Search Results (21)

Maternal uniparental disomy of chromosome 15 [UPD(15)mat] and imprinting defects account for about 30% of cases of Prader–Willi syndrome (PWS). Mosaic UPD(15)mat is rare and may escape routine testing. We describe a 45-year-old male patient in whom persistent clinical suspicion of PWS was not genetically confirmed by repeated methylation-based analyses. Clinical manifestations included neonatal hypotonia with low birth weight, early hyperphagia, severe obesity, short stature, growth hormone deficiency, type 2 diabetes mellitus, dyslipidemia, and MASLD/MASH with compensated cirrhosis. He presented with very mild neurodevelopmental impairment. Following the detection of proteinuria and microalbuminuria from age 22 years, focal segmental glomerulosclerosis was diagnosed upon renal biopsy. A family history of cerebrovascular events was recorded. Combined SNP-array and MS-MLPA analyses across tissues established a diagnosis of PWS due to mosaic UPD(15)mat. The mosaic fraction, estimated by SNP-array, was approximately 10% in peripheral blood and 40% in buccal cells; MS-MLPA detected abnormal methylation only in buccal cells, explaining the previous negative blood-based results. Exome sequencing identified the paternally inherited pathogenic NOTCH3 variant NM_000435.2:c.3016C>T, p.(Arg1006Cys). Subsequent brain MRI showed chronic vascular-type leukoencephalopathy consistent with CADASIL, despite the absence of overt ischemic events in the proband. Collectively, these investigations established a dual molecular diagnosis of PWS due to mosaic UPD(15)mat and NOTCH3-related CADASIL. This report highlights the pivotal role of clinical genetics in assessing the precise diagnosis in rare diseases. With respect to PWS, it demonstrates that mosaicism can lead to a missed diagnosis when the genetic investigation is limited to peripheral blood. In addition, following the diagnosis of CADASIL, and based on the available evidence linking NOTCH3 to renal physiology and disease, we discuss whether NOTCH3-related renal microangiopathy may have contributed to the renal phenotype. However, given the patient’s multiple renal risk factors, FSGS was considered most likely multifactorial, and a causal association with CADASIL cannot be established from this single case. Full article

Diabetic cardiomyopathy (DCM) under glucolipotoxic stress is sustained by a reactive oxygen species (ROS)-driven circuit in which oxidative DNA damage and nitrosative injury prime NLR family pyrin domain containing 3 (NLRP3) inflammasome assembly, triggering caspase-1 activation, gasdermin D (GSDMD) cleavage, and pyroptotic cardiomyocyte death that propagates apoptosis and fibrotic remodeling. Whether melatonin can disrupt this oxidative-pyroptotic axis when both hyperglycemia and dyslipidemia coexist, the metabolic context most refractory to current therapy has not been established. Apolipoprotein E-deficient (ApoE⁻/⁻) mice were subjected to streptozotocin-induced hyperglycemia and high-fat diet-induced dyslipidemia, then treated with oral melatonin (20 mg/kg/day) for 8 weeks. Despite unchanged fasting glycemia, melatonin attenuated cardiac oxidative stress, reducing 8-OHdG and inducible nitric oxide synthase while restoring Nrf2. Suppression of nuclear factor-κB and NLRP3 was accompanied by lowered interleukin-1β, caspase-1, and GSDMD, indicating disrupted inflammasome priming and pyroptotic execution. Downstream pathology was concurrently attenuated, with reduced TUNEL-positive cardiomyocytes, normalized Bax/Bcl-2 ratio, lower natriuretic peptide expression, diminished interstitial fibrosis, and improved electrocardiographic parameters. These findings position melatonin as a cardioprotective agent that operates despite persistent fasting hyperglycemia, acting through combined attenuation of lipid burden, cumulative glycemic stress, oxidative stress, and inflammatory signaling to arrest downstream apoptotic and fibrotic remodeling under glucolipotoxic conditions, providing a mechanistic rationale for adjunctive melatonin therapy in DCM. Full article

