Abstract
BackgroundLysosomal acid lipase deficiency (LALD) is an autosomal recessive inborn error of lipid metabolism characterized by impaired lysosomal hydrolysis and consequent accumulation of cholesteryl esters and triglycerides. The phenotypic spectrum is diverse, ranging from severe, neonatal onset failure to thrive, hepatomegaly, hepatic fibrosis, malabsorption and adrenal insufficiency to childhood-onset hyperlipidemia, hepatomegaly, and hepatic fibrosis. Sebelipase alfa enzyme replacement has been approved by the Food and Drug Administration for use in LALD after demonstrating dramatic improvement in transaminitis and dyslipidemia with initiation of enzyme replacement therapy.MethodsA chart review was performed on 2 patients with childhood-onset, symptomatic LALD with persistent dyslipidemia despite appropriate enzyme replacement therapy to identify biological pathways and risk factors for incomplete response to therapy.ResultsTwo patients with attenuated, symptomatic LALD had resolution of transaminitis on enzyme replacement therapy without concomitant effect on dyslipidemia despite dose escalation and no evidence of antibody response to enzyme.ConclusionEnzyme replacement therapy does not universally resolve all complications of LALD. Persistent dyslipidemia remains a clinically significant issue, likely related to the complex metabolic pathways implicated in LALD pathogenesis. We discuss the possible mechanistic basis for this unexpected finding and the implications for curative LALD therapy.
Highlights
Lysosomal acid lipase deficiency (LALD) is an autosomal recessive inborn error of lipid metabolism characterized by impaired lysosomal hydrolysis and consequent accumulation of cholesteryl esters and triglycerides
Lysosomal acid lipase deficiency (LALD, Online Mendelian Inheritance in Man number 278000) is a rare, autosomal recessive inborn error of lipid metabolism caused by biallelic pathogenic variants in the LIPA gene, which encodes the enzyme lysosomal acid lipase (LAL)
Wolman Disease is characterized by hepatosplenomegaly, cholestasis, hepatic fibrosis, failure to thrive, malabsorption, and adrenal insufficiency, and was universally fatal without bone marrow transplantation prior to the arrival of enzyme replacement therapy [1]
Summary
Lysosomal acid lipase deficiency (LALD) is an autosomal recessive inborn error of lipid metabolism characterized by impaired lysosomal hydrolysis and consequent accumulation of cholesteryl esters and triglycerides. Sebelipase alfa enzyme replacement has been approved by the Food and Drug Administration for use in LALD after demonstrating dramatic improvement in transaminitis and dyslipidemia with initiation of enzyme replacement therapy. Wolman Disease is characterized by hepatosplenomegaly, cholestasis, hepatic fibrosis, failure to thrive, malabsorption, and adrenal insufficiency, and was universally fatal without bone marrow transplantation prior to the arrival of enzyme replacement therapy [1]. CESD typically presents during mid-childhood to late adulthood with hepatomegaly with or without splenomegaly, transaminitis, Treatment for LALD was historically supportive until 2015 with Food and Drug Administration (FDA) approval of enzyme replacement therapy (ERT). A Phase III trial of biweekly enzyme replacement for 52 weeks demonstrated dramatic clinical and biochemical improvement, including normalization or near-normalization of alanine aminotransferase (ALT) levels, improved lipid parameters including reduction in low-density lipoprotein cholesterol (LDL-C) and triglycerides and increased high-density lipoprotein cholesterol (HDL-C) levels, and decreased hepatic fat content [7]
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