Norum disease

is a lipoprotein metabolism disorder characterised by progressive corneal opacification and markedly reduced plasma HDL-cholesterol. Clinical diagnosis is typically made in adulthood, often after the corneal phenotype prompts ophthalmological referral. The opacities are diffuse and dot-like, develop gradually across the stroma and may eventually impair visual acuity. Plasma HDL-cholesterol is severely reduced from early adulthood, frequently to levels barely measurable on routine lipid panels.

Clinical presentation is otherwise frequently subtle, with no systemic, neurological or significant haematological involvement, and the diagnosis is often delayed for many years; persistent corneal opacities together with persistently low HDL-cholesterol on routine lipid testing remain the most consistent diagnostic clues.

In contrast to the related disorder familial LCAT deficiency, fish eye disease spares the kidneys: the proteinuria, haemolytic anaemia and progressive renal failure that characterise familial LCAT deficiency do not occur in fish eye disease.

Due to insufficient data, no reliable statement on prevalence can currently be made. A identified 53 published cases of fish eye disease across 219 publications, indicating an ultra-rare condition.

is caused by partial deficiency of lecithin: cholesterol acyltransferase, resulting from biallelic germline pathogenic variants in LCAT (16q22.1). The enzyme normally esterifies free cholesterol on circulating lipoproteins. In fish eye disease, partial loss of LCAT activity selectively impairs esterification on HDL (α-activity lost), whereas activity on ApoB-containing lipoproteins is preserved (β-activity retained). This residual activity accounts for the milder phenotype and the absence of renal involvement compared with complete enzyme deficiency.

is inherited in an autosomal recessive manner. Both parents of an affected individual are obligate heterozygous carriers and are typically clinically unaffected. The recurrence risk for siblings is 25%. Predictive testing of at-risk relatives is informative once the familial pathogenic variants have been identified. Prenatal molecular testing is technically possible once the familial pathogenic variants have been identified.

The diagnosis rests on biochemical and ophthalmological findings. Slit-lamp examination demonstrates diffuse, dot-like corneal opacities; lipid panel shows markedly reduced plasma HDL-cholesterol. Plasma LCAT activity assays distinguish fish eye disease from familial LCAT deficiency: total LCAT activity is approximately half of normal with retained activity on ApoB-containing lipoproteins, whereas activity on HDL is selectively lost.

• Establishing the diagnosis: a molecular finding confirms the clinical suspicion and provides a definitive diagnosis at the genetic level.
• Informing clinical management: identification of the causative variants is a prerequisite for targeted medical care; specific management decisions are made by the treating physicians in consultation with the affected individual.
• Family member testing: identification of the familial pathogenic variants enables targeted predictive testing of at-risk relatives.

• Vitali C, Bajaj A, Nguyen C, Schnall J, Chen J, Stylianou K, et al. A systematic review of the natural history and biomarkers of primary lecithin acyltransferase deficiency. J Lipid Res. 2022;63(3):100169. doi:10.1016/j.jlr.2022.100169. PMID:; PMCID: PMC8953693
• Kuroda M, Bujo H, Yokote K, Murano T, Yamaguchi T, Ogura M, et al. Current status of familial LCAT deficiency in Japan. J Atheroscler Thromb. 2021;28(7):679-91. doi:10.5551/jat.RV17051. PMID:; PMCID: PMC8265425.
• Pavanello C, Ossoli A. HDL and chronic kidney disease. Atheroscler Plus. 2023;52:9-17. doi:10.1016/j.athplu.2023.04.001. PMID:; PMCID: PMC10182177