RARE DISEASE
Familial LCAT deficiency
Familial LCAT deficiency
Familial LCAT deficiency
Synonyms: Complete LCAT deficiency, FLD, Norum disease
Synonyms: Complete LCAT deficiency, FLD, Norum disease
Synonyms: Complete LCAT deficiency, FLD, Norum disease
Drug discovery
1
drug
With orphan designation
Overview
Familial LCAT deficiency (FLD) is a rare autosomal recessive disorder caused by mutations in the LCAT gene (16q22.1), resulting in complete loss of lecithin-cholesterol acyltransferase activity [1][5]. This disrupts cholesterol esterification, causing extremely low HDL levels, corneal opacities (onset in childhood), hemolytic anemia, and progressive renal dysfunction, often leading to end-stage renal failure by the fourth decade [1][13][17]. Extrarenal manifestations include hepatosplenomegaly and atherosclerosis in some cases [10][19]. Diagnosis involves lipid profiling, genetic testing, and renal biopsy showing glomerular lipid deposits [5][13].
Therapies
Symptomatic care: ACE inhibitors/ARBs for proteinuria, statins for dyslipidemia, and erythropoietin for anemia [7][9].
Renal replacement: Hemodialysis or kidney transplantation for ESRD; disease recurrence post-transplant reported [7][13].
Emerging therapies: Gene therapy (AAV-hLCAT) and recombinant LCAT replacement show promise in preclinical studies [3][17].
Categories: rare endocrine diseases, rare genetic diseases, rare hematological diseases, rare inborn errors of metabolism, rare ophthalmic disorders, rare renal diseases, rare transplant-related disorders
Research Papers
144 drug discovery papers about Familial LCAT deficiency, with 2 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
144 drug discovery papers about Familial LCAT deficiency, with 2 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-02-21 | Lecithin-cholesterol acyltransferase deficiency with the finding of "zebra bodies": A diagnostic challenge in the context of suspected Fabry disease.
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.
2026-01-19 | Lecithin-Cholesterol Acyltransferase Deficiency as a Rare Cause of Bilateral Corneal Opacities: A Case Report of a Novel Frameshift Mutation.
Lecithin-cholesterol acyltransferase (LCAT) deficiency is a rare autosomal recessive disorder of lipid metabolism characterized by corneal opacification, hemolytic anemia, and chronic kidney disease. We describe the ophthalmic, systemic, and genetic findings of a patient with LCAT deficiency and report a novel frameshift mutation in the LCAT gene. Ophthalmic findings may represent the first clinical sign and guide the diagnosis. A 50-year-old white male with end-stage renal disease on hemodialysis and a history of recurrent hemolytic anemia was referred for bilateral corneal opacities. Despite diffuse opacification involving all corneal layers, his best corrected visual acuity remained 20/20 in both eyes with normal color vision, although contrast sensitivity was reduced. Laboratory testing revealed normocytic, normochromic anemia, low HDL cholesterol, and reduced apolipoprotein A levels. Genetic analysis identified compound heterozygosity in the LCAT gene: a novel frameshift variant c.580_598del p.(Ala194Serfs*64), classified as likely pathogenic, and the previously described missense variant c.619G>A p.(Gly207Ser), also classified as likely pathogenic. This case highlights the importance of considering metabolic disorders in the differential diagnosis of bilateral corneal opacities and expands the genetic spectrum of LCAT deficiency by reporting a novel frameshift mutation.
2026-01-16 | Quantitative Assessment of Visual Function in Japanese Patients With Lecithin-Cholesterol Acyltransferase Gene Abnormalities: A Case-Control Study.
Introduction Fish-eye disease (FED) and familial lecithin-cholesterol acyltransferase (LCAT) deficiency (FLD) are rare. The aim of this study was to compare visual function between patients with LCAT abnormalities - namely, FED and FLD - and healthy controls. Methods This retrospective, comparative case-control study included four patients with FLD or FED (LCAT group) who presented with cloudy corneas at Miyata Eye Hospital between 2018 and 2024. Four age- and sex-matched individuals with normal results on ophthalmic examination were included as controls. We reviewed medical records for best-corrected visual acuity (BCVA), corneal astigmatism, forward light scattering, and contrast sensitivity. The parameters were compared between the groups. Results Sixteen eyes of eight women were included, including eight eyes of four patients with cloudy corneas in the LCAT group (two with FLD and six with FED) and eight eyes of four controls. The mean BCVA and corneal astigmatism revealed no significant intergroup differences. However, forward scattering was significantly higher in the LCAT group than in the control group (p = 0.007). The area under the log-contrast sensitivity function was significantly lower in the LCAT group than in the control group (p = 0.017). Conclusions Despite normal BCVA, patients with LCAT abnormalities (FLD and FED) showed considerably increased forward light scattering and decreased contrast sensitivity compared with the controls, indicating subtle but substantial visual functional impairment.
