Rapidly progressive renal failure to reveal LCAT deficiency in an Algerian family.

Lecithin-cholesterol acyltransferase (LCAT) deficiency is an autosomal recessive disorder that can reveal two different diseases: a very interesting nephrological picture of complete enzyme deficiency characterized by the association of dyslipidemia, corneal opacities, anemia, and progressive nephropathy; and a partial form (fish-eye disease) with dyslipidemia and progressive corneal opacities only. We report herein the case of a 35-year-old man who presented hypertension, renal symptomatology of rapidly progressive glomerulonephritis associates: nephrotic proteinuria, severe renal failure, in combination with annular corneal opacities, anemia, and dyslipidemia. The diagnosis of familial LCAT deficiency was confirmed by clinical examination, characteristic dyslipidemia, undetectable LCAT levels in plasma, and positive family history.

Two Cases of Acquired High-Density Lipoprotein Deficiency with Immunoglobulin G4-Related Lecithin-Cholesterol Acyltransferase Autoantibody.

Lecithin-cholesterol acyltransferase (LCAT) plays a significant role in the progression from premature to mature high-density lipoprotein (HDL) in circulation. Consequently, primary or secondary LCAT deletion or reduction naturally results in low serum HDL cholesterol levels. Recently, rare cases of acquired HDL deficiency with LCAT autoantibodies have been reported, mainly from Japan, where LCAT autoantibodies of immunoglobulin G (IgG) caused the HDL deficiency. Here to our knowledge, we report for the first time two cases of acquired HDL deficiency caused by IgG4 linked LCAT autoantibodies with or without a high serum IgG4 level. Furthermore, these cases can extend to a new concept of "IgG4 autoimmune disease" from the viewpoint of verifying the serum autoantibody and/or renal histopathology.

Novel therapeutic opportunities for familial lecithin:cholesterol acyltransferase deficiency: promises and challenges.

PURPOSE OF REVIEW: Genetic lecithin:cholesterol acyltransferase (LCAT) deficiency is a rare, inherited, recessive disease, which manifests as two different syndromes: Familial LCAT deficiency (FLD) and Fish-eye disease (FED), characterized by low HDL-C and corneal opacity. FLD patients also develop anaemia and renal disease. There is currently no therapy for FLD, but novel therapeutics are at different stages of development. Here, we summarize the most recent advances and the opportunities for and barriers to the further development of such therapies. RECENT FINDINGS: Recent publications highlight the heterogeneous phenotype of FLD and the uncertainty over the natural history of disease and the factors contributing to disease progression. Therapies that restore LCAT function (protein and gene replacement therapies and LCAT activators) showed promising effects on markers of LCAT activity. Although they do not restore LCAT function, HDL mimetics may slow renal disease progression. SUMMARY: The further development of novel therapeutics requires the identification of efficacy endpoints, which include quantitative biomarkers of disease progression. Because of the heterogeneity of renal disease progression among FLD individuals, future treatments for FLD will have to be tailored based on the specific clinical characteristics of the patient. Extensive studies of the natural history and biomarkers of the disease will be required to achieve this goal.

A novel homozygous frameshift mutation in the APOA1 gene associated with marked high-density lipoprotein deficiency.

The proband was a 53-year-old Japanese woman. Despite having no atherosclerotic vascular lesions on a physiological examination, markedly decreased levels of high-density lipoprotein (HDL) were always noted at her annual medical checkup. She also had corneal opacities but neither xanthoma nor tonsillar hypertrophy. A biochemical examination showed decreased levels of both apolipoprotein A-I (apoA-I) (<5 mg/dL) and lecithin-cholesterol acyltransferase (LCAT) activity. Her brother and son also had low concentrations of HDL-cholesterol, suggesting the presence of a genetic abnormality. Therefore, a sequence analysis of the genes for ABCA1, LCAT and apoA-I proteins was performed in the proband. The analysis of the APOA1 gene revealed a novel homozygous two-nucleotide deletion in exon 4 (c.614_615delTC), which causes a frameshift after residue 205 of the apoA-I protein (p.Leu205fs). Since no mutation has been found in the ABCA1 or LCAT gene, functional abnormalities of the carboxyl-terminal region of the apoA-I protein in lipid binding might have caused the low HDL-cholesterol levels and decreased LCAT activity, possibly associated with corneal opacities but not premature CAD, in the patient.

