-
Revista de Neurologia Nov 2020Hypokalemic periodic paralysis is a neuromuscular disease characterized by a combination of flaccid paralysis episodes (or muscular weakness) that are related to low...
INTRODUCTION
Hypokalemic periodic paralysis is a neuromuscular disease characterized by a combination of flaccid paralysis episodes (or muscular weakness) that are related to low levels of potassium in blood. As a consequence of its low prevalence, there are still clinical and management aspects to characterize.
PATIENTS AND METHODS
A systematic review of the clinical cases published in the last decade has been developed by analyzing demographic and genetic features, the episodes' characteristics, the received treatments, the response to them and also, the differences and evolution of patients depending on the most prevalent genetic alterations: CACNA1S and SCN4A.
RESULTS
A total of 33 articles were included, allowing 40 individuals to be reviewed. The average age of onset of symptoms was 15.3 ± 9.7 years. The most frequent altered gene was CACNA1S in 20 (60.5%) cases. It was observed that subjects presenting an alteration of the gene responsible for the calcium channel, CACNA1S, presented lower serum potassium levels, own triggers and a higher proportion of subjects showing dyspnea during the crisis. Only 50% of the subjects respond to classical oral treatment with acetazolamide. Potassium-sparing diuretics and antiepileptics drugs emerge as an alternative.
CONCLUSION
Hypokalemic periodic paralysis has an heterogeneous clinical expression with phenotypic differences linked to different genetic mutations. The common preventive treatment response is suboptimal. Prospective studies are needed to discern the best therapeutic option based on genetic load.
Topics: Acetazolamide; Age of Onset; Calcium Channels, L-Type; Gene Frequency; Humans; Hypokalemic Periodic Paralysis; NAV1.4 Voltage-Gated Sodium Channel; Potassium
PubMed: 33085076
DOI: 10.33588/rn.7109.2020377 -
International Journal of Molecular... Oct 2021The Epithelial Sodium Channel/Degenerin (ENaC/DEG) family is a superfamily of sodium-selective channels that play diverse and important physiological roles in a wide...
The Epithelial Sodium Channel/Degenerin (ENaC/DEG) family is a superfamily of sodium-selective channels that play diverse and important physiological roles in a wide variety of animal species. Despite their differences, they share a high homology in the pore region in which the ion discrimination takes place. Although ion selectivity has been studied for decades, the mechanisms underlying this selectivity for trimeric channels, and particularly for the ENaC/DEG family, are still poorly understood. This systematic review follows PRISMA guidelines and aims to determine the main components that govern ion selectivity in the ENaC/DEG family. In total, 27 papers from three online databases were included according to specific exclusion and inclusion criteria. It was found that the G/SxS selectivity filter (glycine/serine, non-conserved residue, serine) and other well conserved residues play a crucial role in ion selectivity. Depending on the ion type, residues with different properties are involved in ion permeability. For lithium against sodium, aromatic residues upstream of the selectivity filter seem to be important, whereas for sodium against potassium, negatively charged residues downstream of the selectivity filter seem to be important. This review provides new perspectives for further studies to unravel the mechanisms of ion selectivity.
