A NOVEL VARIANT OF LYSOSOMAL ACID LIPASE IN CHOLESTERYL ESTER STORAGEDISEASE-ASSOCIATED WITH MILD PHENOTYPE AND IMPROVEMENT ON LOVASTATIN

Cholesterol ester storage disease (CESD) is a rare congenital disorder of lipid metabolism, with mutation of the lysosomal acid lipase gene, causing chronic liver disease, usually before adolescence, We here de scribe three adult siblings with CESD diagnosed by light microscopic d emonstration of excessive lysosomal storage of lipids with accumulatio n of foamy cells in liver biopsies and by a decrease in acid lipase ac tivity (2-3% of controls), One patient (male, 46a) had extensive liver fibrosis, another (female, 58a) had cirrhosis of the liver, The third patient had died from variceal haemorrhage (female, 56a), Using seque nce analysis of RT-PCR products of LAL mRNA, the patients were identif ied as compound heterozygotes for a G-->A substitution at position -1 of the exon 8 splice donor site and a point mutation at the second all ele, resulting in a His(108)-->Pro shift, In two patients, therapy wit h lovastatin was initialed, which led to normalisation of serum choles terol and triglyceride levels, After 12 months, liver biopsy demonstra ted a significant decrease in vacuolisation of hepatocytes, with fewer and smaller droplets, Semi-automated computer-assisted image analysis of electron microscopic sections demonstrated a decrease in the hepat ocellular lysosomal area from 20.5+/-7.1% to 11.7+/-6.5% (p<0.05) and 41.7+/-5.1% to 33.4+/-4.4% (p<0.01), We conclude that in two siblings with a novel LAL variant and mild phenotype of CESD, lovastatin decrea sed both serum lipid concentrations and hepatocellular lysosomal conte nt.