Sterol-C4-methyl oxidase deficiency, caused by pathogenic variants in MSMO1, is an ultra-rare inborn error of distal cholesterol biosynthesis characterized by heterogeneous multisystem manifestations. We describe a five-year-old Saudi boy born to consanguineous parents who presented with severe early-onset erosive psoriasiform dermatitis, mild developmental delay, and microcephaly at birth, with subsequent normalization of head circumference. Ophthalmologic evaluation revealed ulcerative blepharitis without structural ocular abnormalities or congenital cataracts. Whole-exome sequencing identified a novel homozygous MSMO1 missense variant (NM_006745.4:c.403T>C; p.Trp135Arg). Segregation analysis confirmed heterozygous carrier status in both parents and unaffected siblings. Baseline serum lipid fractions were within reference limits, consistent with previously reported MSMO1 cases in which routine lipid parameters may remain normal. Targeted metabolic therapy consisting of oral atorvastatin (10 mg daily), topical atorvastatin, and dietary cholesterol supplementation resulted in rapid dermatologic improvement within 8 weeks, with sustained clinical benefit at three-month follow-up; however, partial relapse occurred following temporary treatment interruption. This case expands the phenotypic spectrum of MSMO1 deficiency, highlighting a predominantly cutaneous presentation with mild neurological involvement and absence of cataracts.

Although there are conflicting clinical data on the efficacy of weight reduction in reducing secondary events in patients with comorbid overweight and obesity (OAO) and cardiovascular disease (CVD), there is excellent epidemiological and biological evidence of a cause-effect relationship between OAO, CVD, and other systemic complications. There is also new interventional evidence that pharmacotherapies improve cardiovascular, hepatic, and renal outcomes in individuals with OAO and pre-existing CVD. New trial data confirm that not all weight loss strategies are equal in terms of reducing cardiovascular risk. Using Global Burden of Disease data and a pooled analysis of registry data on ~30,000 patients with CVD, we estimate that about 34 million patients across the Middle East could benefit from secondary prevention of CVD by targeting OAO phenotypes. Implementing secondary prevention in practice will require updating clinical guidelines on both obesity management and CVD secondary prevention, as well as policy changes that allow for reimbursement. Crucially, it will also require a philosophical shift that there exist distinct OAO phenotypes for which treatment success is not solely dictated by weight loss. The cumulative burden of future cardiovascular risk is set to increase, mandating comprehensive strategies to implement secondary prevention in at-risk groups, including children.

[This corrects the article DOI: 10.3389/fmed.2025.1670282.].

Pitavastatin, indicated for lowering low-density lipoprotein cholesterol (LDL-C), is particularly beneficial for patients who experience side effects with other statins. When used in combination with other cholesterol-lowering medications, such as ezetimibe, pitavastatin can enhance LDL-C reduction, improving patient outcomes and facilitating achievement of LDL-C targets. This paper reviews the available literature on the use of pitavastatin for cardiovascular (CV) protection in patients with dyslipidemia, drawing on both published evidence and insights from lipidologists and cardiologists who participated in an advisory board. It highlights pitavastatin's effectiveness in managing dyslipidemia and its potential to mitigate CV complications, particularly in patients with atherosclerotic cardiovascular disease (ASCVD). Feedback from practicing healthcare providers across several countries in the Middle East, including Kuwait, Saudi Arabia, the United Arab Emirates, Lebanon, and Jordan, emphasizes the importance of early intervention and achieving optimal LDL-C levels to reduce CV risk. It also underscores the relevance of adhering to international guidelines for dyslipidemia management in regional clinical practice. This paper offers practical recommendations to address challenges and improve the management of dyslipidemia in the Middle East through the use of pitavastatin, with the aim of achieving LDL-C targets and reducing CV events.