Obesity exhibits pronounced sex-dependent differences in susceptibility and progression; however, the molecular mechanisms coordinating central energy sensing with peripheral thermogenic responses remain incompletely defined. Selenoprotein F (SELENOF), an endoplasmic reticulum (ER)-resident member of the selenoprotein family involved in protein quality control and redox-sensitive metabolic regulation, has not previously been investigated in the context of diet-induced obesity. In the present study, WT and SELENOF-deficient mice subjected to a 16-week high-fat diet (HFD) were combined with primary brown adipocyte experiments to determine the role of SELENOF in systemic metabolic homeostasis. SELENOF deficiency markedly aggravated HFD-induced weight gain, adipose tissue expansion, dyslipidemia, and hyperleptinemia selectively in female mice, whereas no genotype-dependent effects were observed in males. Mechanistically, SELENOF deficiency intensified hypothalamic ER stress and leptin resistance, as reflected by increased GRP78, p-IRE1α, and p-PERK expression together with SOCS3 upregulation, reduced STAT3 phosphorylation, and activation of the IKK/NF-κB inflammatory pathway. In parallel, SELENOF deficiency reduced circulating free triiodothyronine (FT₃) levels and the ratio of free triiodothyronine to free thyroxine (FT₃/FT₄ ratio), and suppressed DIO2 and UCP1 expression in brown adipose tissue (BAT). Experiments in primary brown adipocytes further showed that SELENOF deficiency did not disrupt proximal β3-adrenergic signaling but attenuated the downstream induction of DIO2 and UCP1. Collectively, these findings provide preliminary evidence that SELENOF is associated with sex-dependent metabolic adaptation during HFD-induced stress by linking hypothalamic proteostasis with the thyroid hormone-related thermogenic signaling program in BAT. Full article

Background/Objectives: The role of speckle-tracking echocardiography in the diagnosis of stable coronary artery disease (CAD) remains controversial. The aim of this study was to assess the diagnostic accuracy of global longitudinal strain (GLS) in predicting significant CAD. Methods: In this prospective study, 103 symptomatic patients referred for invasive coronary angiography were enrolled. All patients underwent resting echocardiography with GLS assessment prior to angiography. Exclusion criteria included acute coronary syndrome, known history of CAD, and the presence of left ventricular wall motion abnormalities. Significant CAD was defined as ≥50% stenosis in at least one major epicardial coronary artery. Results: The mean patient age was 63.8 ± 9.3 years, with 78.6% being male. Hypertension was present in 63.1% of patients, dyslipidemia in 77.7%, diabetes mellitus in 22.3%, smoking history in 71.9%, and a family history of premature CAD in 24.3%. Significant CAD was identified in 45.6% (n = 47), while the remaining 54.3% (n = 56) had non-significant or no coronary artery disease. Patients with significant CAD exhibited significantly lower GLS values compared to those without (−15.73 ± 2.64% vs. −17.6 ± 1.85%, p = 0.001). A GLS threshold of >−16.3 predicted significant CAD with 66% sensitivity and 73.2% specificity (AUC = 0.692, p = 0.001). GLS demonstrated diagnostic accuracy in identifying disease in individual coronary territories, with AUCs of 0.754 for the left anterior descending artery (LAD), 0.714 for the left circumflex artery (LCx), and 0.723 for the right coronary artery (RCA). Diagnostic performance improved when GLS was combined across all three territories (AUC = 0.796). Conclusions: Resting myocardial GLS is accurate in detecting ischemic myocardial dysfunction and can accurately predict significant stenosis of the respective coronary branch subtending the segments. Full article

