The lysosomal acid lipase deficiency spectrum from infancy to adulthood: a multidisciplinary experience

Lysosomal acid lipase (LAL) deficiency, an ultrarare autosomal recessive disorder related to LIPA gene variants, presents two clinical phenotypes: Wolman's disease (WD), which occurs early with severe presentation, and Cholesteryl Ester Storage Disease (CESD) with a milder and variable course mainly affecting lipid metabolism and liver function. Misdiagnosis risk, treatment effectiveness and long-term outcome are significant issues. Enzyme replacement therapy (ERT) represents the only effective choice in WD. This study aims to address diagnostic and therapeutic challenges and to explore the long-term effects of lipid-lowering therapy (LLT) in CESD.

We retrospectively analyzed data collected over the last 30 years from seven LAL deficiency (LAL-D) patients, 2 WD infants and 5 CESD children and adults, including biochemical analysis, LAL enzyme activity, LIPA gene variants, carotid intima-media thickness and liver assessments by ultrasound, magnetic resonance imaging, transient elastography and biopsy. The variability of first clinical presentation delayed the diagnosis of CESD (from 4 to 52 years). WD twin infants presented with severe liver and gastrointestinal symptoms and died before 9 months of age. Ezetimibe treatment led to LDL-C and ALT improvement in 4/5 CESD patients (LDL-C 19 %, ALT 21.6 % mean decreases) without progression of liver fibrosis in the mid-to long-term follow-up.

LAL-D mimics hyperlipidemias and liver disorders making a definitive diagnosis mandatory. Patients with CESD presentation should benefit from first level treatment with LLT before considering ERT which represents the option in case of unresponsiveness or symptoms progression while it represents the elective therapy for WD.