BackgroundEpidermolysis Bullosa (EB) is a rare genetic disorder that results in fragile skin and blistering and may lead to mucous membrane involvement. The disease manifests in several subtypes, among which the most serious conditions are dystrophic and junctional EB. This study intends to highlight the recurrent and novel genetic abnormalities that cause EB in the Western region of Saudi Arabia.MethodsTwelve Middle Eastern Arab families affected by Epidermolysis Bullosa (EB) were recruited from dermatology clinic from King Abdullah Medical Complex in Jeddah. Detailed clinical phenotyping was conducted for each patient to document EB-associated symptoms and to accurately determine the disease subtypes. Whole Exome Sequencing (WES) was performed to identify genetic variants associated with EB, and the resulting variants were classified by the guidelines of the American College of Medical Genetics and Genomics (ACMG). Additionally, multiple bioinformatics tools were employed to evaluate the pathogenicity of the detected variants. Variant segregation with disease phenotype was confirmed within the families using Sanger sequencing.ResultsWe identified 11 genetic variants, including three novel variants, in the COL7A1 (NM_000094.4), COL17A1 (NM_000494.4), and LAMB3 (NM_000228.3) genes across 12 EB families. The COL7A1 variants included frameshift variants (c.5924_5927del and c.6268_6269del), nonsense variants (c.1633C > T, c.1837C > T, c.2005C > T, and c.5888G > A), missense variants (c.4448G > A and c.8245G > A), and splice-site variants (c.6751-1G > A and c.8305-1G > A). Additionally, a splice-site variant was identified in COL17A1 (NM_000494.4; c.1394G > A) and another in LAMB3 (NM_000228.3; c.1977-1G > A). Bioinformatics analysis predicted these variants to be likely pathogenic because they disrupt collagen VII, XVII, and laminin 332, proteins essential for skin stability. Frameshift and nonsense variants introduce premature stop codons, leading to truncated or degraded transcripts. Splice-site variants likely cause aberrant splicing, disrupting the reading frame and impairing protein function.ConclusionWES is an effective first-line diagnostic tool for identifying EB-associated variants. This study reveals locus and allelic heterogeneity in EB cases from Saudi Arabia. The findings underscore the importance of early genetic screening for improving genetic counseling in high-consanguinity populations and emphasize the need for large-scale genetic studies in the country.

BackgroundFamilial hypercholesterolemia (FH) and non-genetic hypercholesterolemia (HC) are both associated with elevated low-density cholesterol (LDL-C) levels, which increase the risk of cardiovascular disease. However, their underlying metabolic disturbances differ significantly. Untargeted metabolomics offers a powerful approach for identifying disease-specific metabolic signatures and potential biomarkers, thereby contributing to precision medicine applications.MethodsA high-resolution metabolomics analysis was performed using ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) on plasma samples from FH, HC, and healthy Saudi individuals. Differentially expressed metabolites were identified through univariate and multivariate analyses, followed by pathway enrichment analysis using the KEGG database.ResultsMetabolic profiling revealed distinct alterations in bile acid biosynthesis and steroid metabolism pathways in FH. Cholic acid was significantly downregulated, while 17α-hydroxyprogesterone (17α-OHP) was significantly elevated in FH. In contrast, HC was characterized by increased uric acid and choline levels, along with dysregulation in oleic acid and linoleic acid metabolism. Notably, both FH and HC groups were dysregulated in Sphinganine, D-α-hydroxyglutaric acid, and pyridoxamine.ConclusionThis study demonstrates the utility of untargeted metabolomics in distinguishing FH from HC, identifying 17α-OHP and cholic acid as potential FH biomarkers, while uric acid and choline may serve as HC-specific metabolic markers. These findings provide new insights for personalized interventions, enhancing disease stratification and therapeutic decision-making between genetic and non-genetic hypercholesterolemia.