2025-11-03 | Abstract 4367648: Fish-Eye Disease: A Case Report
Description of Case: A 26-year-old female was referred to cardiology with bilateral corneal opacifications of four years’ duration, with no change in her visual acuity. Her workup revealed a high-density lipoprotein cholesterol (HDL-C) level of less than 10 mg/dL and a low-density lipoprotein cholesterol (LDL-C) level of 182 mg/dL, prompting genetic evaluation for disorders of lipid metabolism. She was found to have a heterozygous mutation, c.440C>T (p.Thr147Ile), and variant of uncertain significance, c.715G>A (p.Gly239Ser) in the lecithin-cholesterol acyltransferase ( LCAT ) gene. Additional studies showed low-normal serum cholesterol esters and no evidence of hematologic abnormalities or renal dysfunction. Based on these findings and her corneal opacifications, a clinical diagnosis of partial LCAT deficiency, or Fish-Eye Disease (FED), was made. Given her lipid abnormalities and the increased risk of atherosclerosis associated with FED, a high-potency statin was prescribed. Her LDL-C decreased from 182 mg/dL to 124 mg/dL. Discussion: FED is an autosomal recessive disorder of lipid metabolism caused by mutations in the LCAT gene, resulting in partial loss of enzymatic activity. LCAT catalyzes the esterification of free cholesterol, a key step in reverse cholesterol transport; esterification is lost in HDL-C (i.e., alpha activity) and conserved in lipoproteins containing apolipoprotein B (i.e., beta activity). Consequently, FED is biochemically characterized by reduced HDL-C and plasma cholesterol esters and elevated LDL-C, very-low-density lipoprotein cholesterol, triglycerides, and/or plasma unesterified cholesterol. Clinically, these patients typically present with worsening corneal opacities and decreased visual acuity and are at increased risk of atherosclerosis due to preserved beta activity. In contrast, patients may have complete loss of LCAT activity and present with more severe sequelae, a disease known as familial LCAT deficiency (FLD). Absent LCAT activity leads to unesterified cholesterol accumulation, which disrupts red blood cell membranes and deposits in the renal mesangium, leading to hemolytic anemia and renal dysfunction. It is therefore important to promptly determine the degree of LCAT activity loss and manage patients accordingly. Measuring LCAT activity, both alpha and beta, is the best diagnostic test. FED should be treated primarily with lipid-lowering medications, whereas FLD requires monitoring for anemia and renal dysfunction.
2025-10-01 | PS13.4: Autologous transplantation of LCAT gene-transduced adipocytes enabled long-term LCAT replacement in a patient with LCAT deficiency in first in human clinical trial.
Introduction: Familial lecithin:cholesterol acyltransferase (LCAT) deficiency (FLD) syndrome is an autosomal recessive disease characterized by low plasma LCAT activity and severe dysfunction of HDL with subsequent impaired lipoprotein metabolisms. Patients often develop complications such as corneal opacity, hemolytic anemia, and renal dysfunction. In plasma protein deficiency such as LCAT deficiency, gene therapy-mediated continuous enzyme replacement is the most suitable therapeutic approach. We have postulated adipocyte-based ex vivo gene therapy-mediated enzyme replacement therapy (ERT), in which genetically-modified adipocytes (GMAC) reside at transplanted sites to continuously supply therapeutic proteins. We have applied our GMAC technology to treat FLD via transplantation of LCAT gene-transduced autologous preadipocytes (LCAT-GMAC). Methods: The ex vivo gene therapy protocol has been approved under the Act on Securement of Safety of Regenerative Medicine in Japan. A patient was enrolled in January of 2017, and LCAT-GMAC was administered subcutaneously with fibrin glue, which is a clinically applicable scaffold, and the clinical evaluation of the prescribed observation and subsequent follow-up period (total of 240 weeks after administration) was completed, then safety as well as efficacy of the LCAT-GMAC has been investigated in the patient.Results: Post administration pain was observed, however, no other treatment-related adverse effects were observed. In addition, no replication-competent retrovirus in patient’s blood sample or tumorigenicity of the LCAT-GMAC was observed. Increased serum LCAT activity has sustained for 240 weeks. Together with changes in laboratory values related to lipid metabolism, the long-term amelioration of abnormal lipoprotein metabolism was suggested in the patient. The hemoglobin-haptoglobin complex produced with hemolytic anemia was also reduced, which suggested improved vulnerability of erythrocytes. The patient is still undergoing follow-up and still has persistent LCAT activity in his blood eight years after the administration of LCAT-GMAC.Conclusion: These results suggest that LCAT-GMAC is a curative ex vivo gene/cell therapy product for FLD patients, and the following multicenter clinical trials are currently underway to obtain regulatory approval. In conclusion, the GMAC technology will provide a novel platform for ex vivo gene therapy mediated ERT for a variety of intractable diseases.
