Persistent dyslipidemia in treatment of lysosomal acid lipase deficiency

BACKGROUND: 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. 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. METHODS: A 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. RESULTS: Two 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. CONCLUSION: Enzyme 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.