Lysosomal Acid Lipase Deficiency Lipid Insights December 9, 2013 Daniel J. Rader, MD LAL Deficiency . History . Pathophysiology and genetic epidemiology . Liver disease . Dyslipidemia and atherosclerosis . Diagnostic considerations . Therapeutic considerations . Summary Biology of Lysosomal Acid Lipase LDL particle lysosome Free cholesterol and free fatty acids nucleus Hepatocyte Lysosomal Acid Lipase (LAL) Deficiency: A single disease, with marked clinical heterogeneity LAL Deficiency is sometimes called: . Wolman disease (infantile presentation with growth failure) . Cholesteryl Ester Storage Disease or CESD (LAL deficiency presentation in children and adults) . Acid Cholesteryl Ester Hydrolase Deficiency, Type 2 . Acid Lipase Disease . Cholesteryl Ester Hydrolase Deficiency Storage Disease . LIPA Deficiency LAL Deficiency . History . Pathophysiology and genetic epidemiology . Liver disease . Dyslipidemia and atherosclerosis . Diagnostic considerations . Therapeutic considerations . Summary A brief history: The first phenotypic descriptions . Abramov, Shorr, and Wolman, 1956: “Generalized xanthomatosis with calcified adrenals” (“Wolman” disease) . Fredrickson, 1963: “Cholesterol ester storage disease” – “…likely a specific hepatic defect in cholesterol ester metabolism.” . Patrick and Lake : “Deficiency of an acid lipase in Wolman’s disease”, Nature, 1969 . Burke and Schubert : “Deficient activity of hepatic acid lipase in cholesterol ester storage disease”, Science, 1972 . Cortner et al: “Genetic variation of lysosomal acid lipase”, Pediatric Research, 1976 . Goldstein, et al: “Role of lysosomal acid lipase in the metabolism of plasma Low density lipoprotein,” JBC, 1975 . Anderson, et al: Cloning of the lysosomal acid lipase cDNA, JBC, 1991 . Anderson, et al: Mutations at the lysosomal acid cholesterol esterase gene locus in Wolman disease. Proc Natl Acad Sci USA, 1994 . Klima H, et al: “A splice junction mutation causes deletion of a 72-base exon from the mRNA for lysosomal acid lipase in a patient with cholesteryl ester storage disease.” J Clin Invest, 1993. A brief history: Unraveling the molecular basis (1) the protein . Abramov, Shorr, and Wolman, 1956: “Generalized xanthomatosis with calcified adrenals” (“Wolman” disease) . Fredrickson, 1963: “Cholesterol ester storage disease” – “…likely a specific hepatic defect in cholesterol ester metabolism.” . Patrick and Lake : “Deficiency of an acid lipase in Wolman’s disease”, Nature, 1969 . Burke and Schubert : “Deficient activity of hepatic acid lipase in cholesterol ester storage disease”, Science, 1972 . Cortner et al: “Genetic variation of lysosomal acid lipase”, Pediatric Research, 1976 . Goldstein, et al: “Role of lysosomal acid lipase in the metabolism of plasma Low density lipoprotein,” JBC, 1975 . Anderson, et al: Cloning of the lysosomal acid lipase cDNA, JBC, 1991 . Anderson, et al: Mutations at the lysosomal acid cholesterol esterase gene locus in Wolman disease. Proc Natl Acad Sci USA, 1994 . Klima H, et al: “A splice junction mutation causes deletion of a 72-base exon from the mRNA for lysosomal acid lipase in a patient with cholesteryl ester storage disease.” J Clin Invest, 1993. A brief history: Unraveling the molecular basis (2) the gene . Abramov, Shorr, and Wolman, 1956: “Generalized xanthomatosis with calcified adrenals” (“Wolman” disease) . Fredrickson, 1963: “Cholesterol ester storage disease” – “…likely a specific hepatic defect in cholesterol ester metabolism.” . Patrick and Lake : “Deficiency of an acid lipase in Wolman’s disease”, Nature, 1969 . Burke and Schubert : “Deficient activity of hepatic acid lipase in cholesterol ester storage disease”, Science, 1972 . Cortner et al: “Genetic variation of lysosomal acid lipase”, Pediatric Research, 1976 . Goldstein, et al: “Role of lysosomal acid lipase in the metabolism of plasma Low density lipoprotein,” JBC, 1975 . Anderson, et al: Cloning of the lysosomal acid lipase cDNA, JBC, 1991 . Anderson, et al: Mutations at the lysosomal acid cholesterol esterase gene locus in Wolman disease. Proc Natl Acad Sci USA, 1994 . Klima H, et al: “A splice junction mutation causes deletion of a 72-base exon from the mRNA for lysosomal acid lipase in a patient with cholesteryl ester storage disease.” J Clin Invest, 1993. LAL Deficiency . History . Pathophysiology and genetic epidemiology . Liver disease . Dyslipidemia and atherosclerosis . Diagnostic considerations . Therapeutic considerations . Summary Biology of Lysosomal Acid Lipase Deficiency Healthy Individuals LAL Deficient Patients LDL particle LDL particle lysosome lysosome Free cholesterol and free fatty acids nucleus nucleus Hepatocyte • Accumulation of abnormal lipid in lysosome AND • Disruption of normal lipid homeostasis LAL Deficiency: One