Concept: Lysosomal lipase
Clinical Features of Lysosomal Acid Lipase Deficiency - a Longitudinal Assessment of 48 Children and Adults
- Journal of pediatric gastroenterology and nutrition
- Published over 2 years ago
To characterize key clinical manifestations of lysosomal acid lipase deficiency (LAL D) in children and adults.
Infants presenting with lysosomal acid lipase deficiency have marked failure to thrive, diarrhea, massive hepatosplenomegaly, anemia, rapidly progressive liver disease, and death typically in the first 6 months of life; the only available potential treatment has been hematopoietic stem cell transplantation, which is associated with high morbidity and mortality in this population. The study objective was to evaluate safety and efficacy (including survival) of enzyme replacement with sebelipase alfa in infants with lysosomal acid lipase deficiency. This is an ongoing multicenter, open-label, phase 2/3 study conducted in nine countries. The study enrolled infants with growth failure prior to 6 months of age with rapidly progressive lysosomal acid lipase deficiency; they received once-weekly doses of sebelipase alfa initiated at 0.35 mg/kg with intrapatient dose escalation up to 5 mg/kg. The main outcome of interest is survival to 12 months and survival beyond 24 months of age.
- Genetics in medicine : official journal of the American College of Medical Genetics
- Published over 2 years ago
The purpose of this study was to enhance understanding of lysosomal acid lipase deficiency (LALD) in infancy.
The erythrocyte osmotic resistance test as screening tool for cholesterol-related lysosomal storage diseases
- Clinica chimica acta; international journal of clinical chemistry
- Published 3 days ago
Erythrocyte volume regulation and membrane elasticity are essential for adaptation to osmotic and mechanical stress, and life span. Here, we evaluated whether defective cholesterol trafficking caused by the rare lysosomal storages diseases (LSDs), Niemann-Pick type C (NPC) and Lysosomal acid lipase (LAL) deficiency (LALD) impairs these properties. Moreover, we tested whether measurements of cholesterol membrane content and osmotic resistance serve as a screening test for these LSDs.
Deficiency of lysosomal acid lipase (LAL) causes Wolman disease and cholesterol ester storage disease. With the recent introduction of enzyme replacement therapy to manage LAL deficiency comes the need for a reliable assay of LAL enzymatic activity that can be applied to dried blood spots (DBS).
Lysosomal acid lipase deficiency (LAL-D) causes progressive cholesteryl ester and triglyceride accumulation in the lysosomes of hepatocytes and monocyte-macrophage system cells, resulting in a systemic disease with various manifestations that may go unnoticed. It is indispensable to recognize the deficiency, which can present in patients at any age, so that specific treatment can be given. The aim of the present review was to offer a guide for physicians in understanding the fundamental diagnostic aspects of LAL-D, to successfully aid in its identification.
Although only a small proportion of cholesterol in the body is esterified, in several diseases marked expansion of the esterified cholesterol (EC) pool occurs. These include Wolman disease (WD) and Cholesteryl Ester Storage Disease (CESD) which both result from mutations in LIPA, the gene that encodes lysosomal acid lipase (LAL). The respective contributions that our three cholesterol esterifying enzymes make to EC production, especially in disorders like CESD, are not well defined. The current studies represent a detailed exploration of our earlier findings in young male LAL-deficient mice also missing sterol-O-acyltransferase 2 (SOAT2, also called ACAT2). Here we show that, even as they aged, male and female Lal -/-: Soat2 -/- mice, compared to Lal -/-: Soat2 +/+ littermates, had appreciably less hepatomegaly as well as a marked reduction in the level of sequestration of EC, in liver transaminase activities, and in hepatic mRNA expression levels for markers of inflammation. Loss of SOAT2 function also dramatically curtailed EC entrapment in the small intestine of the LAL-deficient mice. Together, these data imply that SOAT2 inhibition, if applied concurrently with enzyme replacement therapy for LAL deficiency, may blunt the re-esterification of newly released unesterified cholesterol thereby improving clinical outcomes.
- Revista paulista de pediatria : orgao oficial da Sociedade de Pediatria de Sao Paulo
- Published 4 months ago
To describe a case of cholesteryl ester storage disease (CESD) and discuss the importance of liver biopsy for diagnosis.
CRISPR/Cas9-Mediated Gene Editing in Human iPSC-Derived Macrophage Reveals Lysosomal Acid Lipase Function in Human Macrophages
- Arteriosclerosis, thrombosis, and vascular biology
- Published 5 months ago
To gain mechanistic insights into the role of LIPA(lipase A), the gene encoding LAL (lysosomal acid lipase) protein, in human macrophages.
Childhood/Adult-onset Lysosomal Acid Lipase Deficiency (LAL-D) is a recessive disorder due to loss of function variants of LAL, the enzyme which hydrolyses cholesteryl esters, derived from internalized apoB containing lipoproteins. The disease is characterized by multi-organ involvement including the liver, spleen, intestine and cardiovascular system. The aim of this study was the clinical and molecular characterization of 14 (13 unrelated) previously unreported patients with childhood-onset LAL-D.