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Neurology Research International 2021Sickle cell anemia (SCA) is an inherited autosomal recessive disease. It is caused due to point mutation that substitutes glutamate with valine at the sixth amino acid... (Review)
Review
Sickle cell anemia (SCA) is an inherited autosomal recessive disease. It is caused due to point mutation that substitutes glutamate with valine at the sixth amino acid position of the beta chain of hemoglobin molecules leading to the sickling of the red blood cells and decreased structural deformability. Silent cerebral infarcts are the most common neurological complication of SCA, while overt stroke comprises substantial burden in patients with SCA. This meta-analysis aimed to find the pooled prevalence of overt stroke in SCA patients and discuss the importance of screening them. PubMed, Embase, and Google Scholar were the electronic databases used to search the studies. A total of 765 articles were retrieved upon detailed searching in the abovementioned databases. After a series of removing duplicate articles, title and abstract screening, and full-text review, 20 articles were found eligible and included in the study. The total number of participants from all the included studies was 3,956, and pooled prevalence of stroke in patients with sickle cell anemia in Asia was found to be 5% (95% CI: 4%, 6%) with a range from 1 to 41%. Stroke occurrence in sickle cell anemia patients is an emergency complication that needs immediate intervention and management. Because of the high prevalence of stroke in patients with sickle cell anemia, clinicians should focus on its prevention and treatment strategies.
PubMed: 34150339
DOI: 10.1155/2021/9961610 -
Movement Disorders Clinical Practice Sep 2019The frequency and presentation of each of the most common forms of spinocerebellar ataxias (SCAs) varies widely. In the case of the Americas, this diversity is... (Review)
Review
BACKGROUND
The frequency and presentation of each of the most common forms of spinocerebellar ataxias (SCAs) varies widely. In the case of the Americas, this diversity is particularly dynamic given additional social, demographic, and cultural characteristics.
OBJECTIVE
To describe the regional prevalence and clinical phenotypes of SCAs throughout the continent.
METHODS
A literature search was performed in both MEDLINE and LILACS databases. The research was broadened to include the screening of reference lists of systematic review articles for additional studies. Investigations dating from the earliest available through 2019. Only studies in English, Portuguese, and Spanish were included. We analyzed publications with genetically confirmed cases only, ranging from robust samples with epidemiological data to case reports and case series from each country or regions.
RESULTS
Overall, SCA3 is the most common form in the continent. Region-specific prevalence and ranking of the common forms vary. On the other hand, region-specific phenotypic variations were not consistently found based on the available literature analyzed, with the exception of the absence of epilepsy in SCA10 consistently described in a particular cluster of cases in South Brazil.
CONCLUSION
Systematic, multinational studies analyzing in detail the true frequencies of SCAs across the Americas as well as distinct clinical signs and clues of each form would be ideal to look for these potential variations.
PubMed: 31538086
DOI: 10.1002/mdc3.12822 -
Pharmaceuticals (Basel, Switzerland) Jun 2022Autosomal recessive cerebellar ataxias (ARCAs) are a heterogeneous group of rare neurodegenerative inherited disorders. The resulting motor incoordination and... (Review)
Review
Autosomal recessive cerebellar ataxias (ARCAs) are a heterogeneous group of rare neurodegenerative inherited disorders. The resulting motor incoordination and progressive functional disabilities lead to reduced lifespan. There is currently no cure for ARCAs, likely attributed to the lack of understanding of the multifaceted roles of antioxidant defense and the underlying mechanisms. This systematic review aims to evaluate the extant literature on the current developments of therapeutic strategies that target oxidative stress for the management of ARCAs. We searched PubMed, Web of Science, and Science Direct Scopus for relevant peer-reviewed articles published from 1 January 2016 onwards. A total of 28 preclinical studies fulfilled the eligibility criteria for inclusion in this systematic review. We first evaluated the altered cellular processes, abnormal signaling cascades, and disrupted protein quality control underlying the pathogenesis of ARCA. We then examined the current potential therapeutic strategies for ARCAs, including aromatic, organic and pharmacological compounds, gene therapy, natural products, and nanotechnology, as well as their associated antioxidant pathways and modes of action. We then discussed their potential as antioxidant therapeutics for ARCAs, with the long-term view toward their possible translation to clinical practice. In conclusion, our current understanding is that these antioxidant therapies show promise in improving or halting the progression of ARCAs. Tailoring the therapies to specific disease stages could greatly facilitate the management of ARCAs.