Background: Traditional cardiovascular disease risk prediction models generate a combined risk assessment for myocardial infarction (MI) and ischemic stroke (IS), which may inadequately reflect the distinct etiologies and disparate risk factors of MI and IS. We aim to develop prediction models that separately estimate the risks of MI and IS. Methods: Our analysis included 6,242,404 individuals over 40 years old who participated in a cardiovascular health screening examination in 2009. Potential predictors were selected based on a literature review and the available data. Cox proportional hazards models were used to construct 5-year risk prediction models for MI, and IS. Model performance was assessed through discrimination and calibration. Results: During a follow-up of 39,322,434.39 person-years, 89,140 individuals were diagnosed with MI and 116,259 with IS. Both models included age, sex, body mass index, smoking, alcohol consumption, physical activity, diabetes, hypertension, dyslipidemia, chronic kidney disease, and family history. Statin use was factored into the classification of dyslipidemia. The c-indices for the prediction models were 0.709 (0.707–0.712) for MI, and 0.770 (0.768–0.772) for IS. Age and hypertension exhibited a more pronounced effect on IS risk prediction than MI, whereas smoking, body mass index, dyslipidemia, and chronic kidney disease showed the opposite effect. The models calibrated well for low-risk individuals. Conclusions: Our findings underscore the necessity of tailored risk assessments for MI and IS to facilitate the early detection and accurate identification of heterogeneous at-risk populations for atherosclerotic cardiovascular disease. Full article

Background and objectives: There is increasing evidence suggesting that lifestyle factors play a significant role in the development of hypertension and dyslipidemia. Rather than occurring individually, these conditions often coexist. Therefore, the aim of this study was to investigate the individual and combined effects of lifestyle factors on the risk of hypertension only, dyslipidemia only, and their comorbidity. Methods: This study included 9608 adults aged 19 years and above from the cross-sectional Korean National Health Examination Study between 2019 and 2021. An unhealthy lifestyle score was derived from five factors: smoking, alcohol consumption, body mass index (BMI), diet, and physical activity. Each participant was assigned an unhealthy lifestyle score based on the cumulative number of unhealthy factors present. A logistic regression model and multinomial logistic regression were used to estimate odds ratios (ORs) with 95% confidence intervals (95% CIs) after adjusting for confounders. The analysis aimed to assess the association between an unhealthy lifestyle and the risk of hypertension, dyslipidemia, and their comorbidity. Results: The prevalence of hypertension only, dyslipidemia only, and their comorbidity was 12.9%, 19.6%, and 16.4%, respectively. In the multivariable model, higher odds of hypertension alone were significantly associated with alcohol consumption and BMI status. Dyslipidemia alone and the comorbidity of hypertension and dyslipidemia were associated with all individual lifestyle factors. When compared to individuals with the highest unhealthy lifestyle score (4–5 scores), those with the lowest score (0–1 scores) had increased ORs of 5.38 (95% CI: 3.15–9.19), 4.08 (95% CI: 2.84–5.85), and 16.0 (95% CI: 9.34–27.5) for hypertension only, dyslipidemia only, and their comorbidity, respectively. Furthermore, even after stratifying by family history, individuals with the lowest lifestyle score were still associated with hypertension, dyslipidemia, and their comorbidity compared to those with the highest lifestyle score, regardless of their family history. Conclusion: These findings demonstrate a positive association between unhealthy lifestyle factors and the risk of comorbidity of hypertension and dyslipidemia, as well as hypertension and dyslipidemia alone. Moreover, lifestyle factors may influence the risk of hypertension and dyslipidemia, even in individuals with a family history of these conditions. Full article

Obesity might adversely affect the health and well-being of children and their families. Childhood obesity has crucial implications for health, both during childhood and as they age. It is highly associated with many acute problems and is commonly present during childhood, making visits and hospital admissions polarized in this group of children. The problems that may affect these children can be medical, such as asthma, chronic inflammation, orthopedic abnormalities, liver disease, diabetes mellitus or dyslipidemia. Long-term consequences of cardiovascular risk factors, the persistence of obesity and premature mortality are common among adults who had obesity during their early lives. Additionally, they could also suffer from psychological issues, such as low self-esteem, which puts them at risk of a much more serious psychosocial problem that may lead to depression, as well as a disruption in educational achievements and social relationships. A healthy diet, physical activity, adequate sleep, and limited screen time are all preventive measures that should be implemented at the family and community levels, preferably through well-structured programs. Furthermore, pharmacological management of childhood obesity is limited and only used after non-pharmacological interventions have failed or in the late stages of obesity. However, recent guidelines advocate the early use of medical interventions. Approved pharmacotherapeutic options include orlistat, phentermine/topiramate combination and liraglutide. There are several other options approved primarily for other specific forms of obesity or for other indications, including setmelanotide, metformin, lisdexamfetamine, zonisamide and fluoxetine. Bariatric surgery is a safe and effective option in cases with extreme obesity and comorbidities considering the need for long-term monitoring and support for cases and their families post-surgery. This review aims to discuss and highlight the recent evidence regarding risk factors, clinical consequences, prevention, and treatment of childhood obesity. Full article

