Abstract
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.
Highlights
Familial LCAT deficiency (FLD) is an ultra-rare autosomal recessive disorder that causes progressive chronic kidney disease (CKD) and early end-stage renal disease (ESRD), usually by the 4th decade of life [1]
Subjects were classified as Fish-eye disease (FED) patients if they had corneal opacity and HDL-C levels below the reference threshold or, in the absence of HDL-C levels, α-LCAT enzymatic activity
A diagram summarizing the classification of subjects into categories is presented in the supplemental methods section. 146 patients met the criteria for FLD and 53 met the criteria for FED classification (Table 1)
Summary
Familial LCAT deficiency (FLD) is an ultra-rare autosomal recessive disorder that causes progressive CKD and early end-stage renal disease (ESRD), usually by the 4th decade of life [1]. It is caused by pathogenic variants in the gene encoding for LCAT, an enzyme mainly secreted by the liver that is solely responsible for the esterification of cholesterol in plasma lipoproteins [2]. Biallelic mutations in the LCAT gene that reduce LCAT secretion or function result in LCAT deficiency, which manifests as two related but different syndromes: Familial LCAT deficiency (FLD) and Fish-eye disease (FED) (Orphanet: an online database of rare diseases and orphan drugs; http://www.orpha.net; Accession numbers: ORPHA:79293 and ORPHA:79292). The difference in phenotype between FLD and FED has been attributed to the extent of residual LCAT activity, with variants associated with complete (α and β) loss of activity causing FLD and variants associated with partial loss of α and β activity, or complete loss of only α activity, but with preserved β activity causing FED [7]
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