Familial hypercholesterolemia (FH) results in elevated levels of LDL-C, increasing the risk of developing cardiovascular disease. This study aims to identify genetic causes and examine the connection between genetic variants and the resulting genotype-protein phenotype in Saudi FH patients. Whole-exome sequencing (WES) and Sanger sequencing were employed to detect causative variants in affected Saudi FH families and their healthy relatives. Computational tools, including RNA stability analysis, molecular dynamics simulations, and molecular docking were used to assess the impact of these variants on mRNA stability and protein structure, particularly LDLR-LDLRAP1 interactions. WES identified two pathogenic variants in the LDLR gene in two Saudi FH families: c.103 C>T p.(Gln35Ter) and c.2416dup p.(Val806GlyfsTer11), both absent in healthy relatives and regional databases. The c.103 C>T variant alters the secondary RNA structure of LDLR, potentially affecting its stability and function. The c.2416dupG variant truncates the LDLR cytoplasmic tail, disrupting the NPXY-LDLRAP1 interaction and impairing receptor internalization. Molecular dynamics simulations using Desmond revealed increased structural flexibility and altered interaction dynamics in the LDLR protein due to the c.2416dup variant, suggesting further impacts on the protein's functional integrity. In conclusion, this study identifies rare pathogenic variants c.2416dup and c.103 C>T in LDLR in extended Saudi Arabian families. It demonstrates the integration of bioinformatics methods with sequencing data to characterize and elucidate the pathogenic effects of genetic variants, providing comprehensive insights into the intricate interplay between LDLR genetic variants and their molecular impacts in FH patients.

Background: Lipoprotein(a) (Lp[a]) is a genetically inherited, independent risk factor for atherosclerotic cardiovascular disease. Despite increasing international emphasis on its clinical relevance, routine Lp(a) testing remains limited, particularly in developing healthcare systems. Materials and Methods: We conducted a nationwide, cross-sectional survey of 354 clinicians across Saudi Arabia to assess their knowledge, testing practices, perceived barriers related to Lp(a), and readiness for future implementation. Responses were analysed using descriptive statistics and multivariable logistic regression. Results: Only 16.4% of clinicians correctly identified the guideline-recommended Lp(a) threshold (50 mg/dL) and 11.5% reported routine testing. Barriers included test unavailability (22.7%), cost (18.6%) and limited awareness (14.8%). Knowledge was significantly higher among male clinicians, those with >15 years of experience, and those who had read the national dyslipidaemia guidelines. Conclusions: Despite seeing patients at risk, Saudi clinicians demonstrate low Lp(a) knowledge and testing adoption. Structured education, national guidelines and accessible testing are urgently needed to close this gap and reduce preventable cardiovascular events.

In this study, we describe the synthesis, preliminary in vitro and in vivo anti-inflammatory investigations, and molecular docking along with molecular dynamic simulation of novel bisuracil and their corresponding dihydropyrido[2,3-d:6,5-d']dipyrimidine derivatives using microwave synthesis workstation. The purity of all newly synthesized compounds was checked by TLC and elucidation of their structures was confirmed by IR, 1H, 13C NMR and High-Resolution Mass Spectrometry (HRMS) in addition to, elemental analysis. Analysis of the in vitro results revealed that the bisuracil compounds 2d and 2a were the most potent candidates and had much superior anti-inflammatory activity and COX-2 selectivity than the reference drug celecoxib. Most of the novel compounds exhibited strong in vivo anti-inflammatory activity using carrageenan-induced paw edema bioassay in rats compared to indomethacin. The in-silico studies revealed that the intermolecular interactions of the most active compounds 2d and 2a with COX-2 protein allosteric site were inspected through the docking approach, which revealed noteworthy binding interactions. Following that, the interaction's stability was considered using a typical atomistic 100 ns dynamic simulation study. Several parameters prevailed from MD simulation trajectories were manipulated and authorized to approve the stability of the complex between the novel bisuracil compound 2d and the COX-2 allosteric site under the dynamic conditions.