2026-02-21 | Lecithin-cholesterol acyltransferase deficiency with the finding of "zebra bodies": A diagnostic challenge in the context of suspected Fabry disease.
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.
2026-01-19 | Lecithin-Cholesterol Acyltransferase Deficiency as a Rare Cause of Bilateral Corneal Opacities: A Case Report of a Novel Frameshift Mutation.
Lecithin-cholesterol acyltransferase (LCAT) deficiency is a rare autosomal recessive disorder of lipid metabolism characterized by corneal opacification, hemolytic anemia, and chronic kidney disease. We describe the ophthalmic, systemic, and genetic findings of a patient with LCAT deficiency and report a novel frameshift mutation in the LCAT gene. Ophthalmic findings may represent the first clinical sign and guide the diagnosis. A 50-year-old white male with end-stage renal disease on hemodialysis and a history of recurrent hemolytic anemia was referred for bilateral corneal opacities. Despite diffuse opacification involving all corneal layers, his best corrected visual acuity remained 20/20 in both eyes with normal color vision, although contrast sensitivity was reduced. Laboratory testing revealed normocytic, normochromic anemia, low HDL cholesterol, and reduced apolipoprotein A levels. Genetic analysis identified compound heterozygosity in the LCAT gene: a novel frameshift variant c.580_598del p.(Ala194Serfs*64), classified as likely pathogenic, and the previously described missense variant c.619G>A p.(Gly207Ser), also classified as likely pathogenic. This case highlights the importance of considering metabolic disorders in the differential diagnosis of bilateral corneal opacities and expands the genetic spectrum of LCAT deficiency by reporting a novel frameshift mutation.
2026-01-16 | Quantitative Assessment of Visual Function in Japanese Patients With Lecithin-Cholesterol Acyltransferase Gene Abnormalities: A Case-Control Study.
Introduction Fish-eye disease (FED) and familial lecithin-cholesterol acyltransferase (LCAT) deficiency (FLD) are rare. The aim of this study was to compare visual function between patients with LCAT abnormalities - namely, FED and FLD - and healthy controls. Methods This retrospective, comparative case-control study included four patients with FLD or FED (LCAT group) who presented with cloudy corneas at Miyata Eye Hospital between 2018 and 2024. Four age- and sex-matched individuals with normal results on ophthalmic examination were included as controls. We reviewed medical records for best-corrected visual acuity (BCVA), corneal astigmatism, forward light scattering, and contrast sensitivity. The parameters were compared between the groups. Results Sixteen eyes of eight women were included, including eight eyes of four patients with cloudy corneas in the LCAT group (two with FLD and six with FED) and eight eyes of four controls. The mean BCVA and corneal astigmatism revealed no significant intergroup differences. However, forward scattering was significantly higher in the LCAT group than in the control group (p = 0.007). The area under the log-contrast sensitivity function was significantly lower in the LCAT group than in the control group (p = 0.017). Conclusions Despite normal BCVA, patients with LCAT abnormalities (FLD and FED) showed considerably increased forward light scattering and decreased contrast sensitivity compared with the controls, indicating subtle but substantial visual functional impairment.