Plasma FA composition in familial LCAT deficiency indicates SOAT2-derived cholesteryl ester formation in humans.

Mutations in the LCAT gene cause familial LCAT deficiency (Online Mendelian Inheritance in Man ID: #245900), a very rare metabolic disorder. LCAT is the only enzyme able to esterify cholesterol in plasma, whereas sterol O-acyltransferases 1 and 2 are the enzymes esterifying cellular cholesterol in cells. Despite the complete lack of LCAT activity, patients with familial LCAT deficiency exhibit circulating cholesteryl esters (CEs) in apoB-containing lipoproteins. To analyze the origin of these CEs, we investigated 24 carriers of LCAT deficiency in this observational study. We found that CE plasma levels were significantly reduced and highly variable among carriers of two mutant LCAT alleles (22.5 [4.0-37.8] mg/dl) and slightly reduced in heterozygotes (218 [153-234] mg/dl). FA distribution in CE (CEFA) was evaluated in whole plasma and VLDL in a subgroup of the enrolled subjects. We found enrichment of C16:0, C18:0, and C18:1 species and a depletion in C18:2 and C20:4 species in the plasma of carriers of two mutant LCAT alleles. No changes were observed in heterozygotes. Furthermore, plasma triglyceride-FA distribution was remarkably similar between carriers of LCAT deficiency and controls. CEFA distribution in VLDL essentially recapitulated that of plasma, being mainly enriched in C16:0 and C18:1, while depleted in C18:2 and C20:4. Finally, after fat loading, chylomicrons of carriers of two mutant LCAT alleles showed CEs containing mainly saturated FAs. This study of CEFA composition in a large cohort of carriers of LCAT deficiency shows that in the absence of LCAT-derived CEs, CEs present in apoB-containing lipoproteins are derived from hepatic and intestinal sterol O-acyltransferase 2.

LCAT- targeted therapies: Progress, failures and future.

Lecithin: cholesterol acyltransferase (LCAT) is the only enzyme in plasma which is able to esterify cholesterol and boost cholesterol esterify with phospholipid-derived acyl chains. In order to better understand the progress of LCAT research, it is always inescapable that it is linked to high-density lipoprotein (HDL) metabolism and reverse cholesterol transport (RCT). Because LCAT plays a central role in HDL metabolism and RCT, many animal studies and clinical studies are currently aimed at improving plasma lipid metabolism by increasing LCAT activity in order to find better treatment options for familial LCAT deficiency (FLD), fish eye disease (FED), and cardiovascular disease. Recombinant human LCAT (rhLCAT) injections, cells and gene therapy, and small molecule activators have been carried out with promising results. Recently rhLCAT therapies have entered clinical phase II trials with good prospects. In this review, we discuss the diseases associated with LCAT and therapies that use LCAT as a target hoping to find out whether LCAT can be an effective therapeutic target for coronary heart disease and atherosclerosis. Also, probing the mechanism of action of LCAT may help better understand the heterogeneity of HDL and the action mechanism of dynamic lipoprotein particles.

A systematic review of the natural history and biomarkers of primary lecithin:cholesterol acyltransferase deficiency.

Syndromes associated with LCAT deficiency, a rare autosomal recessive condition, include fish-eye disease (FED) and familial LCAT deficiency (FLD). FLD is more severe and characterized by early and progressive chronic kidney disease (CKD). No treatment is currently available for FLD, but novel therapeutics are under development. Furthermore, although biomarkers of LCAT deficiency have been identified, their suitability to monitor disease progression and therapeutic efficacy is unclear, as little data exist on the rate of progression of renal disease. Here, we systematically review observational studies of FLD, FED, and heterozygous subjects, which summarize available evidence on the natural history and biomarkers of LCAT deficiency, in order to guide the development of novel therapeutics. We identified 146 FLD and 53 FED patients from 219 publications, showing that both syndromes are characterized by early corneal opacity and markedly reduced HDL-C levels. Proteinuria/hematuria were the first signs of renal impairment in FLD, followed by rapid decline of renal function. Furthermore, LCAT activity toward endogenous substrates and the percentage of circulating esterified cholesterol (EC%) were the best discriminators between these two syndromes. In FLD, higher levels of total, non-HDL, and unesterified cholesterol were associated with severe CKD. We reveal a nonlinear association between LCAT activity and EC% levels, in which subnormal levels of LCAT activity were associated with normal EC%. This review provides the first step toward the identification of disease biomarkers to be used in clinical trials and suggests that restoring LCAT activity to subnormal levels may be sufficient to prevent renal disease progression.

