摘要
Wolman disease is a rare autosomal recessive disorder caused by mutations in the LIPA gene (10q23.31). The LIPA gene encodes lysosomal acid lipase (LAL), which plays a key role in hydrolysis of the cholesteryl esters and triglycerides. Two unrelated families from Bulgaria were referred for genetic testing with clinical diagnosis Wolman disease. Sanger sequencing of all coding exons and exon-intron boundaries of the LIPA gene was performed. The index patients were found to be homozygous for two different mutations in the LIPA gene: a missense mutation, c.260G > T, p.Gly87Val, which affects the enzyme active site and a splice-site change, c.822+1G > A, which most probably destroys the enzyme polypeptide chain. These two completely different types of mutations along the LIPA gene resulted in a very similar phenotype involving liver, kidney, gastrointestinal, muscle and blood disturbances. As consanguinity is not typical for the Bulgarian population, a possible explanation of the homozygosity could be presence of endemic regions for given mutations. To check this hypothesis, selective screening for these mutations was performed in two presumable endemic regions in Bulgaria. Altogether, 100 newborns were screened for p.Gly87Val mutation and the detected carrier frequency was about 1% (1/100), while in the group of 100 newborns screened for the c.822 + 1G > A mutation the detected carrier frequency was 2% (2/100). The results indicate a high recurrence risk of Wolman disease in these particular Bulgarian regions of about 1:10000. These findings are from crucial importance for the inhabitants of the corresponding parts of Bulgaria. They may benefit from early genetic testing and adequate genetic counselling during family planning.
Wolman disease is a rare autosomal recessive disorder caused by mutations in the LIPA gene (10q23.31). The LIPA gene encodes lysosomal acid lipase (LAL), which plays a key role in hydrolysis of the cholesteryl esters and triglycerides. Two unrelated families from Bulgaria were referred for genetic testing with clinical diagnosis Wolman disease. Sanger sequencing of all coding exons and exon-intron boundaries of the LIPA gene was performed. The index patients were found to be homozygous for two different mutations in the LIPA gene: a missense mutation, c.260G > T, p.Gly87Val, which affects the enzyme active site and a splice-site change, c.822+1G > A, which most probably destroys the enzyme polypeptide chain. These two completely different types of mutations along the LIPA gene resulted in a very similar phenotype involving liver, kidney, gastrointestinal, muscle and blood disturbances. As consanguinity is not typical for the Bulgarian population, a possible explanation of the homozygosity could be presence of endemic regions for given mutations. To check this hypothesis, selective screening for these mutations was performed in two presumable endemic regions in Bulgaria. Altogether, 100 newborns were screened for p.Gly87Val mutation and the detected carrier frequency was about 1% (1/100), while in the group of 100 newborns screened for the c.822 + 1G > A mutation the detected carrier frequency was 2% (2/100). The results indicate a high recurrence risk of Wolman disease in these particular Bulgarian regions of about 1:10000. These findings are from crucial importance for the inhabitants of the corresponding parts of Bulgaria. They may benefit from early genetic testing and adequate genetic counselling during family planning.
