Lecithin-cholesterol acyltransferase (LCAT) deficiency is a rare autosomal recessive disorder resulting from mutations in the LCAT gene, which leads to abnormal lipoprotein metabolism. This results in markedly reduced high-density lipoprotein cholesterol and the accumulation of lipoprotein X, leading to renal, corneal, and hemolytic damage. Two clinical variants have been described: familial LCAT deficiency (FLD) and fish-eye disease (FED). We report the case of a 41-year-old male with a history of hypertension, tinnitus, and progressive hearing loss, who presented with bilateral corneal opacity since childhood. Laboratory studies revealed significant proteinuria (2.56 g/24 h), preserved renal function (creatinine 0.85 mg/dL), mild anemia (Hb 10.2 g/dL), and extremely low HDL cholesterol (1.3 mg/dL). Renal biopsy showed focal segmental glomerulosclerosis and mesangial expansion. Electron microscopy demonstrated concentric lamellar inclusions known as "zebra bodies," a finding typically associated with Fabry disease. However, α-galactosidase A activity was normal, and genetic testing for Fabry disease was negative. Further genetic analysis identified the variant c.757 p.(Gln253Argfs*11) in the LCAT gene, confirming the diagnosis of familial LCAT deficiency. This case highlights the importance of differentiating LCAT deficiency from Fabry disease, given their overlapping clinical and histological features. Moreover, it represents the first description of "zebra bodies" in LCAT deficiency, emphasizing the diagnostic complexity and the need for a multidisciplinary approach to ensure accurate diagnosis and appropriate management.

Mutations in the lecithin-cholesterol acyltransferase (LCAT) gene, which catalyzes the esterification of cholesterol, result in two types of autosomal recessive disorders: Familial LCAT deficiency (FLD) and Fish Eye Disease (FED). While both phenotypes are characterized by corneal opacities and different forms of dyslipidemia, such as low levels of high-density lipoprotein-cholesterol (HDL-C), FLD exhibits more severe clinical manifestations like splenomegaly, anemia, and renal failure. We describe the first clinically and genetically confirmed case of FLD in Colombia which corresponds to a 46-year-old woman with corneal opacity, hypothyroidism, and dyslipidemia, who does not have any manifestations of renal failure, with two pathogenic heterozygous missense variants in the LCAT gene: LCAT (NM_000229.2):c.803G>A (p.Arg268His) and LCAT (NM_000229.2):c.368G>C (p.Arg123Pro). In silico analysis of the mutations predicted the physicochemical properties of the mutated protein, causing instability and potentially decreased LCAT function. These compound mutations highlight the clinical heterogeneity of the phenotypes associated with LCAT gene mutations. Lecithin cholesterol acyltransferase (LCAT) deficiency is a rare inherited syndrome characterized by the partial or complete absence of LCAT enzyme activity. LCAT is an enzyme attached to both high-density lipoprotein (HDL) and low-density lipoprotein (LDL) particles and is responsible for the esterification of cholesterol, a crucial step in the metabolism of HDL particles. Deficiency of LCAT leads to impaired HDL metabolism, resulting in abnormal lipid profiles and predisposing to complications. There are 2 clinical variants of the disease. The first is familial LCAT deficiency that involves a complete deficiency of the enzyme. The second is Fish-eye disease characterized by a partial deficiency of the enzyme.

Lecithin:cholesterol acyltransferase (LCAT) deficiencies represent severe disorders characterized by aberrant cholesterol esterification in plasma, leading to life-threatening conditions. This study investigates the efficacy of Compound 2, a piperidinyl pyrazolopyridine allosteric activator that binds the membrane-binding domain of LCAT, in rescuing the activity of LCAT variants associated with disease. The variants K218N, N228K, and G230R, all located in the cap and lid domains of LCAT, demonstrated notable activity restoration in response to Compound 2. Molecular dynamics simulations and structural modeling indicate that these mutations disrupt the lid and membrane binding domain, with Compound 2 potentially dampening these structural alterations. Conversely, variants such as M252K and F382V in the cap and α/β-hydrolase domain, respectively, exhibited limited or no rescue by Compound 2. Future research should prioritize in vivo investigations that would validate the therapeutic potential of Compound 2 and related activators in familial LCAT deficiency patients with mutations in the cap and lid of the enzyme. SIGNIFICANCE STATEMENT: Lecithin:cholesterol acyltranferase (LCAT) catalyzes the first step of reverse cholesterol transport, namely the esterification of cholesterol in high density lipoprotein particles. Somatic mutations in LCAT lead to excess cholesterol in blood plasma and, in severe cases, kidney failure. In this study, we show that recently discovered small molecule activators can rescue function in LCAT-deficient variants when the mutations occur in the lid and cap domains of the enzyme.

Low high-density lipoprotein cholesterol (HDL-C) is a risk factor for cardiovascular disease. Very low HDL-C levels (less than 20 mg/dL), however, were uncommonly seen and can be due to genetic defects involving the metabolic pathway of high-density lipoprotein (HDL). We encountered a 50-year-old Chinese man who was only noticed to have extremely low HDL-C levels after surviving recurrent episodes of myocardial infarction. Further workup revealed the undetectable level of apolipoprotein A-I, the absence of HDL on gel electrophoresis, and a novel heterozygous splicing variant in the ABCA1 gene, which was predicted to be pathogenic by in silico analysis. To the best of our knowledge, this is the first reported Hong Kong Chinese with ABCA1 deficiency and probable Tangier disease. The association of ABCA1 deficiency/Tangier disease and accelerated atherosclerosis is discussed. Clinicians should be aware of the differential diagnoses of very low HDL-C, which could be divided into genetic and acquired causes. Genetic low HDL syndromes include apoA-I deficiency, Tangier disease, and familial LCAT deficiency, each of which has characteristic clinical features and can be differentiated from the other further by apoA-I measurement, lipoprotein analysis, and genetic testing. Patients with ABCA1 deficiency and Tangier disease are at risk of premature coronary artery disease and should be aggressively screened and treated for cardiovascular risk factors and established cardiovascular diseases. Revascularization strategy and indications for coronary artery bypass grafting in patients with Tangier disease and coronary artery disease follow that as for patients without Tangier disease.

Familial lecithin:cholesterol acyltransferase (LCAT) deficiency (FLD) is an ultra-rare autosomal recessive disease characterized by very low high-density lipoprotein cholesterol (HDL-C) levels, corneal opacity, anemia, and progressive renal disease. The rate and severity of renal disease are variable across FLD patients and the biomarkers and risk factors for disease progression are poorly understood. Here we report a 30 year-long comparative analysis of the clinical and laboratory biomarkers in an FLD patient with accelerated renal decline, who underwent two kidney and one liver transplantations. Results show that elevated triglyceride and non-HDL-C levels may promote the formation of LpX and accelerate renal function decline, whereas markers of anemia may be early predictors. Conversely, corneal opacity progresses at a steady rate and does not correlate with lipid, hematologic, or renal biomarkers. Our study suggests that monitoring of markers of anemia may aid the early detection and timely management of kidney disease with conservative therapies. Furthermore, it suggests that controlling hypercholesterolemia and hypertriglyceridemia may help improve renal disease prognosis.