Clinical Dilemma of Corneal Opacity, Very Low High-density Lipoprotein, and Nephrotic Syndrome: Mystery Revealed.

Lecithin-cholesterol acyltransferase (LCAT) is a liver enzyme necessary for the formation of cholesteryl esters in plasma from free cholesterol. The rare autosomal recessive disease resulting from familial deficiency of this enzyme can lead to nephropathy with kidney involvement generally being the most common cause of death. In addition, the disease process can engender corneal opacity, very low high-density lipoprotein, normochromic anemia, and nephropathy. We present this case of a 35-year-old male who initially visited for a second opinion for renal failure and nephrotic range proteinuria. He underwent renal biopsy which displayed focal segmental glomerulosclerosis-type injury pattern and was started on futile high-dose steroid therapy. A second renal biopsy coincided with the development of corneal opacity leading to a confirmatory testing of LCAT deficiency through biochemistry panel.

A novel pathogenic variant in LCAT causing FLD. A case report.

BACKGROUND: Fish-eye disease (FED) is due to a partial deficiency in LCAT activity. Nevertheless, Familial lecithin-cholesterol acyltransferase deficiency (FLD), also called Norum disease, appears when the deficiency is complete. They are both rare genetic disorders inherited in an autosomal recessive manner. Clinical signs include decreased circulating HDL cholesterol and dense corneal opacity. Kidney injuries also affect patients suffering from FLD. The diagnosis of FLD is based on the presence of characteristic signs and symptoms and confirmed by genetic testing. CASE PRESENTATION: We present a case of a 63-year-old man showing an altered lipid profile with low HDL cholesterol, chronic kidney disease (CKD) and corneal disorders. He was referred to genetic counseling in order to discard genetic LCAT deficiency due to decreased visual acuity caused by corneal opacity. A massive DNA sequencing was conducted using a multigene panel associated with lipid metabolism disturbances. RESULTS AND GENETIC FINDINGS: Two likely pathogenic variants in LCAT were identified and later confirmed by Sanger sequencing. Both (c.491 G > A and c.496 G > A) were missense variants that originated an amino acid substitution (164Arginine for Histidine and 166Alanine for Threonine, respectively) modifying the protein sequence and its 3D structure. CONCLUSIONS: FLD and FED sharing common biochemical features, and the existence of other diseases with similar clinical profiles underline the need for a timely differential diagnosis aiming to address patients to preventive programs and future available therapies. This case, added to the reduced number of publications previously reported regarding FLD and FED, contributes to better understanding the genetic characteristics, clinical features, and diagnosis of these syndromes.

The HDL mimetic CER-001 remodels plasma lipoproteins and reduces kidney lipid deposits in inherited lecithin:cholesterol acyltransferase deficiency.

BACKGROUND: Kidney failure is the major cause of morbidity and mortality in familial lecithin:cholesterol acyltransferase deficiency (FLD), a rare inherited lipid disorder with no cure. Lipoprotein X (LpX), an abnormal lipoprotein, is primarily accountable for nephrotoxicity. METHODS: CER-001 was tested in an FLD patient with dramatic kidney disease for 12 weeks. RESULTS: Infusions of CER-001 normalized the lipoprotein profile, with a disappearance of the abnormal LpX in favour of normal-sized LDL. The worsening of kidney function was slowed by the treatment, and kidney biopsy showed a slight reduction of lipid deposits and a stabilization of the disease. In vitro experiments demonstrate that CER-001 progressively reverts lipid accumulation in podocytes by a dual effect: remodelling plasma lipoproteins and removing LpX-induced lipid deposit. CONCLUSION: This study demonstrates that CER-001 may represent a therapeutic option in FLD patients. It also has the potential to be beneficial in other renal diseases characterized by kidney lipid deposits.

LCAT deficiency: a systematic review with the clinical and genetic description of Mexican kindred.