Lipid variations have been frequently observed in global populations that can affect health status. Mainly studies have been conducted on the type 2 diabetic population, but limited data is available on newly diagnosed ones to unravel complications and risk predictors independent of disease progression. This study comprising 244 individuals was carried out to assess the lipid abnormalities in newly diagnosed diabetics and non-diabetics. The clinical and socio-demographic data were collected and analyzed using independent samples t-test and linear regression. Serum lipid variations were observed individually and in combination. The individuals in group I (diabetics with dyslipidemia) revealed elevated levels of low-density lipoprotein and serum triglycerides higher than in group II (non-diabetics with dyslipidemia). The frequency of deranged total cholesterol in group I was observed to be higher than in group II. Independent samples t-test showed a significant mean difference in variables between the two groups. Linear regression analysis showed a significant variable outcome for predictors between high-density lipoprotein (HDL) and physical activity (B= −0.043, 95% CI: −0.80, −0.006) and total cholesterol (TC) with family history (B= −0.062, 95% CI: −0.123, −0.001). The findings conclude that lipid levels deranged independently regardless of type 2 diabetes mellitus and present as an early onset in type 2 diabetes instead of later stage complication. These derangements of lipid levels are an independent risk factor for future cardiovascular pathology. Full article

Low-density lipoprotein cholesterol (LDL-C) plays a crucial role in the development of atherosclerosis. Statin therapy is the standard treatment for lowering LDL-C in primary and secondary prevention. However, some patients do not reach optimal LDL-C target levels or do not tolerate statins, especially when taking high doses long-term. Combining statins with different therapeutic approaches and testing other new drugs is the future key to reducing the burden of cardiovascular disease (CVD). Recently, several new cholesterol-lowering drugs have been developed and approved; others are promising results, enriching the pharmacological armamentarium beyond statins. Triglycerides also play an important role in the development of CVD; new therapeutic approaches are also very promising for their treatment. Familial hypercholesterolemia (FH) can lead to CVD early in life. These patients respond poorly to conventional therapies. Recently, however, new and promising pharmacological strategies have become available. This narrative review provides an overview of the new drugs for the treatment of dyslipidemia, their current status, ongoing clinical or preclinical trials, and their prospects. We also discuss the new alternative therapies for the treatment of dyslipidemia and their relevance to practice. Full article

Primary hypercholesterolemia is characterized by elevated LDL-cholesterol (LDL-C) levels isolated in autosomal dominant hypercholesterolemia (ADH) or associated with elevated triglyceride levels in familial combined hyperlipidemia (FCHL). Rare APOE variants are known in ADH and FCHL. We explored the APOE molecular spectrum in a French ADH/FCHL cohort of 5743 unrelated probands. The sequencing of LDLR, PCSK9, APOB, and APOE revealed 76 carriers of a rare APOE variant, with no mutation in LDLR, PCSK9, or APOB. Among the 31 APOE variants identified here, 15 are described in ADH, 10 in FCHL, and 6 in both probands. Five were previously reported with dyslipidemia and 26 are novel, including 12 missense, 5 synonymous, 2 intronic, and 7 variants in regulatory regions. Sixteen variants were predicted as pathogenic or likely pathogenic, and their carriers had significantly lower polygenic risk scores (wPRS) than carriers of predicted benign variants. We observed no correlation between LDL-C levels and wPRS, suggesting a major effect of APOE variants. Carriers of p.Leu167del were associated with a severe phenotype. The analysis of 11 probands suggests that carriers of an APOE variant respond better to statins than carriers of a LDLR mutation. Altogether, we show that the APOE variants account for a significant contribution to ADH and FCHL. Full article

