LCAT – Fish Eye Disease

Lecithin:cholesterol acyltransferase (LCAT) is a key enzyme in plasma cholesterol esterification, crucial for HDL maturation. Fish eye disease (FED) is a rare autosomal recessive disorder characterized by severe HDL deficiency and dense corneal opacities (PMID:1588268). Affected individuals exhibit near‐absent HDL‐associated LCAT activity but retain partial activity toward non‐HDL lipoproteins.

Biallelic pathogenic variants in LCAT underlie FED. Over 30 unrelated probands carrying missense, frameshift, splice, and small‐deletion alleles have been reported, with most variants leading to selective loss of HDL‐esterification capacity. A representative variant is c.440C>T (p.Thr147Ile), identified in a Dutch kindred with three generations of affected individuals (PMID:1588268).

Segregation analyses in multiple families confirm autosomal recessive inheritance. For example, four homozygous probands with an Asp131Asn substitution co-segregate with FED features in a pedigree of four affected individuals and their 34 heterozygous relatives (PMID:8675648), and 13 Italian families yielded four FED cases among 82 members (PMID:15994445).

Functional assays demonstrate that FED‐associated LCAT variants disrupt HDL‐specific esterification while sparing LDL activity. In vitro expression of p.Thr123Ile shows >90% loss of HDL substrate activity but preserved LDL esterification (PMID:8448345), and studies of multiple mutants reveal impaired secretion or altered cofactor interaction in human embryonic kidney cells (PMID:7721870). These data establish a partial loss‐of‐function mechanism concordant with the human phenotype.

No substantial conflicting evidence has been reported. The clinical spectrum of FED overlaps with familial LCAT deficiency (FLD) but can be distinguished by residual non‐HDL LCAT activity and absence of renal failure. Genetic testing of LCAT is essential to differentiate FED from FLD, Tangier disease, and apoA-I deficiency.

Key Take-home: Biallelic LCAT variants cause autosomal recessive fish eye disease via partial LCAT deficiency; targeted genetic testing guides diagnosis and management of corneal opacities with severe HDL deficiency.

References

• Journal of internal medicine • 1992 • Familial high-density-lipoprotein deficiency causing corneal opacities (fish eye disease) in a family of Dutch descent. PMID:1588268
• The Journal of clinical investigation • 1995 • A unique genetic and biochemical presentation of fish-eye disease. PMID:8675648
• Arteriosclerosis, thrombosis, and vascular biology • 2005 • The molecular basis of lecithin:cholesterol acyltransferase deficiency syndromes: a comprehensive study of molecular and biochemical findings in 13 unrelated Italian families. PMID:15994445
• Journal of lipid research • 1993 • Recombinant lecithin:cholesterol acyltransferase containing a Thr123→Ile mutation esterifies cholesterol in low density lipoprotein but not in high density lipoprotein. PMID:8448345
• The Journal of biological chemistry • 1995 • In vitro expression of structural defects in the lecithin-cholesterol acyltransferase gene. PMID:7721870

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