BACKGROUND: LCAT (lecithin-cholesterol acyltransferase) deficiency is characterized by two distinct phenotypes, familial LCAT deficiency (FLD) and Fish Eye disease (FED). This is the first systematic review evaluating the ethnic distribution of LCAT deficiency, with particular emphasis on Latin America and the discussion of three Mexican-Mestizo probands. METHODS: A systematic review was conducted following the PRISMA (Preferred Reporting Items for Systematic review and Meta-Analysis) Statement in Pubmed and SciELO. Articles which described subjects with LCAT deficiency syndromes and an assessment of the ethnic group to which the subject pertained, were included. RESULTS: The systematic review revealed 215 cases (154 FLD, 41 FED and 20 unclassified) pertaining to 33 ethnic/racial groups. There was no association between genetic alteration and ethnicity. The mean age of diagnosis was 42 ± 16.5 years, with fish eye disease identified later than familial LCAT deficiency (55 ± 13.8 vs. 41 ± 14.7 years respectively). The prevalence of premature coronary heart disease was significantly greater in FED vs. FLD. In Latin America, 48 cases of LCAT deficiency have been published from six countries (Argentina (1 unclassified), Brazil (38 FLD), Chile (1 FLD), Columbia (1 FLD), Ecuador (1 FLD) and Mexico (4 FLD, 1 FED and 1 unclassified). Of the Mexican probands, one showed a novel LCAT mutation. CONCLUSIONS: The systematic review shows that LCAT deficiency syndromes are clinically and genetically heterogeneous. No association was confirmed between ethnicity and LCAT mutation. There was a significantly greater risk of premature coronary artery disease in fish eye disease compared to familial LCAT deficiency. In FLD, the emphasis should be in preventing both cardiovascular disease and the progression of renal disease, while in FED, cardiovascular risk management should be the priority. The LCAT mutations discussed in this article are the only ones reported in the Mexican- Amerindian population.

Correction of Familial LCAT Deficiency by AAV-hLCAT Prevents Renal Injury and Atherosclerosis in Hamsters-Brief Report.

[Figure: see text].

Current Status of Familial LCAT Deficiency in Japan.

Lecithin cholesterol acyltransferase (LCAT) is a lipid-modification enzyme that catalyzes the transfer of the acyl chain from the second position of lecithin to the hydroxyl group of cholesterol (FC) on plasma lipoproteins to form cholesteryl acylester and lysolecithin. Familial LCAT deficiency is an intractable autosomal recessive disorder caused by inherited dysfunction of the LCAT enzyme. The disease appears in two different phenotypes depending on the position of the gene mutation: familial LCAT deficiency (FLD, OMIM 245900) that lacks esterification activity on both HDL and ApoB-containing lipoproteins, and fish-eye disease (FED, OMIM 136120) that lacks activity only on HDL. Impaired metabolism of cholesterol and phospholipids due to LCAT dysfunction results in abnormal concentrations, composition and morphology of plasma lipoproteins and further causes ectopic lipid accumulation and/or abnormal lipid composition in certain tissues/cells, and serious dysfunction and complications in certain organs. Marked reduction of plasma HDL-cholesterol (HDL-C) and corneal opacity are common clinical manifestations of FLD and FED. FLD is also accompanied by anemia, proteinuria and progressive renal failure that eventually requires hemodialysis. Replacement therapy with the LCAT enzyme should prevent progression of serious complications, particularly renal dysfunction and corneal opacity. A clinical research project aiming at gene/cell therapy is currently underway.

CER-001 ameliorates lipid profile and kidney disease in a mouse model of familial LCAT deficiency.

OBJECTIVE: CER-001 is an HDL mimetic that has been tested in different pathological conditions, but never with LCAT deficiency. This study was designed to investigate whether the absence of LCAT affects the catabolic fate of CER-001, and to evaluate the effects of CER-001 on kidney disease associated with LCAT deficiency. METHODS: Lcat-/- and wild-type mice received CER-001 (2.5, 5, 10 mg/kg) intravenously for 2 weeks. The plasma lipid/ lipoprotein profile and HDL subclasses were analyzed. In a second set of experiments, Lcat-/- mice were injected with LpX to induce renal disease and treated with CER-001 and then the plasma lipid profile, lipid accumulation in the kidney, albuminuria and glomerular podocyte markers were evaluated. RESULTS: In Lcat-/- mice a decrease in total cholesterol and triglycerides, and an increase in HDL-c was observed after CER-001 treatment. While in wild-type mice CER-001 entered the classical HDL remodeling pathway, in the absence of LCAT it disappeared from the plasma shortly after injection and ended up in the kidney. In a mouse model of renal disease in LCAT deficiency, treatment with CER-001 at 10 mg/kg for one month had beneficial effects not only on the lipid profile, but also on renal disease, by limiting albuminuria and podocyte dysfunction. CONCLUSIONS: Treatment with CER-001 ameliorates the dyslipidemia typically associated with LCAT deficiency and more importantly limits renal damage in a mouse model of renal disease in LCAT deficiency. The present results provide a rationale for using CER-001 in FLD patients.

