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International Journal of Molecular... May 2024Inherited muscular diseases (MDs) are genetic degenerative disorders typically caused by mutations in a single gene that affect striated muscle and result in progressive... (Review)
Review
Inherited muscular diseases (MDs) are genetic degenerative disorders typically caused by mutations in a single gene that affect striated muscle and result in progressive weakness and wasting in affected individuals. Cardiac muscle can also be involved with some variability that depends on the genetic basis of the MD (Muscular Dystrophy) phenotype. Heart involvement can manifest with two main clinical pictures: left ventricular systolic dysfunction with evolution towards dilated cardiomyopathy and refractory heart failure, or the presence of conduction system defects and serious life-threatening ventricular arrhythmias. The two pictures can coexist. In these cases, heart transplantation (HTx) is considered the most appropriate option in patients who are not responders to the optimized standard therapeutic protocols. However, cardiac transplant is still considered a relative contraindication in patients with inherited muscle disorders and end-stage cardiomyopathies. High operative risk related to muscle impairment and potential graft involvement secondary to the underlying myopathy have been the two main reasons implicated in the generalized reluctance to consider cardiac transplant as a viable option. We report an overview of cardiac involvement in MDs and its possible association with the underlying molecular defect, as well as a systematic review of HTx outcomes in patients with MD-related end-stage dilated cardiomyopathy, published so far in the literature.
Topics: Humans; Cardiomyopathy, Dilated; Heart Transplantation; Muscular Dystrophies
PubMed: 38791328
DOI: 10.3390/ijms25105289 -
Children (Basel, Switzerland) Apr 2024CACNA1C gene encodes the alpha 1 subunit of the CaV1.2 L-type Ca2+ channel. Pathogenic variants in this gene have been associated with cardiac rhythm disorders such as... (Review)
Review
CACNA1C gene encodes the alpha 1 subunit of the CaV1.2 L-type Ca2+ channel. Pathogenic variants in this gene have been associated with cardiac rhythm disorders such as long QT syndrome, Brugada syndrome and Timothy syndrome. Recent evidence has suggested the possible association between CACNA1C mutations and neurologically-isolated (in absence of cardiac involvement) phenotypes in children, giving birth to a wider spectrum of CACNA1C-related clinical presentations. However, to date, little is known about the variety of both neurological and non-neurological signs/symptoms in the neurologically-predominant phenotypes. We conducted a systematic review of neurologically-predominant presentations without cardiac conduction defects, associated with CACNA1C mutations. We also reported a novel de novo missense pathogenic variant in the CACNA1C gene of a children patient presenting with constructional, dressing and oro-buccal apraxia associated with behavioral abnormalities, mild intellectual disability, dental anomalies, gingival hyperplasia and mild musculoskeletal defects, without cardiac conduction defects. The present study highlights the importance of considering the investigation of the CACNA1C gene in children's neurological isolated syndromes, and expands the phenotype of the CACNA1C related conditions. In addition, the present study highlights that, even in absence of cardiac conduction defects, nuanced clinical manifestations of the Timothy syndrome (e.g., dental and gingival defects) could be found. These findings suggest the high variable expressivity of the CACNA1C gene and remark that the absence of cardiac involvement should not mislead the diagnosis of a CACNA1C related disorder.
