HOMOZYGOSITY FOR A SPLICE JUNCTION MUTATION IN EXON-8 OF THE GENE ENCODING LYSOSOMAL ACID LIPASE IN A SPANISH KINDRED WITH CHOLESTEROL ESTER STORAGE DISEASE (CESD)

Deficiency of lysosomal acid lipase is expressed in two distinct recog nizable phenotypes. Wolman disease represents the severe early onset f orm, whereas cholesterol ester storage disease is the more benign late onset type. Previous studies have indicated that compound heterozygos ity consisting of a G --> A mutation at the 3'-splice junction of exon 8 (E8SJM-allele) together with a null allele of the gene encoding lys osomal acid lipase leads to cholesterol ester storage disease. We have now observed homozygosity for the G --> A splice junction mutation in a non-related Spanish kindred with the same disease. As expected, the residual activity of lysosomal acid lipase is higher in this case, su ggesting that the E8SJM-allele is associated with low residual acid li pase activity. However, the phenotype of the homozygous propositus is more severe compared with the previously described case, indicating th at no direct relationship exists between the genotype or residual LAL activity and the precise cholesterol or triglyceride levels in a given patient. Nevertheless, our findings provide convincing evidence that homozygosity for the E8SJM-allele causes cholesterol ester storage dis ease to at least the same extent as compound heterozygosity consisting of this allele and a null allele.