PubMed: 35745683
DOI: 10.3390/ph15060764 -
The Cochrane Database of Systematic... Sep 2019Sickle cell disease is an autosomal recessive inherited haemoglobinopathy which causes painful vaso-occlusive crises due to sickle red blood cell dehydration....
BACKGROUND
Sickle cell disease is an autosomal recessive inherited haemoglobinopathy which causes painful vaso-occlusive crises due to sickle red blood cell dehydration. Vaso-occlusive crises are common painful events responsible for a variety of clinical complications; overall mortality is increased and life expectancy decreased compared to the general population. Experimental studies suggest that intravenous magnesium has proven to be well-tolerated in individuals hospitalised for the immediate relief of acute (sudden onset) painful crisis and has the potential to decrease the length of hospital stay. Some in vitro studies and open studies of long-term oral magnesium showed promising effect on pain relief but failed to show its efficacy. The studies show that oral magnesium therapy may prevent sickle red blood cell dehydration and prevent recurrent painful episodes. There is a need to access evidence for the impact of oral and intravenous magnesium effect on frequency of pain, length of hospital stay and quality of life. This is an updated version of the review.
OBJECTIVES
To evaluate the effects of short-term intravenous magnesium on the length of hospital stay and quality of life in children and adults with sickle cell disease. To determine the effects of long-term oral magnesium therapy on the frequency of painful crises and the quality of life in children and adults with sickle cell disease.
SEARCH METHODS
We searched the Cochrane Haemoglobinopathies Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books.Date of last search of the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register: 03 February 2019.Date of last search of other resources (clinical trials registries): 04 April 2019.
SELECTION CRITERIA
We searched for published and unpublished randomized controlled studies of oral or intravenous magnesium compared to placebo or no magnesium.
DATA COLLECTION AND ANALYSIS
Authors independently assessed the study quality and extracted the data using standard Cochrane methodologies.
MAIN RESULTS
We included five randomized placebo-controlled studies with a total of 386 participants (aged three to 53 years). Of these, two shorter parallel studies (n = 306) compared intravenous magnesium sulphate to placebo (normal saline) for admission to hospital due to a vaso-occlusive crisis, for which we were able to analyse data. The quality of evidence was moderate for studies in this comparison, mainly due to limitations due to risk of bias and imprecision. Two of the three longer-term studies comparing oral magnesium pidolate to placebo had a cross-over design. The third was a parallel factorial study which compared hydroxyurea and oral magnesium to each other and to placebo over a longer period of time; we only present the comparison of oral magnesium to placebo from this study. The quality of evidence was very low with uncertainty of the estimation.The eight-hourly dose levels in the two studies of intravenous magnesium were different; one used 100 mg/kg while the second used 40 mg/kg. Only one of these studies (n = 104) reported the mean daily pain score while hospitalised (a non-significant difference between groups, moderate quality evidence). The second study (n = 202) reported a number of child- and parent-reported quality of life scores. None of the scores showed any difference between treatment groups (low quality evidence). Data from one study (n = 106) showed no difference in length of stay in hospital between groups (low quality evidence). Both studies reported on adverse events, but not defined by severity as we had planned. One study showed significantly more participants receiving intravenous magnesium experienced warmth at infusion site compared to placebo; there were no differences between groups for other adverse events (low quality evidence).Three studies (n = 80) compared oral magnesium pidolate to placebo. None of them reported data which we were able to analyse. One study (n = 24) reported on the number of painful days and stated there was no difference between two groups (low quality evidence). None of the studies reported on quality of life or length of hospital stay. Two studies (n = 68) reported there were no differences in levels of magnesium in either plasma or red blood cells (moderate quality evidence). Two studies (n = 56) reported adverse events. One reported episodes of mild diarrhoea and headache, all of which resolved without stopping treatment. The second study reported adverse events as gastrointestinal disorders, headache or migraine, upper respiratory infections and rash; which were all evenly distributed across treatment groups (moderate quality evidence).