Candida albicans is a commensal fungus that naturally inhabits the vagina. However, overgrowth of C. albicans can result in vulvovaginal candidiasis (VVC), one of the most prevalent fungal infections affecting women. The rapid emergence of azole resistance in C. albicans, in addition to the limited available antifungal agents, complicates the treatment and emphasizes the urgent need for novel therapeutic options. Efflux-mediated azole resistance is a common resistance mechanism in fluconazole (FLZ)-resistant C. albicans. Combination therapy using natural compounds is a potential approach that can restore fluconazole's antifungal activity in azole-resistant isolates via efflux pump inhibition. This study aimed to evaluate the ability of celastrol, a natural triterpene, to retrieve FLZ antifungal activity against azole-resistant C. albicans in vitro and in vivo. Celastrol did not exhibit antifungal activity against the tested clinical isolates; however, the sub-MIC of celastrol inhibited rhodamine 6G (R6G) efflux and increased R6G accumulation inside celastrol-treated C. albicans cells. Synergy was spotted between celastrol and FLZ via a checkerboard assay. Quantification of m-RNA levels of efflux-mediated azole resistance genes within azole-resistant C. albicans demonstrated CDR1 overexpression. Upon celastrol treatment, a significant decline in ABC transporters transcript levels were detected. Moreover, molecular docking demonstrated that celastrol is a potential ABC efflux transporters blocker that successfully fits into target binding pockets. A negligible hemolytic effect of celastrol against human erythrocytes was observed. In the in vivo model of VVC, the combination of FLZ and celastrol in vaginal gel revealed a drastic reduction in the fungal burden with apparently normal vaginal tissue. Celastrol promising in vitro and in vivo findings strengthen its future use for the treatment of azole-resistant C. albicans.

In this study, we describe the synthesis, preliminary in vitro and in vivo anti-inflammatory investigations, and molecular docking along with molecular dynamic simulation of novel bisuracil and their corresponding dihydropyrido[2,3-d:6,5-d']dipyrimidine derivatives using microwave synthesis workstation. The purity of all newly synthesized compounds was checked by TLC and elucidation of their structures was confirmed by IR, 1H, 13C NMR and High-Resolution Mass Spectrometry (HRMS) in addition to, elemental analysis. Analysis of the in vitro results revealed that the bisuracil compounds 2d and 2a were the most potent candidates and had much superior anti-inflammatory activity and COX-2 selectivity than the reference drug celecoxib. Most of the novel compounds exhibited strong in vivo anti-inflammatory activity using carrageenan-induced paw edema bioassay in rats compared to indomethacin. The in-silico studies revealed that the intermolecular interactions of the most active compounds 2d and 2a with COX-2 protein allosteric site were inspected through the docking approach, which revealed noteworthy binding interactions. Following that, the interaction's stability was considered using a typical atomistic 100 ns dynamic simulation study. Several parameters prevailed from MD simulation trajectories were manipulated and authorized to approve the stability of the complex between the novel bisuracil compound 2d and the COX-2 allosteric site under the dynamic conditions.

Familial hypercholesterolemia (FH), an autosomal-dominant hereditary disorder of lipid metabolism, results in significantly elevated plasma levels of low-density cholesterol (LDL-C), significantly increasing the risk of premature cardiovascular disease (CVD). Given the high prevalence of consanguinity in Middle Eastern populations, FH is more common in the region and necessitates tailored diagnostic and therapeutic strategies. This review explores the role of multi-omics approaches—including genomics, transcriptomics, proteomics, metabolomics, lipidomics, and epigenomics—in understanding FH pathophysiology and developing precision medicine strategies tailored to Middle Eastern populations. Recent genomic studies have identified LDLR, APOB, and PCSK9 mutations contributing to a high burden of FH. Metabolomic and lipidomic analyses reveal distinct biochemical alterations, including oxidative stress markers and lipid metabolism disruptions, while transcriptomic and epigenetic findings suggest variations in gene expression and statin responsiveness. Despite these advancements, multi-omics research in the Middle East is limited by high costs, restricted access to genetic testing, and the absence of national FH registries. Multi-omics approaches provide critical insights into FH pathophysiology and treatment. To optimize FH management in the Middle East, efforts should focus on expanding genetic screening programs, integrating multi-omics data into clinical practice, and addressing financial and ethical concerns. Strengthening regional collaborations and leveraging artificial intelligence-based analytics will further enhance precision medicine for FH.Keywords: Familial hypercholesterolemia; Multi-omics; Middle East; Genetic testing

Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive disorder characterized by severe hypertriglyceridemia and recurrent pancreatitis, often manifesting in childhood. The condition results from variants in the lipoprotein lipase (LPL) gene, which lead to impaired fat metabolism. We report the case of an 18-year-old Saudi male with a lifelong history of hypertriglyceridemia and recurrent episodes of pancreatitis. Laboratory investigations revealed severe hypertriglyceridemia and low high-density lipoprotein cholesterol, consistent with FCS. A comprehensive evaluation excluded secondary causes of hyperlipidemia, suggesting a potential genetic basis for the condition. Whole-exome sequencing identified a novel homozygous missense variant (c.1307G> A; p.Gly436Glu) in the LPL gene. Bioinformatics analysis predicted this variant to be deleterious, potentially disrupting the structure and stability of the LPL enzyme and impairing its ability to hydrolyze dietary fats. This finding suggested a causal link between the variant and the patient’s FCS phenotype. This case highlights the importance of molecular diagnosis in FCS, enabling the identification of causative genetic alterations and improving our understanding of the link between LPL dysfunction and severe metabolic disorders.

Purpose:Blood Lp(a) concentration is recognized as an independent risk factor for cardiovascular disease (CVD). Population-based lipoprotein(a) (Lp[a]) research in Saudi Arabia is rare. Thus, the primary goal of this pilot study was to identify age- and sex-specific reference ranges for Lp(a) levels, in addition to the associations between Lp(a) levels and other atherosclerotic markers in Saudi individuals. Patients and methods:A five-year retrospective study of Lp(a) and lipid markers in Saudi patients was conducted using the Al-Borg diagnostics database (2015-2020). The population sample consisted of 361 Saudi individuals aged 18-93 years (162 males, 199 females). An immunoturbidimetric technique was used to determine Lp(a) concentration. Results:The mean and median Lp(a) levels in the study population were 35 nmol/L and 50 nmol/L, respectively. Sex and age did not influence Lp(a) values. Lp(a) values showed a minor correlation with other atherosclerotic markers when the Pearson correlation coefficient was used. In Saudi Arabia, the distribution of Lp(a) concentrations is skewed to the left, favoring lower values. Conclusion:Lp(a) levels in individuals residing in Saudi Arabia were comparable to those observed in other ethnic groups. Additionally, standardizing Lp(a) measurements according to sex and age may enhance broader applicability and facilitate comparisons across different populations. However, larger studies are required to provide more comprehensive data for comparison.

The journal retracts the article, “The Enhanced Cytotoxic and Pro-Apoptotic Effects of Optimized Simvastatin-Loaded Emulsomes on MCF-7 Breast Cancer Cells” [...]

Homozygous familial hypercholesterolaemia (HoFH) is a severe form of FH in which inheritance of two defective or null mutations in genes associated with metabolism of low-density lipoprotein cholesterol (LDL-C) results in extremely high LDL-C, premature atherosclerotic cardiovascular disease (ASCVD) and mortality. Treatment of HoFH comprises a multi-modal approach of statins, ezetimibe, lipoprotein apheresis; and inhibitors of proprotein convertase subtilisin/kexin type, angiopoietin-like protein 3 (ANGPTL3) and microsomal triglyceride transfer protein. These treatments are generally costly, and patients also often require treatment for ASCVD consequent to HoFH. Therefore, in the interests of both economics and preservation of life, disease prevention via genetic screening and counselling is rapidly becoming a key element in the overall management of HoFH. Guidelines are available to assist diagnosis and treatment of HoFH; however, while advancements have been made in the management of the disease, there has been little systematic attention paid to prevention. Additionally, the Middle East/North Africa (MENA) region has a higher prevalence of HoFH than most other regions - chiefly due to consanguinity. This has led to the establishment of regional lipid clinics and awareness programs that have thrown education and awareness of HoFH into sharp focus. Incorporation of principles of prevention, education, awareness, and data from real-world use of existing therapeutics will significantly enhance the effectiveness of future guidelines for the management of HoFH, particularly in the MENA region.