2025-11-03 | Abstract 4367648: Fish-Eye Disease: A Case Report
Description of Case: A 26-year-old female was referred to cardiology with bilateral corneal opacifications of four years’ duration, with no change in her visual acuity. Her workup revealed a high-density lipoprotein cholesterol (HDL-C) level of less than 10 mg/dL and a low-density lipoprotein cholesterol (LDL-C) level of 182 mg/dL, prompting genetic evaluation for disorders of lipid metabolism. She was found to have a heterozygous mutation, c.440C>T (p.Thr147Ile), and variant of uncertain significance, c.715G>A (p.Gly239Ser) in the lecithin-cholesterol acyltransferase ( LCAT ) gene. Additional studies showed low-normal serum cholesterol esters and no evidence of hematologic abnormalities or renal dysfunction. Based on these findings and her corneal opacifications, a clinical diagnosis of partial LCAT deficiency, or Fish-Eye Disease (FED), was made. Given her lipid abnormalities and the increased risk of atherosclerosis associated with FED, a high-potency statin was prescribed. Her LDL-C decreased from 182 mg/dL to 124 mg/dL. Discussion: FED is an autosomal recessive disorder of lipid metabolism caused by mutations in the LCAT gene, resulting in partial loss of enzymatic activity. LCAT catalyzes the esterification of free cholesterol, a key step in reverse cholesterol transport; esterification is lost in HDL-C (i.e., alpha activity) and conserved in lipoproteins containing apolipoprotein B (i.e., beta activity). Consequently, FED is biochemically characterized by reduced HDL-C and plasma cholesterol esters and elevated LDL-C, very-low-density lipoprotein cholesterol, triglycerides, and/or plasma unesterified cholesterol. Clinically, these patients typically present with worsening corneal opacities and decreased visual acuity and are at increased risk of atherosclerosis due to preserved beta activity. In contrast, patients may have complete loss of LCAT activity and present with more severe sequelae, a disease known as familial LCAT deficiency (FLD). Absent LCAT activity leads to unesterified cholesterol accumulation, which disrupts red blood cell membranes and deposits in the renal mesangium, leading to hemolytic anemia and renal dysfunction. It is therefore important to promptly determine the degree of LCAT activity loss and manage patients accordingly. Measuring LCAT activity, both alpha and beta, is the best diagnostic test. FED should be treated primarily with lipid-lowering medications, whereas FLD requires monitoring for anemia and renal dysfunction.
2025-10-01 | PS13.4: Autologous transplantation of LCAT gene-transduced adipocytes enabled long-term LCAT replacement in a patient with LCAT deficiency in first in human clinical trial.
Introduction: Familial lecithin:cholesterol acyltransferase (LCAT) deficiency (FLD) syndrome is an autosomal recessive disease characterized by low plasma LCAT activity and severe dysfunction of HDL with subsequent impaired lipoprotein metabolisms. Patients often develop complications such as corneal opacity, hemolytic anemia, and renal dysfunction. In plasma protein deficiency such as LCAT deficiency, gene therapy-mediated continuous enzyme replacement is the most suitable therapeutic approach. We have postulated adipocyte-based ex vivo gene therapy-mediated enzyme replacement therapy (ERT), in which genetically-modified adipocytes (GMAC) reside at transplanted sites to continuously supply therapeutic proteins. We have applied our GMAC technology to treat FLD via transplantation of LCAT gene-transduced autologous preadipocytes (LCAT-GMAC). Methods: The ex vivo gene therapy protocol has been approved under the Act on Securement of Safety of Regenerative Medicine in Japan. A patient was enrolled in January of 2017, and LCAT-GMAC was administered subcutaneously with fibrin glue, which is a clinically applicable scaffold, and the clinical evaluation of the prescribed observation and subsequent follow-up period (total of 240 weeks after administration) was completed, then safety as well as efficacy of the LCAT-GMAC has been investigated in the patient.Results: Post administration pain was observed, however, no other treatment-related adverse effects were observed. In addition, no replication-competent retrovirus in patient’s blood sample or tumorigenicity of the LCAT-GMAC was observed. Increased serum LCAT activity has sustained for 240 weeks. Together with changes in laboratory values related to lipid metabolism, the long-term amelioration of abnormal lipoprotein metabolism was suggested in the patient. The hemoglobin-haptoglobin complex produced with hemolytic anemia was also reduced, which suggested improved vulnerability of erythrocytes. The patient is still undergoing follow-up and still has persistent LCAT activity in his blood eight years after the administration of LCAT-GMAC.Conclusion: These results suggest that LCAT-GMAC is a curative ex vivo gene/cell therapy product for FLD patients, and the following multicenter clinical trials are currently underway to obtain regulatory approval. In conclusion, the GMAC technology will provide a novel platform for ex vivo gene therapy mediated ERT for a variety of intractable diseases.
Access all drug discovery papers and probability of success in trials forecasts:
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Drug Discovery Landscape
1 orphan drug designation for Familial LCAT deficiency.
1 orphan drug designation for Familial LCAT deficiency.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
recombinant human lecithin:cholesterol acyltransferase (rhLCAT) | proteins | FDA | 2010-09-02 | — | MedImmune |
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