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 about 2 years ago
To characterize key clinical manifestations of lysosomal acid lipase deficiency (LAL D) in children and adults.
- Genetics in medicine : official journal of the American College of Medical Genetics
- Published about 2 years ago
The purpose of this study was to enhance understanding of lysosomal acid lipase deficiency (LALD) in infancy.
CRISPR/Cas9-Mediated Gene Editing in Human iPSC-Derived Macrophage Reveals Lysosomal Acid Lipase Function in Human Macrophages
- Arteriosclerosis, thrombosis, and vascular biology
- Published about 1 month 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.
Best practice in the measurement and interpretation of lysosomal acid lipase in dried blood spots using the inhibitor Lalistat 2
- Clinica chimica acta; international journal of clinical chemistry
- Published 5 months ago
Lysosomal acid lipase deficiency (LAL-D) is an inherited, autosomal recessive lysosomal storage disorder characterized by progressive damage in multiple organ systems. Diagnosis is especially important in infants, in whom the course of disease is rapidly lethal without treatment. The recent regulatory approval of recombinant human lysosomal acid lipase (LAL), sebelipase alfa, merits rapid diagnosis in clinical routine, particularly in infants. A method for measuring LAL activity in dried blood spot (DBS) samples using the highly specific LAL inhibitor Lalistat 2 is available. This method is shown to effectively discriminate between individuals with LAL-D and unaffected controls. With the increase in DBS LAL testing since the original publication of this method, a need to optimise assay performance has been identified. Here, we describe refinements to the DBS assay, including technical modifications, quality control measures and best-practice guidance for interpreting and reporting results. Particular attention is paid to alternatives to the use of mercuric chloride as the stop reagent and the choice of excitation wavelength for 4-methylumbelliferone palmitate under assay conditions at pH4.0. In addition, a simpler method of reporting results is proposed using cutoffs based on percentage mean normal enzyme activity.
No published case of Wolman’s disease has described the prenatal sonographic findings. We present a case in which a third-trimester sonographic examination demonstrated fetal hepatomegaly and bilateral adrenal echogenicity suggestive of diffuse calcification. Wolman’s disease, also known as lysosomal acid lipase (LIPA) deficiency, is a rare autosomal-recessive disorder characterized by complete absence of the LIPA enzyme. The diagnosis of Wolman’s disease was made postnatally by biochemical testing, which indicated absence of LIPA enzyme activity and gene sequencing, which confirmed homozygosity for the G66V mutation within the LIPA gene. © 2017 Wiley Periodicals, Inc. J Clin Ultrasound, 2017.
We aimed to evaluate the influence of white blood cell (WBC) and platelet (PLT) counts on dried blood spot (DBS)-determined lysosomal acid lipase (LAL) activity in a large group of healthy subjects.
Lysosomal acid lipase (LAL) is a lysosomal key enzyme involved in the intracellular hydrolysis of cholesteryl esters and triglycerides. Patients with very low residual LAL activity present with the infantile severe form Wolman disease (WD), while patients with some residual activity develop the less severe disorder known as Cholesteryl ester storage disorder (CESD). We present the clinical, biochemical, and molecular findings of 23 Spanish patients (22 families) with LAL deficiency. We identified eight different mutations, four of them not previously reported. The novel c.966+2T>G mutation accounted for 75% of the Wolman disease alleles, and the frequent CESD associated c.894G>A mutation accounted for 55% of the CESD alleles in our cohort. Haplotype analysis showed that both mutations co-segregated with a unique haplotype suggesting a common ancestor. Our study contributes to the LAL deficiency acknowledgement with novel mutations and with high frequencies of some unknown mutations for WD.
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.
- American journal of cardiovascular drugs : drugs, devices, and other interventions
- Published 11 months ago
Sebelipase alfa (Kanuma(®), Kanuma™), the first commercially available recombinant human lysosomal acid lipase (LAL), is approved in various countries worldwide, including those of the EU, the USA and Japan, as a long-term enzyme replacement therapy for patients diagnosed with LAL deficiency (LAL-D), an ultra-rare, autosomal recessive, progressive metabolic liver disease. In an ongoing study in nine infants presenting with early-onset LAL-D (Wolman disease), open-label treatment with sebelipase alfa significantly improved 1-year survival compared with historical controls. A substantial mortality benefit was maintained at 2 years of age, as was a reduction in disease-related activity. In an ongoing study of 66 children and adults with late-onset LAL-D (cholesteryl ester storage disease), 20 weeks' double-blind treatment with sebelipase alfa significantly reduced multiple disease-related hepatic and lipid abnormalities compared with placebo. Sustained improvements in markers of liver damage and dyslipidaemia were seen after 76 weeks' open-label treatment in an extension of this trial and, similarly, after 2 years' open-label treatment in an extension of another study in nine adults with late-onset LAL-D. Sebelipase alfa therapy has thus far been generally well tolerated, with signs and symptoms consistent with anaphylaxis being the most serious adverse reactions experienced by patients receiving the drug in clinical trials. Due to the rarity of the disease, these studies have enrolled a limited number of patients. Nonetheless, the available data indicate that sebelipase alfa is an effective disease-specific therapy for individuals with LAL-D who have historically been managed using supportive therapies (e.g. cholesterol reduction, hematopoietic stem cell transplantation, and liver transplantation).