Familial partial lipodystrophy (FPLD) is a rare genetic disorder characterized by the selective loss of adipose tissue. Its estimated prevalence is as low as 1 in 1 million. The deficiency of metabolically active adipose tissue is closely linked with a wide range of metabolic complications, such as insulin resistance, lipoatrophic diabetes, dyslipidemia with severe hypertriglyceridemia, hypertension or hepatic steatosis. Moreover, female patients often develop hyperandrogenism, hirsutism, polycystic ovaries and infertility. The two most common types are FPLD type 2 and 3. Variants within LMNA and PPARG genes account for more than 50% of all reported FPLD cases. Because of its high heterogeneity and rarity, lipodystrophy can be easily unrecognized or misdiagnosed. To determine the genetic background of FPLD in a symptomatic woman and her close family, an NGS custom panel was used to sequence LMNA and PPARG genes. The affected patient presented fat deposits in the face, neck and trunk, with fat loss combined with muscular hypertrophy in the lower extremities and hirsutism, all features first manifesting at puberty. Her clinical presentation included metabolic disturbances, including hypercholesterolemia with severe hypertriglyceridemia, diabetes mellitus and hepatic steatosis. This together with her typical fat distribution and physical features raised a suspicion of FPLD. NGS analysis revealed the presence of missense heterozygous variant c.443G>A in exon 4 of PPARG gene, causing glycine to glutamic acid substitution at amino acid position 148, p.(Gly148Glu). The variant was also found in the patient’s mother and son. The variant was not previously reported in any public database. Based on computational analysis, crucial variant localization within DNA-binding domain of PPARγ, available literature data and the variant cosegregation in the patient’s family, novel c.443G>A variant was suspected to be causative. Functional testing is needed to confirm the pathogenicity of the novel variant. Inherited lipodystrophy syndromes represent a heterogenous group of metabolic disorders, whose background often remains unclear. A better understating of the genetic basis would allow earlier diagnosis and targeted treatment implementation. Full article

Low-density lipoprotein cholesterol (LDL-C) and total to high-density lipoprotein cholesterol (TC/HDL-C) ratio are both common risk factors for atherosclerotic cardiovascular diseases (ASCVDs). However, whether high-sensitivity C-reactive protein (hsCRP) has synergistic or attenuated effects on atherogenic dyslipidemia remains unclear. We investigated subclinical carotid atherosclerosis in patients with familial hypercholesterolemia (FH) and their family members. A total of 100 families with 761 participants were prospectively studied. Participants were categorized into four groups according to atherogenic dyslipidemia and inflammatory biomarkers. The group with LDL-C ≥ 160 mg/dL (or TC/HDL-C ratio ≥ 5) combined with hsCRP ≥ 2 mg/L have a thicker carotid intima-media thickness (CIMT) in different common carotid artery (CCA) areas and a higher percentage of high plaque scores compared with other subgroups. Multivariate logistic regression analysis revealed a significantly higher adjusted odds ratio (aOR) for thicker CIMT of 3.56 (95% CI: 1.56–8.16) was noted in those with concurrent LDL-C ≥ 160 mg/dL and hsCRP ≥ 2 mg/L compared with the group with concurrent LDL-C < 160 mg/dL and hsCRP < 2 mg/L. Our results demonstrated that systemic inflammation, in terms of higher hsCRP levels ≥ 2 mg/L, synergistically contributed to atherogenic dyslipidemia of higher LDL-C or a higher TC/HDL-C ratio on subclinical atherosclerosis. Full article