AUTHORS' CONCLUSIONS
Moderate to low quality evidence showed neither intravenous magnesium and oral magnesium therapy has an effect on reducing painful crisis, length of hospital stay and changing quality of life in treating sickle cell disease. Therefore, no definitive conclusions can be made regarding its clinical benefit. Further randomized controlled studies, perhaps multicentre, are necessary to establish whether intravenous and oral magnesium therapies have any effect on improving the health of people with sickle cell disease.
Topics: Adolescent; Adult; Anemia, Sickle Cell; Antisickling Agents; Child; Child, Preschool; Female; Humans; Hydroxyurea; Magnesium; Magnesium Sulfate; Male; Middle Aged; Randomized Controlled Trials as Topic; Young Adult
PubMed: 31498421
DOI: 10.1002/14651858.CD011358.pub3 -
Journal of Pediatric Hematology/oncology May 2023Gaucher disease [GD], an autosomal recessive lysosomal storage disorder, is characterized by progressive lysosomal storage of glucocerebroside in macrophages... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Gaucher disease [GD], an autosomal recessive lysosomal storage disorder, is characterized by progressive lysosomal storage of glucocerebroside in macrophages predominantly in bone, bone marrow, liver, and spleen. Meta-analysis of global GD epidemiology was not available before this study.
METHODS
To provide a systematic review and meta-analysis of birth prevalence and prevalence of GD in multiple countries. MEDLINE and EMBASE databases were searched for original research articles on the epidemiology of GD from inception until July 21, 2021. Meta-analysis, adopting a random-effects logistic model, was performed to estimate the birth prevalence and prevalence of GD.
RESULTS
Eighteen studies that were screened of 1874 records were included for data extraction. The studies that fulfilled the criteria for inclusion involved 15 areas/countries. The global birth prevalence of GD was 1.5 cases [95% confidence interval: 1.0 to 2.0] per 100,000 live births. The global prevalence of GD was 0.9 cases [95% confidence interval: 0.7 to 1.1] per 100,000 inhabitants.
CONCLUSIONS
This is the first comprehensive systematic review that presented quantitative data of GD global epidemiology. Quantitative data on global epidemiology of GD could be the fundamental to evaluate the global efforts on building a better world for GD patients.
Topics: Humans; Gaucher Disease; Liver; Prevalence; Macrophages
PubMed: 35867706
DOI: 10.1097/MPH.0000000000002506 -
Cureus May 2022Somatic () mutations are the most common mutations in various hematological malignancies, such as myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML).... (Review)
Review
A Systematic Review of the Role of Runt-Related Transcription Factor 1 (RUNX1) in the Pathogenesis of Hematological Malignancies in Patients With Inherited Bone Marrow Failure Syndromes.