Disease Presenting Across a Clinical Continuum Adults Children o Minimal residual LAL enzyme activity o Minimal residual LAL enzyme activity o Advanced liver disease o Premature liver o Premature fibrosis/cirrhosis cardiovascular events o Accelerated Infants atherosclerosis o No LAL enzyme o Profound growth failure o Persistent vomitting /diarrhea o Median age of death (3.4 months) LAL Deficiency presenting in infancy (historically also called Wolman Disease) . Marked accumulation of cholesteryl esters and Weight-for-age percentiles: triglycerides in many tissues Boys, birth to 12 months 33.1 . Prominent hepatic and GI manifestations 30.9 28.7 – Persistent vomiting, diarrhea 26.5 97th 24.3 85th 22.1 – Hepatomegaly and liver failure 50th 19.8 15th 17.6 3rd – Splenomegaly Weight Pounds in 15.4 – Abdominal distension 13.2 11 – Profound growth failure 8.8 6.6 LAL Deficient 4.4 . Adrenal calcification frequently present 1 2 3 4 5 6 7 8 9 10 1112 Age (months) . Rapidly progressive and fatal within 1st year of life . No approved treatments; only palliative care . Incidence: 1:300,000 to 1,000,000 – Increased with consanguinity (e.g., Persian Jews) 12 Molecular Epidemiology of LAL Deficiency Presenting in Children and Adults . Many different mutations have been described . A single mutation has been described in 50-60% of the cases of LAL deficiency presenting in children and adults: – A point mutation at Exon 8 Splice Junction (E8SJM) which leads to ~3-5% normally spliced mRNA . Estimated prevalence of 1:40,000 to 1:300,000 – Similar to other lysosomal storage disorders (e.g., Gaucher, Fabry, Pompe). LAL Deficiency: Genetic Epidemiology Author Journal Carriers of E8SJM/ Estimated Sample Size Prevalence* Muntoni et al Arterioscler 10/2023 1:43,000 to 1:78,000 Thromb Vasc Biol ; (German population) 2007 Grabowski et Scriver’s OMMBID; 9/7011 1:159,000 to 1:294,000 al 2012 (European Americans) Scott et al Hepatology; 2013 14/4569 1:111,000 to 1:204,000 (Caucasian + Hispanic) Stitziel et al Arterioscler 88/27,472 1:102,000 to 1:189,000 Thromb Vasc Biol; (European ancestry) 2013 *Range based upon assumption of the “common” E8SJM representing 51 to 69% of all disease causing mutations LAL Deficiency . History . Pathophysiology and genetic epidemiology . Clinical manifestations including liver disease . Dyslipidemia and atherosclerosis . Diagnostic considerations . Therapeutic considerations . Summary LAL Deficiency presenting in childhood or adulthood: a rare disease with a common phenotype . Shortened lifespan and morbidity . Prominent hepatic manifestations – Fatty liver (microvesicular steatosis) – Elevated transaminases – Fibrosis and cirrhosis – Liver failure (often early in life) . Cardiovascular involvement Affected liver removed during transplant – Elevated LDL cholesterol surgery age 9 – Low HDL frequently observed – Variably elevated triglycerides – Accelerated atherosclerosis . Other manifestations: – Splenomegaly – GI manifestations – Lymphadenopathy Clinical Summary (Bernstein et al.; review of 135 cases) Age of onset Male (birth – 44) Female (1 month-68) Distribution of 27% between birth and 1 years, Age of Onset 62% between age 3 and 12 years, 11% during adolescence or as adults. 4% patients whose diagnoses were made at autopsy Hepatomegaly Presented in 99% of patients Splenomegaly Presented in 74% of patients Transaminase Elevated AST and/or ALT activities were present in all cases reporting Levels serum transaminase activities, with significant fluctuations at different time points Bernstein et al. Cholesteryl Ester Storage Disease: Review of the Findings in 135 Reported Patients with an Under-Diagnosed Disease. Journal of Hepatology (2013). Epub Clinical Summary (Bernstein et al.) Liver • Occurred in all pts Dysfunction • Of the 11 reported deaths, the majority (73%) were due to liver and/or Liver failure Failure • Progression to esophageal varices was reported in 12 cases. 4 additional deaths from liver were reported after publication • Death due to liver disease progression occurred at 7 to 56 years old, • 50% of deaths were in patients under 21 years of age. Liver Biopsy • Findings were consistent among patients, and appeared (83%) independent of age, genotype, or other factors • A striking orange-yellow in color and diffuse, uniform microvesicular steatosis with minimal zonal differences within the hepatic lobule. • 72 (64%) had fibrosis and/or cirrhosis • 17 patients (15%) who had both fibrosis and cirrhosis in initial or subsequent biopsies Bernstein et al. Cholesteryl Ester Storage Disease: Review of the Findings in 135 Reported Patients with an Under-Diagnosed Disease. Journal of Hepatology (2013). Epub ALT Abnormal In A Broad Spectrum Of Patients With Late Onset LAL Deficiency ALT Highest recorded Female