Novel LIPA mutations in Mexican siblings with lysosomal acid lipase deficiency

Abstract

Lysosomal acid lipase (LAL) deficiency is an under-recognized lysosomal disease caused by deficient enzymatic activity of LAL. In this report we describe two affected female Mexican siblings with early hepatic complications. At two months of age, the first sibling presented with alternating episodes of diarrhea and constipation, and later with hepatomegaly, elevated transaminases, high levels of total and low-density lipoprotein cholesterol, and low levels of high-density lipoprotein. Portal hypertension and grade 2 esophageal varices were detected at four years of age. The second sibling presented with hepatomegaly, elevated transaminases and mildly elevated low-density lipoprotein and low high-density lipoprotein at six months of age. LAL activity was deficient in both patients. Sequencing of LIPA revealed two previously unreported heterozygous mutations in exon 4: c.253C>A and c.294C>G. These cases highlight the clinical continuum between the so-called Wolman disease and cholesteryl ester storage disease, and underscore that LAL deficiency represents a single disease with a degree of clinical heterogeneity.

Keywords: Cholesteryl ester storage disease; Liver fibrosis; Dyslipidemia; Liver steatosis; Wolman disease

Core tip: Lysosomal acid lipase deficiency is a rare genetic disorder related to the metabolism of cholesterol and triglycerides inside the lysosome. In this report, we present the findings from two siblings with no lysosomal acid lipase activity caused by two previously unidentified mutations in exon 4 of LIPA. The patients had early hepatic presentation, including severe cirrhosis and esophageal varices in the elder sibling, underscoring the significant morbidity that can occur at all ages of lysosomal acid lipase deficiency and highlighting possible compensatory mechanisms in liver function in children.