Spontaneous Atherosclerosis in Aged LCAT-Deficient Hamsters With Enhanced Oxidative Stress-Brief Report.

OBJECTIVE: LCAT (lecithin cholesterol acyltransferase) deficiency results in severe low HDL (high-density lipoprotein). Although whether LCAT is pro- or antiatherosclerosis was in debate in mouse studies, our previous study clearly shows that LCAT deficiency (LCAT-/-) in hamster accelerates atherosclerotic development on high-fat diet. However, unlike in hypercholesterolemia and hypertriglyceridemia, whether LCAT deficiency could lead to spontaneous atherosclerosis has not been studied yet in animal models. We, therefore, sought to investigate the atherosclerosis in LCAT-/- hamsters on standard laboratory diet and explore the potential underlying mechanisms. Approach and Results: Young (<8 months) and aged (>16 months) male and female wild-type and LCAT-/- hamsters on standard laboratory diet were used. Compared with age- and sex-matched wild-type hamsters, LCAT-/- hamsters showed a complete loss of plasma HDL and an increase in triglyceride by 2- to 8-fold at different stages of age. In aged LCAT-/- hamsters, the lesion areas at the aortic roots were ≈40×104 µm3 in males and 18×104 µm3 in females, respectively, which were consistent with the en face plaques observed in male (1.2%) and (1.5%) female groups, respectively. The results of plasma malondialdehyde measurement showed that malondialdehyde concentrations were markedly elevated to 54.4 µmol/L in males and 30 µmol/L in females, which are significantly associated with the atherosclerotic lesions. CONCLUSIONS: Our study demonstrates the development of spontaneous atherosclerotic lesions in aged male and female LCAT-/- hamsters with higher plasma oxidative lipid levels independent of plasma total cholesterol levels, further confirming the antiatherosclerotic role of LCAT.

Progression of chronic kidney disease in familial LCAT deficiency: a follow-up of the Italian cohort.

Familial LCAT deficiency (FLD) is a rare genetic disorder of HDL metabolism, caused by loss-of-function mutations in the LCAT gene and characterized by a variety of symptoms including corneal opacities and kidney failure. Renal disease represents the leading cause of morbidity and mortality in FLD cases. However, the prognosis is not known and the rate of deterioration of kidney function is variable and unpredictable from patient to patient. In this article, we present data from a follow-up of the large Italian cohort of FLD patients, who have been followed for an average of 12 years. We show that renal failure occurs at the median age of 46 years, with a median time to a second recurrence of 10 years. Additionally, we identify high plasma unesterified cholesterol level as a predicting factor for rapid deterioration of kidney function. In conclusion, this study highlights the severe consequences of FLD, underlines the need of correct early diagnosis and referral of patients to specialized centers, and highlights the urgency for effective treatments to prevent or slow renal disease in patients with LCAT deficiency.

Genetic, biochemical, and clinical features of LCAT deficiency: update for 2020.

PURPOSE OF REVIEW: Genetic LCAT deficiency is a rare metabolic disorder characterized by low-plasma HDL cholesterol levels. Clinical manifestations of the disease include corneal opacification, anemia, and renal disease, which represents the major cause of morbidity and mortality in carriers. RECENT FINDINGS: Biochemical and clinical manifestations of the disease are very heterogeneous among carriers. The collection of large series of affected individuals is needed to answer various open questions on this rare disorder of lipid metabolism, such as the cause of renal damage in patients with complete LCAT deficiency and the cardiovascular risk in carriers of different LCAT gene mutations. SUMMARY: Familial LCAT deficiency is a rare disease, with serious clinical manifestations, which can occur in the first decades of life, and presently with no cure. The timely diagnosis in carriers, together with the identification of disease biomarkers able to predict the evolution of clinical manifestations, would be of great help in the identification of carriers to address to future available therapies.