Cholesteryl ester storage disease (CESD) and Wolman disease (WD) are both 
autosomal recessive disorders associated with reduced activity and genetic 
defects of lysosomal acid lipase (LAL). The strikingly more severe course of WD 
is caused by genetic defects of LAL that leave no residual enzymatic activity. 
Mutations at the exon 8/intron 8 transition of the LAL gene have been identified 
in several CESD and WD patients and are responsible for the manifestation of the 
disease. We have determined the genetic defect in a 3-month-old boy of African 
origin affected by WD. No enzymatic activity of the lysosomal acid lipase was 
detectable in white blood cells and cultured fibroblasts. Analysis of his LAL 
cDNA and genomic DNA revealed that he was homozygous for a mutation at position 
-3 of the exon 8 splice donor site. A C-->T transition leads to a nonsense codon 
and to a premature termination of the LAL protein at amino acid 277. Due to this 
mutation, a shorter LAL mRNA species was also generated that lacked exon 8 and 
was deficient of the nonsense codon. As a consequence, the protein synthesis 
proceeded to the natural termination codon, but the enzyme generated had an 
internal deletion of 24 amino acids (254-277) and was also inactive. These 
findings, together with our previous observations when analyzing the mutations 
in WD and CESD patients lead to the conclusion that the more severe WD is due to 
mutations that absolutely abolish lysosomal acid lipase (LAL) enzyme activity 
and the cholesteryl ester storage disease phenotype is due to mutations that 
allow some residual LAL activity to be manifested.