To investigate associations between fruit consumption and lipid profiles, and to further explore a satisfactory level of frequency and daily fruit intake for children and adolescents. A national sample of 14,755 children and adolescents aged 5–19 years from seven provinces in China were recruited. Fasting blood samples were collected to test the lipid profile. Information regarding fruit consumption and other characteristics was collected by questionnaires. Logistic regression models adjusting for confounding covariates were applied to calculate the odds ratio (OR) and 95% confidence interval (95% CI). Participants who consumed fruits for 6–7 days per week had lower risks of high triglycerides (OR: 0.66, 95% CI: 0.58–0.75), dyslipidemia (OR: 0.77, 95% CI: 0.68–0.86), and hyperlipidemia (OR: 0.72, 95% CI: 0.63–0.81), compared to fruit consumption of 0–2 days per week. Risks of high triglycerides, dyslipidemia and hyperlipidemia of those who consumed fruits for 0.75–1.5 servings each day also decreased, compared to the insufficient fruit intake. The combined effects of high frequency and moderate daily intake of fruit on lipid disorders did not change essentially. The associations were more evident in girls, younger children and those whose families had higher educational levels. Moderate fruit consumption was associated with lower odds of lipid disorders, predominantly in girls, younger participants, and those came from higher-educated families. These findings supported the health effect of moderate fruit intake frequently to improve the childhood lipid profiles. Full article

Familial hypercholesterolemia (FH) is the most common genetic disorder of lipid metabolism, characterized by increased levels of total and LDL plasma cholesterol, which leads to premature atherosclerosis and coronary heart disease. FH phenotype has considerable genetic heterogeneity and phenotypic variability, depending on LDL receptor activity and lifestyle. To improve diagnosis and patient management, here, we characterized two single nucleotide missense substitutions at Methionine 1 of the human LDLR gene (c.1A>T/p.(Met1Leu) and c.1A>C/p.(Met1Leu)). We used a combination of Western blot, flow cytometry, and luciferase assays to determine the effects of both variants on the expression, activity, and synthesis of LDLR. Our data show that both variants can mediate translation initiation, although the expression of variant c.1A>T is very low. Both variants are in the translation initiation codon and codify for the same amino acid p.(Met1Leu), yet they lead to different levels of impairment on LDLR expression and activity, corroborating different efficiencies of the translation initiation at these non-canonical initiation codons. The functional data of these variants allowed for an improved American College of Medical Genetics (ACMG) classification for both variants, which can allow a more personalized choice of the lipid-lowering treatment and dyslipidemia management, ultimately improving patients’ prognosis. Full article

One strategy to promote physical activity (PA) is for health care providers to give exercise prescriptions (ExRx) that refer to community-based facilities. However, facilitators and barriers specific to urban programs in the US for under-resourced women are unknown. Thus the purpose of this formative research was to explore ExRx barriers and facilitators specific to US under-resourced women to inform future intervention targets and strategies. This mixed-methods community-engaged research was conducted in partnership with an urban women’s only wellness center that exchanged ExRx for free access (1–3 months). Qualitative semi-structured interviews and validated quantitative questionnaires (SF-12, International Physical Activity Questionnaire, Physical Activity Self-Efficacy, Physical Activity Stage of Change, and Barriers to Physical Activity, Social Support for Exercise, and Confusion, Hubbub, and Order Scale) were administered by phone and guided by the socio-ecological model. ExRx utilization was defined as number visits/week divided by membership duration. Means and percentages were compared between ≥1 visit/week vs. <1 visit/week with t-tests and chi-square, respectively. Women (n = 30) were 74% Black, 21–78 years of age, 50% had ≤ high school diploma, and 69% had household incomes ≤45,000/year. Women with ≥1 visit/week (n = 10; 33%) reported more education and higher daily activity, motivation, number of family CVD risk factors and family history of dyslipidemia compared with <1 visit/week. Facilitators among women with ≥1 visit/week were “readiness” and “right timing” for ExRx utilization. Barriers among women with <1 visit/week (n = 20; 67%) were “mismatched expectations” and “competing priorities”. Common themes among all women were “sense of community” and “ease of location”. ExRx utilization at an US urban wellness center may be dependent on a combination of multi-level factors including motivation, confidence, peer support, location and ease of access in under-sourced women. Additional resources may be needed to address mental and/or physical health status in additional to physical activity specific programming. Full article