Somatic () mutations are the most common mutations in various hematological malignancies, such as myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Mono-allelic mutations in germline cells may cause familial platelet disorder (FPD), an inherited bone marrow failure syndrome (IBMFS) associated with an increased lifetime risk of AML. It is suspected that additional mutations may play a role in the pathogenesis of hematological malignancies in IBMFS. This review aims to study the role of mutations in the pathogenesis of hematological malignancies in patients with IBMFS. A PubMed database search was conducted using the following medical subject heading (MeSH) terms: "inherited bone marrow failure syndromes," "hematological neoplasms," "gene expression regulation, leukemic," "RUNX1 protein, human," "RUNX1 protein, mouse," and "Neutropenia, Severe Congenital, Autosomal recessive." Three studies published in 2020 were identified as meeting our inclusion and exclusion criteria. Leukemic progression in severe congenital neutropenia was used as a disease model to evaluate the clinical, molecular, and mechanistic basis of mutations identified in hematological malignancies. Studies in mice and genetically reprogrammed or induced pluripotent stem cells (iPSCs) have shown that isolated mutations are weakly leukemogenic and only initiate hyperproduction of immature hematopoietic cells when in combination with () mutations. Despite this, whole-exome sequencing (WES) performed on leukemogenic transformed cells revealed that all AML cells had an additional mutation in the () gene that caused hyperproduction of the ten-eleven translocation (TET2) protein. This protein causes inflammation in cells with mutations. This process is thought to be critical for clonal myeloid malignant transformation (CMMT) of leukemogenic cells. In conclusion, the combinations of and mutations have a prominent effect on myeloid differentiation resulting in the hyperproduction of myeloblasts. In other studies, it has been noted that the mutations in and genes are not sufficient for the full transformation of leukemogenic cells to AML, and an additional clonal mutation in the gene is essential for full transformation to occur. These data have implicitly demonstrated that mutations are critical in the pathogenesis of various hematological malignancies, and further investigations into the role of are paramount for the development of new cancer treatments.
PubMed: 35765406
DOI: 10.7759/cureus.25372 -
Orphanet Journal of Rare Diseases Jan 2023Woodhouse-Sakati syndrome (WSS) is a rare, autosomal recessive genetic disorder with variable clinical manifestations mainly affecting the endocrine and nervous systems.... (Review)
Review
BACKGROUND
Woodhouse-Sakati syndrome (WSS) is a rare, autosomal recessive genetic disorder with variable clinical manifestations mainly affecting the endocrine and nervous systems. The aim of this study was to systematically review the genetic basis of WSS and report the genetic variants and clinical phenotypes associated with the disease.
METHODS
PubMed, Science Direct, Scopus, and Web of Science databases were searched from the time of inception until June 2022. Broad search terms were used to capture the literature describing all genetic variants associated with WSS. The search keywords used are "Woodhouse Sakati" along with the term "mutation" OR "gene" OR "variant" OR "polymorphism".
RESULTS
Twenty-five eligible studies were included in this study. One hundred and eighty-five patients in 97 families from 12 different countries were diagnosed with WSS. In patients from the Greater Middle East (GME) region, consanguineous marriages were common (67%). Thirteen different DCAF17 variants were associated with WSS development (including 8 identified in the GME region). The most frequent variant was a frameshift deletion variant (c.436delC, p.Ala147Hisfs*9) unique to Arabs that was reported in 11 cases from Tunisia, Kuwait, Qatar, Bahrain, and Saudi Arabia. There were no clear genotype-phenotype correlations for the different variants.
CONCLUSIONS
This systematic review highlights the molecular basis and clinical manifestations of WSS globally, including the GME region, where the disease is prevalent due to consanguinity. Additional studies are now needed to understand the genotype-phenotype correlation for different DCAF17 variants and their impact on the phenotypic heterogeneity observed in WSS patients.