PubMed: 38790536
DOI: 10.3390/children11050541 -
Diagnostics (Basel, Switzerland) May 2024Microsatellite Instability (MSI-H) occurs in approximately 15% of non-metastatic colon cancers, influencing patient outcomes positively compared to microsatellite stable... (Review)
Review
Microsatellite Instability (MSI-H) occurs in approximately 15% of non-metastatic colon cancers, influencing patient outcomes positively compared to microsatellite stable (MSS) cancers. This systematic review focuses on the prognostic significance of KRAS, NRAS, and BRAF mutations within MSI-H colon cancer. Through comprehensive searches in databases like MEDLINE, EMBASE, and others until 1 January 2024, we selected 8 pertinent studies from an initial pool of 1918. These studies, encompassing nine trials and five observational studies involving 13,273 patients, provided insights into disease-free survival (DFS), survival after recurrence, and overall survival. The pooled data suggest that while KRAS and BRAF mutations typically predict poorer outcomes in MSS colorectal cancer, their impact is less pronounced in MSI contexts, with implications varying across different stages of cancer and treatment responses. In particular, adverse effects of these mutations manifest significantly upon recurrence rather than affecting immediate DFS. Our findings confirm the complex interplay between genetic mutations and MSI status, emphasizing the nuanced role of MSI in modifying the prognostic implications of KRAS, NRAS, and BRAF mutations in colon cancer. This review underscores the importance of considering MSI alongside mutational status in the clinical decision-making process, aiming to tailor therapeutic strategies more effectively for colon cancer patients.
PubMed: 38786299
DOI: 10.3390/diagnostics14101001 -
Obesity Reviews : An Official Journal... May 2024The recent development of next-generation sequencing (NGS) technologies has led to an increase of mutation screening reports of monogenic obesity genes in diverse... (Review)
Review
Sequencing methods, functional characterization, prevalence, and penetrance of rare coding mutations in panels of monogenic obesity genes from the leptin-melanocortin pathway: A systematic review.
The recent development of next-generation sequencing (NGS) technologies has led to an increase of mutation screening reports of monogenic obesity genes in diverse experimental designs. However, no study to date has summarized their findings. Two reviewers independently conducted a systematic review of MEDLINE, Embase, and Web of Science Core Collection databases from inception to September 2022 to identify monogenic non-syndromic obesity gene screening studies. Of 1051 identified references, 31 were eligible after title and abstract screening and 28 after full-text reading and risk of bias and quality assessment. Most studies (82%) used NGS methods. The number of genes screened varied from 2 to 12 genes from the leptin-melanocortin pathway. While all the included studies used in silico tools to assess the functional status of mutations, only 2 performed in vitro tests. The prevalence of carriers of pathogenic/likely pathogenic monogenic mutations is 13.24% on average (heterozygous: 12.31%; homozygous/heterozygous composite: 0.93%). As no study reported the penetrance of pathogenic mutations on obesity, we estimated that homozygous carriers exhibited a complete penetrance (100%) and heterozygous carriers a variable penetrance (3-100%). The review provides an exhaustive description of sequencing methods, functional characterization, prevalence, and penetrance of rare coding mutations in monogenic non-syndromic obesity genes.
PubMed: 38779716
DOI: 10.1111/obr.13754 -
F1000Research 2024Previous studies have linked genetics to knee osteoarthritis. Angiotensin-converting enzyme (ACE) gene I/D polymorphism may cause OA. However, evidence remains... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Previous studies have linked genetics to knee osteoarthritis. Angiotensin-converting enzyme (ACE) gene I/D polymorphism may cause OA. However, evidence remains inconsistent. This study examines knee OA risk and ACE gene I/D polymorphism.
METHODS
We explored Europe PMC, Medline, Scopus, and Cochrane Library using keywords. Three assessment bias factors were assessed using the Newcastle-Ottawa Scale (NOS). Criteria for inclusion: (1) Split the study population into knee OA patients and healthy controls; (2) Analysed the ACE gene I/D polymorphism; (3) Case-control or cross-sectional surveys. Studies with non-knee OA, incomplete data, and no full-text were excluded. The odds ratio (OR) and 95% confidence intervals (95% CI) were calculated using random-effect models.
RESULTS
A total of 6 case-control studies consist of 1,226 patients with knee OA and 1,145 healthy subjects as controls were included. Our pooled analysis revealed that a significant association between ACE gene I/D polymorphism and risk of knee OA was only seen in the dominant (DD + ID vs. II) [OR 1.69 (95% CI 1.14 - 2.50), p = 0.009, I2 = 72%], and ID vs. II [OR 1.37 (95% CI 1.01- 1.86), p = 0.04, I2 = 43%] genotype models. Other genotype models, including recessive (DD vs. ID + II), alleles (D vs. I), DD vs. ID, and DD vs. II models did not show a significant association with knee OA risk. Further regression analysis revealed that ethnicity and sex may influence those relationships in several genotype models.