Topics: Amiloride; Animals; Epithelial Sodium Channels; Humans; Ion Transport; Lithium; Molecular Dynamics Simulation; Mutagenesis, Site-Directed; Protein Structure, Quaternary; Sodium
PubMed: 34681656
DOI: 10.3390/ijms222010998 -
Diabetes/metabolism Research and Reviews Nov 2021More than 1000 variants of the ATP-binding cassette transporter subfamily C member 8 (ABCC8) gene have been reported in neonatal diabetes mellitus. Up to now only 55... (Review)
Review
More than 1000 variants of the ATP-binding cassette transporter subfamily C member 8 (ABCC8) gene have been reported in neonatal diabetes mellitus. Up to now only 55 ABCC8 variants were associated with Maturity-Onset Diabetes of the Young 12 (MODY12). We present a c.3544C>T p.(Arg1182Trp) ABCC8 variant in a 35-year-old women who had pronounced microvascular diabetic complications and a charcot arthropathy necessitating a lower limb amputation. The unusual severity of the disease course prompted us to perform a systematic review of all genetic variants in MODY12. The present mutation has mostly been associated with neonatal diabetes and in only three papers reporting a MODY12. The 55 MODY12 variants show a large clinical heterogeneity, even in relatives with the same mutation, ranging from mild impaired glucose tolerance to severe insulin-dependent diabetes mellitus. HbA1c at diagnosis ranged from 5% to 14% and age at diagnosis ranged from 2 to 53 years. However, several case reports lack documentation of diabetic complications. Hence, more detailed reports remain necessary to improve insight in MODY12 pathophysiology and outcome. In this article current data regarding therapeutic management are provided, and key points to consider for the individual patient affected by MODY12 are presented.
Topics: Adult; Diabetes Mellitus, Type 2; Female; Glucose Intolerance; Humans; Infant, Newborn; Middle Aged; Mutation; Sulfonylurea Receptors
PubMed: 34014594
DOI: 10.1002/dmrr.3459 -
Systems Biology in Reproductive Medicine Aug 2021Recent evidence suggests that gamete-imprinted genes play a role in embryo and placenta development and growth. This systematic review aimed to evaluate whether altered...
Recent evidence suggests that gamete-imprinted genes play a role in embryo and placenta development and growth. This systematic review aimed to evaluate whether altered methylation of sperm-imprinted genes associates with sperm DNA fragmentation (SDF), pregnancy loss rate and assisted reproductive technique (ART) outcome. To accomplish this, Pubmed, MEDLINE, Cochrane, Academic One Files, Google Scholar, and Scopus databases were used for search strategy from each database inception until December 2020. Specific keywords were used. Studies satisfying the PECOS (Population, Exposure, Comparison/Comparator, Outcomes, Study design) model were retrieved. Ten studies could be included in the qualitative analysis. A significant association was reported between increased SDF rate and aberrant methylation of / and genes by two studies. A significantly lower methylation was found in patients with idiopathic recurrent pregnancy loss (RPL) and in infertile patients compared to fertile men. Methylation of /, and / were similar in patients with RPL and controls. The ART outcome was similar in patients with aberrant and normal methylation of /, and . By contrast, a study showed an association between altered GLT2 methylation and more inferior ART results. If further confirmed by well-sized studies, these data might be helpful to identify possible epigenetic predictors of ART outcome. Particularly, aberrant methylation of and genes might represent interesting targets that deserve further investigation.
Topics: Abortion, Habitual; DNA Methylation; Female; Genomic Imprinting; Humans; KCNQ1 Potassium Channel; Male; Pregnancy; RNA, Long Noncoding; Reproductive Techniques, Assisted; Spermatozoa
PubMed: 34080930
DOI: 10.1080/19396368.2021.1909667 -
Italian Journal of Pediatrics Apr 2021The existing treatment options for neonatal seizures have expanded over the last few decades, but no consensus has been reached regarding the optimal therapeutic...
AIM
The existing treatment options for neonatal seizures have expanded over the last few decades, but no consensus has been reached regarding the optimal therapeutic protocols. We systematically reviewed the available literature examining neonatal seizure treatments to clarify which drugs are the most effective for the treatment of specific neurologic disorders in newborns.
METHOD
We reviewed all available, published, literature, identified using PubMed (published between August 1949 and November 2020), that focused on the pharmacological treatment of electroencephalogram (EEG)-confirmed neonatal seizures.
RESULTS
Our search identified 427 articles, of which 67 were included in this review. Current knowledge allowed us to highlight the good clinical and electrographic responses of genetic early-onset epilepsies to sodium channel blockers and the overall good response to levetiracetam, whose administration has also been demonstrated to be safe in both full-term and preterm newborns.