Topics: Humans; Molecular Epidemiology; Middle East; Diabetes Mellitus; Alopecia; Nuclear Proteins; Ubiquitin-Protein Ligase Complexes
PubMed: 36721231
DOI: 10.1186/s13023-023-02614-8 -
Trends in Cardiovascular Medicine Jan 2023Rare variants in JPH2 have been associated with a range of cardiac disease, including hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), arrhythmias, and... (Review)
Review
Rare variants in JPH2 have been associated with a range of cardiac disease, including hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), arrhythmias, and sudden cardiac death (SCD); however, our understanding of how variants in JPH2 correspond to specific modes of inheritance and correlate clinical phenotypes has not been comprehensively explored. In this systematic review, we assess current case reports and series that describe patients with JPH2 variants and cardiac disease. We identified a total of 61 variant-positive individuals, approximately 80% of whom had some form of cardiac disease, including 47% HCM, 18% DCM, and 14% arrhythmia/SCD. In analyzing the 24 probands described in the studies, we found that autosomal recessive, loss-of-function variants are associated with severe, early onset DCM, while autosomal dominant missense variants are associated with a wider range of cardiac disease, including HCM, arrhythmia, SCD, and cardiac conduction disease.
Topics: Humans; Membrane Proteins; Heart; Cardiomyopathy, Hypertrophic; Cardiomyopathy, Dilated; Death, Sudden, Cardiac
PubMed: 34861382
DOI: 10.1016/j.tcm.2021.11.006 -
Kidney International Reports Sep 2022Autosomal dominant polycystic kidney disease (ADPKD) is a progressive genetic kidney disease. Studies of ADPKD presented results using different outcome measures. We...
INTRODUCTION
Autosomal dominant polycystic kidney disease (ADPKD) is a progressive genetic kidney disease. Studies of ADPKD presented results using different outcome measures. We aimed to summarize outcomes reported in ADPKD studies, including composite outcomes.
METHODS
We conducted a systematic review of published studies that included patients with ADPKD and measured kidney-related outcomes. We searched published databases and included all studies regardless of design with at least 100 participants for observational studies. We excluded studies that were limited to dialysis, transplant, or pregnancy outcomes in patients with ADPKD.
RESULTS
This review includes data from 175 published articles (49 randomized controlled trials, 2 interventional clinical trials, 30 analyses, and 94 observational studies). We identified 214 different outcomes, and we categorized them into the 24 main outcome domains. In addition, the review identified 13 articles that reported 9 different composite outcomes.
CONCLUSION
The finding highlights the inconsistency in the outcomes reported by researchers and how they are measured in ADPKD studies. The variability in the outcomes reported supports the need to standardize outcomes in ADPKD studies.
PubMed: 36090492
DOI: 10.1016/j.ekir.2022.06.012 -
Biomolecules Jan 2022Pathogenic missense variants in are associated with DFNA9, an autosomal dominantly inherited type of progressive sensorineural hearing loss with or without vestibular... (Meta-Analysis)
Meta-Analysis Review
Pathogenic missense variants in are associated with DFNA9, an autosomal dominantly inherited type of progressive sensorineural hearing loss with or without vestibular dysfunction. This study is a comprehensive overview of genotype-phenotype correlations using the PRISMA and HuGENet guidelines. Study characteristics, risk of bias, genotyping and data on the self-reported age of onset, symptoms of vestibular dysfunction, normative test results for vestibular function, and results of audiovestibular examinations were extracted for each underlying pathogenic variant. The literature search yielded 48 studies describing the audiovestibular phenotypes of 27 DFNA9-associated variants in . Subsequently, meta-analysis of audiometric data was performed by constructing age-related typical audiograms and by performing non-linear regression analyses on the age of onset and progression of hearing loss. Significant differences were found between the calculated ages of onset and progression of the audiovestibular phenotypes of subjects with pathogenic variants affecting either the LCCL domain of cochlin or the vWFA2 and Ivd1 domains. We conclude that the audiovestibular phenotypes associated with DFNA9 are highly variable. Variants affecting the LCCL domain of cochlin generally lead to more progression of hearing loss when compared to variants affecting the other domains. This review serves as a reference for prospective natural history studies in anticipation of mutation-specific therapeutic interventions.
Topics: Extracellular Matrix Proteins; Genetic Association Studies; Hearing Loss, Sensorineural; Humans; Mutation; Prospective Studies; Vestibular Diseases
PubMed: 35204720
DOI: 10.3390/biom12020220