CONCLUSIONS
Dominant and ID vs. II ACE gene I/D polymorphism models increased knee OA risk significantly. More research with larger samples and different ethnic groups is needed to confirm our findings. After ethnicity subgroup analysis, some genetic models in our study showed significant heterogeneities, and most studies are from Asian countries with Asian populations, with little evidence on Arabs.
Topics: Humans; Case-Control Studies; Genetic Association Studies; Genetic Predisposition to Disease; INDEL Mutation; Osteoarthritis, Knee; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Risk Factors
PubMed: 38779312
DOI: 10.12688/f1000research.140233.1 -
Zhonghua Wei Chang Wai Ke Za Zhi =... May 2024The incidence of early-onset colorectal cancer (EOCRC) is increasing globally; however, the molecular characteristics and prognosis of sporadic EOCRC are unclear. In... (Meta-Analysis)
Meta-Analysis
The incidence of early-onset colorectal cancer (EOCRC) is increasing globally; however, the molecular characteristics and prognosis of sporadic EOCRC are unclear. In this systematic review and meta-analysis, we aimed to investigate the incidence of gene mutations and their association with cancer survival in sporadic EOCRC, focusing on six common gene mutations ( and ). Ovid Embase and Ovid Medline electronic databases were searched for studies involving patients with sporadic EOCRC (i.e., diagnosed with colorectal cancer before the age of 50 years and with no evidence of hereditary syndromes predisposing to colorectal cancer). The included articles were evaluated using quality assessment tools. Meta-analysis was performed using random-effects and fixed-effects models. Cochran's Q statistic and the I2 index were used to assess heterogeneity. The incidence of the six common gene mutations listed above in sporadic EOCRC and their association with cancer survival were evaluated. (1) . A total of 34 articles were included in this meta-analysis. The incidence of gene mutation was 36% (from 13 articles, 95%CI: 19%-55%, =0.043); of gene mutation 30% (from 26 articles, 95%CI: 24%-35%, =0.190); of gene mutation 7% (from 18 articles, 95%CI: 5%-11%, =0.422); of gene mutation 4% (from five articles, 95%CI: 3%-5%, =0.586); of gene mutation 6% (from six articles, 95%CI: 4%-10%, =0.968); and of gene mutation 59% (from 13 articles, 95%CI: 49%-68%, =0.164). (2) Association between gene mutations and survival in sporadic EOCRC A total of six articles were included in this meta-analysis. Compared with wild-type mutant was significantly associated with increased overall mortality risk in patients with EOCRC (pooled HR=2.85, 95%CI: 1.45-5.60, =0.002). Subgroup analysis showed that the incidence of gene mutation was higher in Eastern than in Western countries, whereas the incidence of , and gene mutations was lower. There was no significant difference in the incidence of PTEN gene mutation between different regions. Compared with colorectal cancer occurring in the general population, the incidence of and mutations is lower in EOCRC, whereas the incidence of mutation remains consistent. mutation is associated with increased overall mortality risk in patients with EOCRC.