INTERPRETATION
Our work contributes by confirming the limited availability of evidence that can be used to guide the use of anticonvulsants to treat newborns in clinical practice and examining the efficacy and potentially harmful side effects of currently available drugs when used to treat the developing newborn brain; therefore, our work might also serve as a clinical reference for future studies.
Topics: Anticonvulsants; Channelopathies; Humans; Hypoxia-Ischemia, Brain; Infant, Newborn; Seizures; Sodium Potassium Chloride Symporter Inhibitors; Stroke
PubMed: 33827647
DOI: 10.1186/s13052-021-01027-2 -
American Journal of Cardiovascular... Apr 2020Levosimendan, a calcium sensitizer and potassium channel opener, has been demonstrated to improve myocardial function without increasing oxygen consumption and to show... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Levosimendan, a calcium sensitizer and potassium channel opener, has been demonstrated to improve myocardial function without increasing oxygen consumption and to show protective effects in other organs. Recently, a prospective, randomized controlled trial (RCT) revealed an association between levosimendan use and a possible increased risk of bleeding postoperatively. Levosimendan's anti-platelet effects have been shown in in vitro studies. Current studies do not provide sufficient data to support a relation between perioperative levosimendan administration and increased bleeding risk.
PURPOSE
Our goal was to investigate the relation between perioperative levosimendan administration and increased bleeding risk using a meta-analysis study design.
METHODS
The PubMed, Ovid, EMBASE and Cochrane Library databases were searched for relevant RCTs before July 1, 2019. The outcome parameters included reoperation secondary to increased bleeding in the postoperative period, the amount of postoperative recorded blood loss, and the need for transfusion of packed red blood cells (RBCs) and other blood products.
RESULTS
A total of 1160 patients in nine RCTs (576 in the levosimendan group and 584 in the control group) were included according to our inclusion criteria. Analysis showed that perioperative levosimendan administration neither increased the rate of reoperation secondary to bleeding nor increased the amount of postoperative chest tube drainage when compared with the control group. In terms of blood product transfusion, levosimendan did not influence the requirement for RBC transfusion, platelet transfusion nor fresh frozen plasma (FFP) transfusion. Levosimendan also did not shorten or prolong the aortic cross-clamp time or the cardiopulmonary bypass time.
CONCLUSION
The analyzed parameters, including reoperations due to bleeding, postoperative chest drainage and the requirement for blood products, revealed that levosimendan did not increase postoperative bleeding risk. More studies with a larger sample size are needed to address a more reliable conclusion due to study limitations.
Topics: Blood Transfusion; Cardiac Surgical Procedures; Cardiotonic Agents; Humans; Perioperative Care; Postoperative Hemorrhage; Randomized Controlled Trials as Topic; Risk; Simendan
PubMed: 31523760
DOI: 10.1007/s40256-019-00372-2 -
BMC Endocrine Disorders Nov 2021Maturity Onset Diabetes of the Young (MODY) is an autosomal dominant type of diabetes. Pathogenic variants in fourteen genes are reported as causes of MODY. Its symptoms...
BACKGROUND
Maturity Onset Diabetes of the Young (MODY) is an autosomal dominant type of diabetes. Pathogenic variants in fourteen genes are reported as causes of MODY. Its symptoms overlap with type 1 and type 2 diabetes. Reviews for clinical characteristics, diagnosis and treatments are available but a comprehensive list of genetic variants, is lacking. Therefore this study was designed to collect all the causal variants involved in MODY, reported to date.
METHODS
We searched PubMed from its date of inception to December 2019. The search terms we used included disease names and name of all the known genes involved. The ClinVar database was also searched for causal variants in the known 14 MODY genes.
