👤 Muhammad Danial Che Ramli

Homozygous familial hypercholesterolemia (HoFH) is a rare inherited disorder with an extremely elevated level of low-density lipoprotein (LDL) cholesterol (LDL-C) and accelerated premature coronary artery disease (PCAD). It is primarily caused by a single pathogenic variant of the LDL receptor (LDLR) gene. This report presents 2 rare and unrelated cases of HoFH with compound LDLR mutations. These 2 individuals presented with atypical clinical features and demonstrated variable degrees of hypercholesterolemia. Case 1 is a 36-year-old Malay woman identified during family cascade screening with a pretreated LDL-C of 8.5 mmol/L and a strong family history of PCAD. Case 2 is a 58-year-old Indian woman discovered to have a pretreated LDL-C of 5.2 mmol/L during routine health screening, without a significant family history of hypercholesterolemia or PCAD. Neither patient demonstrated tendon xanthomas or other lipid stigmata. Both patients underwent lipid profiling and targeted next-generation sequencing of FH-related genes (LDLR, APOB, PCSK9, ABCG5, and ABCG8). Two novel LDLR variants were identified in exon 18: c.2548-1₂₅₄₈delGAinsTC (pathogenic) and c.2556₂₅₅₇insTCAGTCTGG (p.Leu853Serfs*12; likely pathogenic) and classified according to American College of Medical Genetics and Genomics guidelines. Case 1 was homozygous for both variants, while Case 2 was homozygous for the splice-site variant and heterozygous for the frameshift variant. Both patients received guideline-directed lipid-lowering therapy and ongoing cardiovascular risk management. Despite biallelic LDLR variants, both patients demonstrated relatively milder hypercholesterolemia and absence of classical HoFH stigmata. The LDLR variants located in exon 18 affecting the cytoplasmic tail domain may be associated with attenuated clinical expression. Recognition of genotype-phenotype variability is crucial for accurate diagnosis, risk stratification, and individualized management of HoFH. Show less

Atherosclerosis is partially driven by the accumulation of oxidised low-density lipoprotein (oxLDL), which facilitates foam cell formation and vascular inflammation. This research examines the efficacy of bamboo charcoal (BC) as a bioactive agent for neutralising oxLDL using both in silico and in vitro methodologies. Molecular docking demonstrated significant binding affinities between BC and essential constituents of oxLDL, such as oxidised cholesterol and apolipoprotein B-100, facilitated by π-π stacking and electrostatic interactions. Molecular dynamics simulations demonstrated the stability of these complexes over 300 ns, indicating sustained molecular interactions. Quantum chemical calculations employing density functional theory showed a narrow HOMO-LUMO gap of 0.45 eV and a significant dipole moment of approximately 45 D, underscoring the reactive and polar characteristics of BC. Electrostatic potential mapping and thermodynamic analyses provided additional evidence for BC's spontaneous and stable binding to oxLDL components. The Oil Red O staining and total cholesterol estimation assays were conducted on oxLDL-treated RAW 264.7 macrophages in vitro indicated that BC significantly decreased macrophage-derived foam cell formation, thereby confirming its ability to reduce oxLDL-induced lipid accumulation. The findings suggest that BC functions as a physical adsorbent and a participant in direct chemical interactions with oxLDL, providing a dual-action therapeutic approach to atherosclerosis. Show less

Despite decades of research, Alzheimer's disease (AD) remains without a curative therapy. While amyloid- and tau-centered approaches have dominated the field, failures of monotherapeutic strategies underscore the need for a broader system-level understanding. Here, this review critically revisits the principal hypotheses of AD pathogenesis, including the amyloid cascade, tauopathy, neuroinflammation, cholinergic dysfunction, oxidative and mitochondrial stress, metal dyshomeostasis, autophagy-lysosomal failure, genetic susceptibility, and infectious triggers. This review synthesizes molecular and cellular evidence from human genetics, neuropathology, and experimental models, correcting common misconceptions and emphasizing interactions between pathways. Neuroinflammation is increasingly recognized as a central hub linking amyloid, tau, and vascular factors, while mitochondrial and lysosomal dysfunctions emerge as amplifiers of proteotoxic stress. Genetic studies highlight apolipoprotein-E ε4 (APOE ε4) as the strongest common risk allele, but also implicate genes involved in endosomal trafficking, lipid metabolism, and immune regulation. Taken together, AD is best understood as a multi-hit disorder in which converging processes, rather than a single driver, dictate disease initiation and progression. This narrative review proposes a systems neurobiology framework that integrates these mechanisms and identifies key points of convergence amenable to therapeutic targeting and biomarker development. Finally, this reappraisal aims to inform future research directions and guide the rational design of multi-target interventions. Show less

Metabolic syndrome (MetS) refers to a cluster of metabolic dysregulations, which include insulin resistance, obesity, atherogenic dyslipidemia and hypertension. The complex pathogenesis of MetS encompasses the interplay between environmental and genetic factors. Environmental factors such as excessive nutrients and sedentary lifestyle are modifiable and could be improved by lifestyle modification. However, genetic susceptibility to MetS, a non-modifiable factor, has attracted the attention of researchers, which could act as the basis for future diagnosis, prognosis, and therapy for MetS. Several cholesterol-related genes associated with each characteristic of MetS have been identified, such as apolipoprotein, lipoprotein lipase (LPL), cholesteryl ester transfer protein (CETP) and adiponectin. This review aims to summarize the genetic information of cholesterol-related genes in MetS, which may potentially serve as biomarkers for early prevention and management of MetS. Show less