Topics: Humans; Adenomatous Polyposis Coli Protein; Colorectal Neoplasms; GTP Phosphohydrolases; Incidence; Membrane Proteins; Mutation; Prognosis; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); PTEN Phosphohydrolase; Tumor Suppressor Protein p53
PubMed: 38778689
DOI: 10.3760/cma.j.cn441530-20240304-00083 -
Archives of Dermatological Research May 2024Methylenetetrahydrofolate reductase (MTHFR) is key to the metabolism of folic acid, with loss of function mutations resulting in elevated homocysteine levels, a known... (Meta-Analysis)
Meta-Analysis Review
Methylenetetrahydrofolate reductase (MTHFR) is key to the metabolism of folic acid, with loss of function mutations resulting in elevated homocysteine levels, a known risk factor for cardiovascular disease. Psoriasis patients may demonstrate hyperhomocysteinemia. To assess for the association between psoriasis and MTHFR C677T and A1298C polymorphisms. A systematic literature search was conducted in MEDLINE, Embase, Cochrane CENTRAL, and Web of Science. Case reports, case-control, cohort, and cross-sectional studies with full-text availability in English were considered. Meta-analysis was conducted with pooled ORs calculated via the random effects model (I2 > 50%). Of 917 records identified, 10 studies were selected for review of 1965 psoriasis patients and 2030 controls. Meta-analysis demonstrated that for MTHFR C677T, there were positive associations between psoriasis and the allele contrast model (C vs T, pooled OR = 1.69, 95% CI = 1.10-2.59), the additive model (CC vs TT, pooled OR = 2.44, 95% CI = 1.06-5.60), the dominant model (CC vs CT + TT, pooled OR = 1.77, 95% CI = 1.06-2.98), and the recessive model (CC + CT vs TT, pooled OR = 2.08, 95% CI = 1.05-4.13). For MTHFR A1298C, there were positive associations between psoriasis and the allele contrast model (A vs C, pooled OR = 3.57, 95% CI = 1.19-10.68), the dominant model (AA vs AC + CC, pooled OR = 4.44, 95% CI = 1.12-17.66), and the overdominant model (AC vs AA + CC, pooled OR = 0.26, 95% CI = 0.07-0.91). There may be a link between the C677T and A1298C polymorphisms with psoriasis diagnosis.
Topics: Psoriasis; Humans; Methylenetetrahydrofolate Reductase (NADPH2); Genetic Predisposition to Disease; Polymorphism, Single Nucleotide; Risk Factors; Alleles
PubMed: 38771513
DOI: 10.1007/s00403-024-02905-5 -
World Journal of Surgery May 2024Several doubts remain regarding the optimal use of neoadjuvant imatinib in gastrointestinal stromal tumors (GISTs), such as ideal treatment duration, patient selection,... (Review)
Review
BACKGROUND
Several doubts remain regarding the optimal use of neoadjuvant imatinib in gastrointestinal stromal tumors (GISTs), such as ideal treatment duration, patient selection, and long-term survival outcomes. This manuscript provides a comprehensive review on neoadjuvant imatinib treatment outcomes and facilitate evidence-based decision-making for the use of imatinib therapy in GISTs.
METHODS
Four databases (PubMed, EMBASE, Scopus, and Cochrane Library) were searched from inception to September 9, 2023. Meta-analyses of proportions were performed for the outcomes of R0 resection, disease responses, and 1-year, 3-year, and 5-year overall survival (OS) as well as 1-year, 3-year, and 5-year disease free survival (DFS). Sensitivity analyses in the form of leave-one-out analyses, meta-regression, and subgroup analyses were performed for outcomes with substantial statistical heterogeneity.
RESULTS
The search yielded 1254 articles, and 36 studies were included in our analysis. Meta-analysis of proportions revealed that 1-year, 3-year, and 5-year OS was 100%, 94%, and 88%, while 1-year, 3-year and 5-year DFS was 99%, 89%, and 79%, respectively. An R0 resection rate of 89% and a disease response rate of 67% was achieved after a mean duration of treatment of 8.41 ± 0.367 months. KIT exon 9 mutation was significantly associated with poorer 5-year DFS.
CONCLUSION
This study quantified key outcomes for neoadjuvant imatinib in locally advanced and metastatic or recurrent GIST. Patients with gastric and rectal tumous stand to benefit from neoadjuvant imatinib with an optimal treatment duration of 8 months. Furthermore, the potential utility of mutational analysis in guiding treatment with neoadjuvant imatinib was demonstrated.