RESULTS
The record revealed 1647 studies and among them, 326 studies were accessed for full-text. Finally, 239 studies were included, as per our inclusion criteria. A total of 1017 variants were identified through literature review and 74 unpublished variants from Clinvar database. The gene most commonly affected was GCK, followed by HNF1a. The traditional Sanger sequencing was used in 76 % of the cases and 65 % of the studies were conducted in last 10 years. Variants from countries like Jordan, Oman and Tunisia reported that the MODY types prevalent worldwide were not common in their countries.
CONCLUSIONS
We expect that this paper will help clinicians interpret MODY genetics results with greater confidence. Discrepancies in certain middle-eastern countries need to be investigated as other genes or factors, like consanguinity may be involved in developing diabetes.
Topics: Adaptor Proteins, Signal Transducing; Apoptosis Regulatory Proteins; Basic Helix-Loop-Helix Transcription Factors; Diabetes Mellitus, Type 2; Glucokinase; Hepatocyte Nuclear Factor 1-alpha; Hepatocyte Nuclear Factor 1-beta; Hepatocyte Nuclear Factor 4; High-Throughput Nucleotide Sequencing; Homeodomain Proteins; Humans; Insulin; Lipase; Paired Box Transcription Factors; Potassium Channels, Inwardly Rectifying; Repressor Proteins; Sequence Analysis, DNA; Sulfonylurea Receptors; Trans-Activators; src-Family Kinases
PubMed: 34763692
DOI: 10.1186/s12902-021-00891-7 -
Journal of Hypertension Dec 2019Reductions in albuminuria of more than 30% are considered a strong marker of delay of chronic kidney disease (CKD) progression. Single renin-angiotensin system (RAS)... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Reductions in albuminuria of more than 30% are considered a strong marker of delay of chronic kidney disease (CKD) progression. Single renin-angiotensin system (RAS) blockade represents the cornerstone of CKD treatment. However, as CKD progression still occurs, other nephroprotective options were explored; mineralocorticoid receptor antagonists (MRA) were tested with generally positive results.
METHODS
We conducted a systematic review and meta-analysis on the effects of MRAs on albuminuria/proteinuria, and adverse events, such as change in renal function and hyperkalemia incidence. A detailed search in electronic databases, clinical trial registries and grey literature was performed to retrieve randomized controlled trials (RCTs) in which administration of an MRA alone or on-top of ACEi/ARB was compared with placebo or active treatment.
RESULTS
Of the 45 initially identified reports, 31, with 2767 participants, were included in analysis of the primary outcome. The use of MRAs (alone or on top of RAS blockade) compared with placebo decreased urine albumin-to-creatinine ratio (UACR) by -24.55% (95% CI -29.57 to -19.53%), urine protein-to-creatinine ratio (UPCR) by -53.93% (95% CI -79% to -28.86%) and 24 h albumin excretion by -32.47% (95% CI -41.1 to -23.85%). MRAs also reduced UACR by -22.48% (95% CI -24.51 to -20.44%) compared with calcium-channel-blockers (CCBs), whereas no differences were found compared with a second ACEi/ARB or nonpotassium-sparing diuretics. Addition of an MRA was associated with change in estimated glomerular filtration rate (eGFR) of -2.38 ml/min per 1.73 m (95% CI -3.51 to -1.25), rise in potassium by 0.22 mEq/l (95% CI 0.16-0.28 mEq/l) and a 2.6-fold increase in hyperkalemia risk (RR 2.63, 95% CI 1.69-4.08) compared with placebo/active control.
CONCLUSION
Use of MRAs alone or on top of RAS blockade confers important antiproteinuric effects in patients with CKD, with a slight increase in mean potassium levels.
Topics: Humans; Mineralocorticoid Receptor Antagonists; Proteinuria; Renal Insufficiency, Chronic
PubMed: 31688290
DOI: 10.1097/HJH.0000000000002187 -
Molecular Medicine Reports Feb 2024Liddle syndrome is an autosomal dominant form of monogenic hypertension that is caused by mutations in , or , which respectively encode the α, β and γ subunits of...
