IHH). KS is a heterogeneous disorder affecting 1 in 5000 males, with a three to fivefold of males over females. KS is associated with mutations in KAL1, FGFR1/FGF8, FGF17, IL17RD, PROK2/PROKR2, NELF, CHD7, HS6ST1, FLRT3, SPRY4, DUSP6, SEMA3A, NELF, and WDR11 genes that are related to defects in neuronal migration. These reproductive and olfactory deficits include a variable non-reproductive phenotype, including sensorineural deafness, coloboma, bimanual synkinesis, craniofacial abnormalities, and/or renal agenesis. Interestingly, defects in PROKR2, FGFR1, FGF8, CHD7, DUSP6, and WDR11 genes are also associated with normosmic IHH, whereas mutations in KISS1/KISSR, TAC3/TACR3, GNRH1/GNRHR, LEP/LEPR, HESX1, FSHB, and LHB are only present in patients with normosmic IHH. In this paper, we summarize the reproductive, neurodevelopmental, and genetic aspects of HH in human pathology.
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Project description:The use of high throughput sequencing (HTS) for the analysis of Spanish olive trees showing leaf yellowing discoloration, defoliation, and/or decline has provided new insights into the olive viruses present in Spain and has opened discussions about the pros and cons of these technologies for diagnostic purposes. In this study, we report for the first time in Spanish orchards the presence of olive leaf yellowing-associated virus (OLYaV), for which the second full coding sequence has been determined. This virus has also been detected in a putative vector, the psyllid Euphyllura olivina. In addition, the presence in Spain of Olea europaea geminivirus (OEGV), recently reported in Italy, has been confirmed, and the full-length sequence of two isolates was obtained by HTS and Sanger sequencing. These results, as well as the detection of other viral sequences related to olive latent virus 3 (OLV-3) and olive viral satellite RNA, raises questions on the biological significance of the findings, about the requirement of standardization on the interpretation of HTS results, and the necessity of additional tests to confirm the relevance of the HTS detection of viral sequences.
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Project description:ContextHereditary cases account for about 5% of all cases of renal cell carcinoma (RCC). With advances in next-generation sequencing, several new hereditary syndromes have been described in the last few years.ObjectiveTo review and summarise the recent preclinical and clinical literature in hereditary renal cancer.Evidence acquisitionA systematic review of the literature was performed in November 2018 using PubMed and OMIM databases, with an emphasis on kidney cancer, genetics and genomics, clinical criteria, and management.Evidence synthesisSeveral autosomal dominant hereditary RCC syndromes have been described, including those related to germline pathogenic variants in VHL, MET, FH, TSC1/TSC2, FLCN, SDHA/B/C/D, BAP1, CDC73, and MITF. Clinical spectrum of SDH, BAP1, and MITF is still being defined, although these appear to be associated with a lower incidence of RCC. FH and likely BAP1 RCC are associated with more aggressive disease. Preclinical and clinical studies show that using systemic therapy that exploits specific genetic pathways is a promising strategy.ConclusionsThere are several well-described hereditary RCC syndromes, as well as recently identified ones, for which the full clinical spectrum is yet to be defined. In the new era of precision medicine, identification of these syndromes may play an important role in management and systemic treatment selection.Patient summaryThis review covers updates in the diagnosis and management of familial kidney cancer syndromes. We describe updates in testing and management of the most common syndromes such as von Hippel-Lindau, and hereditary leiomyomatosis and renal cell carcinoma. We also provide insights into recently described familial kidney cancer syndromes.
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