Inhibitors of alpha-glucosidase have been used to treat type-2 diabetes (T2DM) by preventing the breakdown of carbohydrates into glucose and prevent enhancing glucose conversion. Structure-based virtual screening (SBVS) was used to generate novel chemical scaffold-ligand alpha-glucosidase inhibitors. The databases were screened against the receptor alpha-glucosidase using SBVS and molecular dynamics simulation (MDS) techniques in this study. Based on molecular docking studies, three and two compounds of alpha-glucosidase inhibitors were chosen from a commercial database (ZINC) and an In-house database for this study respectively. The mode of binding interactions of the selected compounds later predicted their alpha-glucosidase inhibitory potential. Finally, one out of three lead compound from ZINC and one out of two lead compound from In-house database were shortlisted based on interactions. Furthermore, MDS and post-MDS strategies were used to refine and validate the shortlisted leads along with the reference acarbose/alpha-glucosidase. The Hits' ability to inhibit alpha-glucosidase was predicted by SBVS, indicating that these compounds have good inhibitory activities. The lead inhibitor's structure may serve as templates for the design of novel inhibitors, and in vitro testing to confirm their anti-diabetic potential is necessary. These insights can help rationally design new effective anti-diabetic drugs. [GRAPHICS] .

Low-density lipoprotein cholesterol (LDL-C) is typically estimated by the Friedewald equation to guide atherosclerotic cardiovascular disease (ASCVD) management despite its flaws. Martin–Hopkins and Sampson-NIH equations were shown to outperform Friedewald’s in various populations. Our aim was to derive a novel equation for accurate LDL-C estimation in Saudi Arabians and to compare it to Friedewald, Martin–Hopkins and Sampson-NIH equations. This is a cross-sectional study on 2245 subjects who were allocated to 2 cohorts; a derivation (1) and a validation cohort (2). Cohort 1 was analyzed in a multiple regression model to derive an equation (equationD) for estimating LDL-C. The agreement between the measured (LDL-CDM) and calculated levels was tested by Bland–Altman analysis, and the biases by absolute error values. Validation of the derived equation was carried out across LDL-C and triglyceride (TG)-stratified groups. The mean LDL-CDM was 3.10 ± 1.07 and 3.09 ± 1.06 mmol/L in cohorts 1 and 2, respectively. The derived equation is: LDL-CD = 0.224 + (TC × 0.919) – (HDL-C × 0.904) – (TG × 0.236) – (age × 0.001) – 0.024. In cohort 2, the mean LDL-C (mmol/L) was estimated as 3.09 ± 1.06 by equationD, 2.85 ± 1.12 by Friedewald, 2.95 ± 1.09 by Martin–Hopkins, and 2.93 ± 1.11 by Sampson-NIH equations; statistically significant differences between direct and calculated LDL-C was observed with the later three equations (P < 0.001). Bland–Altman analysis showed the lowest bias (0.001 mmol/L) with equationD as compared to 0.24, 0.15, and 0.17 mmol/L with Friedewald, Martin–Hopkins, and Sampson-NIH equations, respectively. The absolute errors in all guideline-stratified LDL-C categories was the lowest with equationD, which also showed the best classifier of LDL-C according to guidelines. Moreover, equationD predicted LDL-C levels with the lowest error with TG levels up to 5.63 mmol/L. EquationD topped the other equations in estimating LDL-C in Saudi Arabians as it could permit better estimation when LDL-C is < 2.4 mmol/L, in familial hyperlipidemia, and in hypertriglyceridemia, which improves cardiovascular outcomes in high-risk patients. We recommend further research to validate equationD in a larger dataset and in other populations.

The Journal retracts the article “Application of Nanopharmaceutics for Flibanserin Brain Delivery Augmentation Via the Nasal Route” [...]