PubMed: 38757916
DOI: 10.1002/wjs.12210 -
Expert Opinion on Pharmacotherapy Apr 2024Fabry's disease (FD) is a genetic lysosomal storage disorder characterized by α-galactosidase A (α-Gal A) lost/reduced activity. We aim to systematically assess the... (Review)
Review
INTRODUCTION
Fabry's disease (FD) is a genetic lysosomal storage disorder characterized by α-galactosidase A (α-Gal A) lost/reduced activity. We aim to systematically assess the safety and efficacy of Migalastat, an oral pharmacological chaperone, that has been approved for the treatment of FD in patients with amenable mutations.
METHODS
We conducted literature search following the PRISMA guidelines in major databases up to 4 February 2024, for studies that assessed the clinical outcomes of migalastat in patients with FD. The New Castle Ottawa Scale was used to evaluate the quality of the included studies.
RESULTS
A total of 2141 records were identified through database searches and register searches, amongst which 26 records were screened, and 12 of these were excluded. The remaining 14 reports were sought for retrieval. The 12 retrieved articles were assessed for eligibility and their quality was assessed after their inclusion. Amongst the included studies, 5 were of high quality, 6 were of medium quality, and 1 was of low quality.
CONCLUSION
Migalastat showed varied effects on enzyme activity and substrate levels, with gender-specific differences noted in GL-3 substrate activity and eGFR. Overall, it improved cardiac and renal outcomes similarly to enzyme replacement therapy, with a comparable safety profile.
Topics: Fabry Disease; Humans; 1-Deoxynojirimycin; alpha-Galactosidase; Enzyme Inhibitors; Treatment Outcome
PubMed: 38753367
DOI: 10.1080/14656566.2024.2354466 -
Clinical & Translational Oncology :... May 2024No head-to-head trials had been performed to estimate the relative effectiveness of poly ADP-ribose polymerase inhibitor (PARPi) and androgen receptor signaling...
OBJECTIVES
No head-to-head trials had been performed to estimate the relative effectiveness of poly ADP-ribose polymerase inhibitor (PARPi) and androgen receptor signaling inhibitor (ARSi) in the first-line treatment for metastatic castration-resistant prostate cancer (mCRPC). We aimed to perform a systematic review and network meta-analysis to evaluate the comparative effectiveness of various systemic treatment agents for patients with mCRPC.
METHODS
A comprehensive literature search was conducted for abstracts and full-text articles from the database's inception through April 27, 2023. The study concentrated on assessing radiographic progression-free survival (rPFS) for both overall and homologous recombination repair mutation (HRRm) population, with overall survival (OS) as the secondary measure. Under the Bayesian framework, the overall effect was pooled using the fixed-effects model in base case analysis. Scenario analysis using restricted mean survival time (RMST) methods was performed to test the robustness of the results.
RESULTS
Nine studies with 6,830 patients and 8 unique treatment options were included. Network meta-analysis demonstrated that talazoparib in combination with enzalutamide (TALA + ENZA; overall population, hazard ratio [HR], 0.20; 95% credible interval [CrI]: 0.16-0.26; RMST, 3.51; 95% confidence interval [CI] 2.46-4.60; HRRm population, HR, 0.15; 95% CrI: 0.09-0.23; RMST, 4.14; 95% CI 2.84-5.39) was superior to other treatments in the first-line setting in terms of rPFS. The results of Bayesian framework and RMST models showed consistent efficacy ranks. When extrapolated to overall survival benefit, within the Bayesian framework, olaparib plus abiraterone acetate and prednisone (OLAP + AAP) achieved the highest OS benefit for the overall population, which was not statistically significant when compared to TALA + ENZA. However, TALA + ENZA achieved the highest OS benefit at 3 years by applying RMST.
CONCLUSIONS
We suggest that talazoparib in combination with enzalutamide is probably a preferred treatment agent for the overall population and HRRm patients with mCRPC. Given the limitations of network framework and the modeling assumptions undertaken to finalize the analyses, results should be cautiously interpreted.
PubMed: 38750344
DOI: 10.1007/s12094-024-03506-4