Liddle syndrome is an autosomal dominant form of monogenic hypertension that is caused by mutations in , or , which respectively encode the α, β and γ subunits of the epithelial sodium channel. In the present study, DNA was extracted from leukocytes in peripheral blood obtained from all members of a family with Liddle syndrome. Whole‑exome sequencing and Sanger sequencing were performed to assess the candidate variant and a co‑segregation analysis was conducted. A frameshift mutation in (NM_ 000336: c.1806dupG, p.Pro603Alafs*5) in the family was identified, characterized by early‑onset hypertension and hypokalemia. The mutation led to the truncation of the β subunit of the epithelial sodium channel and a lack of the conservative PY motif. Furthermore, a systematic review of follow‑up data from patients with Liddle syndrome with mutations was performed. The follow‑up data of 108 patients with pathogenic mutations from 47 families were summarized. Phenotypic heterogeneity was evident in patients with Liddle syndrome and early‑onset hypertension was the most frequent symptom. Patients responded well to targeted amiloride therapy with significant improvements in blood pressure and serum potassium concentration. The present study demonstrates that confirmatory genetic testing and targeted therapy can prevent premature onset of clinical endpoint events in patients with Liddle syndrome.
Topics: Humans; Liddle Syndrome; Epithelial Sodium Channels; Frameshift Mutation; Mutation; Hypertension; Potassium
PubMed: 38099339
DOI: 10.3892/mmr.2023.13142 -
BMC Bioinformatics Nov 2019Biologically data-driven networks have become powerful analytical tools that handle massive, heterogeneous datasets generated from biomedical fields. Protein-protein...
An integrative methodology based on protein-protein interaction networks for identification and functional annotation of disease-relevant genes applied to channelopathies.
BACKGROUND
Biologically data-driven networks have become powerful analytical tools that handle massive, heterogeneous datasets generated from biomedical fields. Protein-protein interaction networks can identify the most relevant structures directly tied to biological functions. Functional enrichments can then be performed based on these structural aspects of gene relationships for the study of channelopathies. Channelopathies refer to a complex group of disorders resulting from dysfunctional ion channels with distinct polygenic manifestations. This study presents a semi-automatic workflow using protein-protein interaction networks that can identify the most relevant genes and their biological processes and pathways in channelopathies to better understand their etiopathogenesis. In addition, the clinical manifestations that are strongly associated with these genes are also identified as the most characteristic in this complex group of diseases.
RESULTS
In particular, a set of nine representative disease-related genes was detected, these being the most significant genes in relation to their roles in channelopathies. In this way we attested the implication of some voltage-gated sodium (SCN1A, SCN2A, SCN4A, SCN4B, SCN5A, SCN9A) and potassium (KCNQ2, KCNH2) channels in cardiovascular diseases, epilepsies, febrile seizures, headache disorders, neuromuscular, neurodegenerative diseases or neurobehavioral manifestations. We also revealed the role of Ankyrin-G (ANK3) in the neurodegenerative and neurobehavioral disorders as well as the implication of these genes in other systems, such as the immunological or endocrine systems.
CONCLUSIONS
This research provides a systems biology approach to extract information from interaction networks of gene expression. We show how large-scale computational integration of heterogeneous datasets, PPI network analyses, functional databases and published literature may support the detection and assessment of possible potential therapeutic targets in the disease. Applying our workflow makes it feasible to spot the most relevant genes and unknown relationships in channelopathies and shows its potential as a first-step approach to identify both genes and functional interactions in clinical-knowledge scenarios of target diseases.
METHODS
An initial gene pool is previously defined by searching general databases under a specific semantic framework. From the resulting interaction network, a subset of genes are identified as the most relevant through the workflow that includes centrality measures and other filtering and enrichment databases.
Topics: Channelopathies; Databases, Genetic; Gene Regulatory Networks; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Molecular Sequence Annotation; Protein Interaction Maps
PubMed: 31718537
DOI: 10.1186/s12859-019-3162-1