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u‰‰ŽÒFRobert J. Desnick, Ph.D., M.D.

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Lysosomal Acid Lipase Deficiency (LALD), a readily diagnosable,
under-recognized disease in hepatology and lipidology
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Robert J. Desnick, Ph.D, M.D.
Dean for Genetics and Genomics,
Professor and Chairman of the Department of Genetics and Genomic Sciences
Mount Sinai School of Medicine


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The lysosomal acid lipase (LAL) plays a key role in lysosomal degradation of cholesteryl esters and triglycerides (TG). LAL Deficiency (LALD) consists of two subtypes: infantile-onset type (Wolman disease: WD) and later-onset type (Cholesteryl ester storage disease: CESD). LAL activity is almost completely deficient in WD, in contrast, in CESD it is partialy decreased.
WD is a fatal disease that progresses rapidly. The clinical features are persistent vomiting and/or diarrhea, abdominal distension, massive hepatosplenomegaly and growth failure. The symptoms onset at 1.0 month, and age at diagnosis is 2.6 months. Age at death is 3.7 months with no medication.
Prominent hepatic manifestations of LALD are elevated serum transaminase levels (AST, ALT), hepatosplenomegaly, fatty liver, fibrosis leading to micronodular cirrhosis, and liver failure. LALD patients also have type II hyperlipoproteinemia (high LDL-cholesterol, high TG, and low HDL-cholesterol).
Desnick et al. reported review of LALD in 2013 (Journal of Hepatology 2013 vol.58, 1230-1243). Diagnoses were based on liver biopsies, simple blood test of LAL activity, and/or LAL gene (LIPA) mutations. The characteristic findings of liver biopsy were diffuse microvesicular steatosis involving hepatocytes, Kupffer cells, and macrophages. Immunostaining for both membranous and luminal lysosomal markers was useful for LALD diagnosis. Common LIPA mutation was exon 8 splice-junction mutation (E8SJM-1 G„A). Genotype/phenotype correlations were limited; however, E8SJM-1 G„A homozygotes typically had early-onset, slowly progressive disease.
Treatment of LALD included cholesterol reduction strategies, liver transplantation, and recombinant human LAL (rhLAL) replacement therapy. rhLAL replacement therapy was shown to be effective in animal models, and recently, a phase I/II clinical trial demonstrated its safety and indicated its potential metabolic efficacy. And now, phase III randomized clinical trials are under way.
It is important to raise the awareness of LALD, thereby LALD patients will be lead to greater detection to improve the management and treatment.

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