LCAT – Norum disease

Familial lecithin–cholesterol acyltransferase (LCAT) deficiency, also known as Norum disease, is an autosomal recessive disorder characterized by near‐absent cholesterol esterification, leading to severe hypoalphalipoproteinemia, diffuse corneal opacities, normocytic anemia, proteinuria, and progressive renal insufficiency. Diagnosis rests on demonstration of markedly reduced LCAT activity and mass in plasma, combined with molecular confirmation of biallelic pathogenic variants in LCAT.

Genetic evidence encompasses reports from three original Norwegian kindreds harboring the recurrent c.827T>A (p.Met276Lys) variant (PMID:1516702), alongside >45 additional probands from >20 unrelated families identified worldwide (PMID:7749857). Segregation in multiplex pedigrees—such as compound heterozygotes in a Finnish family carrying c.934_935insC (p.Glu312AlafsTer12) and p.Arg423Cys (PMID:7749857)—confirms autosomal recessive inheritance.

The variant spectrum includes >30 distinct missense substitutions (e.g., p.Arg268His), frameshift and nonsense alleles (e.g., c.321C>A (p.Tyr107Ter)), splice‐site defects, and deep intronic branchpoint mutations causing intron retention (PMID:9555046). Recurrent founder alleles are seen in Norwegian, Finnish, Brazilian, and Japanese populations, with carrier frequencies up to 5% in select cohorts.

Segregation analyses demonstrate pathogenic variants co‐segregating with the Norum phenotype in up to 6 affected relatives per pedigree (PMID:9741700), reinforcing causality. Compound heterozygous and homozygous individuals uniformly exhibit absent LCAT activity and hallmark clinical features.

Functional studies in vitro and in cell models encompass site‐directed mutagenesis, expression in COS and HEK‐293 cells, and biochemical assays confirming loss of alpha‐LCAT and beta‐LCAT activity. For example, branchpoint mutations in intron 4 abrogate splicing and enzyme secretion (PMID:9555046), while missense alleles like p.Thr13Met reduce enzyme stability and HDL activation (PMID:9741700). These data elucidate a loss‐of‐function mechanism consistent with haploinsufficiency and dominant negative absence of activity.

No credible conflicting evidence has been reported. Modifier genes, such as APOE, may influence lipoprotein profiles but do not diminish the core LCAT–Norum disease association. Genetic testing for LCAT variants informs diagnosis, enables family screening, guides dietary and enzyme replacement strategies, and facilitates prognostication of renal outcomes.

Key Take-home: Biallelic loss‐of‐function variants in LCAT cause Norum disease, with robust genetic and functional data supporting a definitive clinical validity, making LCAT sequencing essential for diagnosis and management.

References

• FEBS letters • 1992 • The genetic defect of the original Norwegian lecithin:cholesterol acyltransferase deficiency families. PMID:1516702
• Arteriosclerosis, thrombosis, and vascular biology • 1995 • Two different allelic mutations in a Finnish family with lecithin:cholesterol acyltransferase deficiency. PMID:7749857
• Biochimica et biophysica acta • 1998 • T-->G or T-->A mutation introduced in the branchpoint consensus sequence of intron 4 of lecithin:cholesterol acyltransferase (LCAT) gene: intron retention causing LCAT deficiency. PMID:9555046
• Journal of lipid research • 1998 • Transmission of two novel mutations in a pedigree with familial lecithin:cholesterol acyltransferase deficiency: structure-function relationships and studies in a compound heterozygous proband. PMID:9741700
• American journal of kidney diseases • 2019 • The P274S Mutation of Lecithin-Cholesterol Acyltransferase (LCAT) and Its Clinical Manifestations in a Large Kindred. PMID:31103331
• Journal of lipid research • 1997 • The molecular pathology of lecithin:cholesterol acyltransferase (LCAT) deficiency syndromes. PMID:9162740

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