Uncommon presentation of Cholesteryl Ester Storage Disease (CESD): Description of a case and genetic characterization by next generation sequencing

Background and Aims : The LIPA gene encodes the lysosomal acidic lipase (LAL), an enzyme which hydrolyzes cholesterol esters (CE) and triglycerides (TG). Cholesteryl Ester Storage Disease (CESD) is a rare recessive disease caused by mutations in LIPA gene which result in residual LAL activity. Complete LAL deficiency is associated with a more severe form of disease known as Wolman’s disease. Hyperlipidemia and liver steatosis are common clinical features of CESD.Methods: The proband, a 2 years old child, was evaluated for microcephaly. Routine laboratory data showed total high cholesterol levels (243 mg/dL) and triglycerides (272 mg/dL). Next generation sequencing was carried out on an Ion GeneStudio S5 Plus System using the Ion 540 Chip. We designed a custom panel to analyze candidate genes related to LDL, HDL e triglycerides metabolism.Results: No pathogenic mutations were identified in the major candidate genes for familial hypercholesterolemia and hypertrygliceridemia. However, the proband was found to be carrier of two mutations in LIPA gene (c.883C>T -p.His295Tyr- and c.929G>A - p.Trp310Ter). This result prompted to the assay of LAL activity by DBS Analysis. LAL activity was < 5% of the normal range. The His295Tyr variant is a pathogenic missense mutation associated with CESD, while the Trp310Ter variant has been previously identified in homozygosity in two newborns of Sicilian origin with Wolman's disease. The family cascade screening revealed the presence of His295Tyr mutation in the proband’s father and the Trp310Ter in the proband’s mother.Conclusions: We report a case of CESD with uncommon clinical presentation features compound heterozygous for two mutations in LIPA gene. Background and Aims : The LIPA gene encodes the lysosomal acidic lipase (LAL), an enzyme which hydrolyzes cholesterol esters (CE) and triglycerides (TG). Cholesteryl Ester Storage Disease (CESD) is a rare recessive disease caused by mutations in LIPA gene which result in residual LAL activity. Complete LAL deficiency is associated with a more severe form of disease known as Wolman’s disease. Hyperlipidemia and liver steatosis are common clinical features of CESD. Methods: The proband, a 2 years old child, was evaluated for microcephaly. Routine laboratory data showed total high cholesterol levels (243 mg/dL) and triglycerides (272 mg/dL). Next generation sequencing was carried out on an Ion GeneStudio S5 Plus System using the Ion 540 Chip. We designed a custom panel to analyze candidate genes related to LDL, HDL e triglycerides metabolism. Results: No pathogenic mutations were identified in the major candidate genes for familial hypercholesterolemia and hypertrygliceridemia. However, the proband was found to be carrier of two mutations in LIPA gene (c.883C>T -p.His295Tyr- and c.929G>A - p.Trp310Ter). This result prompted to the assay of LAL activity by DBS Analysis. LAL activity was < 5% of the normal range. The His295Tyr variant is a pathogenic missense mutation associated with CESD, while the Trp310Ter variant has been previously identified in homozygosity in two newborns of Sicilian origin with Wolman's disease. The family cascade screening revealed the presence of His295Tyr mutation in the proband’s father and the Trp310Ter in the proband’s mother. Conclusions: We report a case of CESD with uncommon clinical presentation features compound heterozygous for two mutations in LIPA gene.