Lysosomal Acid Lipase Deficiency Research Articles

A 14-step desensitization protocol for sebelipase alfa hypersensitivity in a patient with Wolman disease and secondary hemophagocytic lymphohistiocytosis.

A 14-step desensitization protocol for sebelipase alfa hypersensitivity in a patient with Wolman disease and secondary hemophagocytic lymphohistiocytosis.

Otras enfermedades hepáticas de causa genética, metabólica y endocrinológica

Liver diseases of genetic origin comprise a series of diseases that manifest as abnormalities in liver structure and/or function due to genetic mutations. This update will discuss some of them, such as alpha-1 antitrypsin deficiency (A1AT), Wilson's disease, lysosomal acid lipase deficiency (LAL-D), and other congenital diseases related to bile acid and bilirubin metabolism.Alpha-1 antitrypsin deficiency is an autosomal codominant condition characterized by a decrease in secretion of alpha-1 antitrypsin protein, which acts as an inhibitor of neutrophil elastase. This results in liver and lung damage due to an accumulation of misfolded protein in hepatocytes and uncontrolled elastase activity. On the other hand, in Wilson's disease, an autosomal recessive disorder, mutations in the ATP7B gene impair copper metabolism. This results in an accumulation of toxic copper in the liver and other organs, causing hepatitis, cirrhosis, and neuropsychiatric manifestations. Lysosomal acid lipase deficiency is an autosomal recessive disorder caused by mutations in the LIPA gene. This results in the accumulation of cholesterol and triglyceride esters in lysosomes, leading to hepatomegaly, hyperlipidemia, and premature atherosclerosis. Finally, the set of diseases related to bilirubin and bile acid metabolism involve abnormalities in the production, transport, and excretion of bilirubin and bile acids. They are associated with cholestasis and hepatocellular damage, which can lead to liver failure and death.

Regional Differences in the Small Intestinal Proteome of Control Mice and of Mice Lacking Lysosomal Acid Lipase.

The metabolic contribution of the small intestine (SI) is still unclear despite recent studies investigating the involvement of single cells in regional differences. Using untargeted proteomics, we identified regional characteristics of the three intestinal tracts of C57BL/6J mice and found that proteins abundant in the mouse ileum correlated with the high ileal expression of the corresponding genes in humans. In the SI of C57BL/6J mice, we also detected an increasing abundance of lysosomal acid lipase (LAL), which is responsible for degrading triacylglycerols and cholesteryl esters within the lysosome. LAL deficiency in patients and mice leads to lipid accumulation, gastrointestinal disturbances, and malabsorption. We previously demonstrated that macrophages massively infiltrated the SI of Lal-deficient (KO) mice, especially in the duodenum. Using untargeted proteomics (ProteomeXchange repository, data identifier PXD048378), we revealed a general inflammatory response and a common lipid-associated macrophage phenotype in all three intestinal segments of Lal KO mice, accompanied by a higher expression of GPNMB and concentrations of circulating sTREM2. However, only duodenal macrophages activated a metabolic switch from lipids to other pathways, which were downregulated in the jejunum and ileum of Lal KO mice. Our results provide new insights into the process of absorption in control mice and possible novel markers of LAL-D and/or systemic inflammation in LAL-D.

High-Dose ERT, Rituximab, and Early HSCT in an Infant with Wolman’s Disease

SummaryWolman’s disease, a severe form of lysosomal acid lipase deficiency, leads to pathologic lipid accumulation in the liver and gut that, without treatment, is fatal in infancy. Although continued enzyme-replacement therapy (ERT) in combination with dietary fat restriction prolongs life, its therapeutic effect may wane over time. Allogeneic hematopoietic stem-cell transplantation (HSCT) offers a more definitive solution but carries a high risk of death. Here we describe an infant with Wolman’s disease who received high-dose ERT, together with dietary fat restriction and rituximab-based B-cell depletion, as a bridge to early HSCT. At 32 months, the infant was independent of ERT and disease-free, with 100% donor chimerism in the peripheral blood.

Impaired lysosomal acidity maintenance in acid lipase-deficient cells leads to defective autophagy

The lysosome is an acid organelle that contains a variety of hydrolytic enzymes and plays a significant role in intracellular degradation to maintain cellular homeostasis. Genetic variants in lysosome-related genes can lead to severe congenital diseases, such as lysosomal storage diseases. In the present study, we investigated the impact of depleting lysosomal acid lipase A (LIPA), a lysosomal esterase that metabolizes esterified cholesterol or triglyceride, on lysosomal function. Under nutrient-rich conditions, LIPA gene knockout (LIPAKO) cells exhibited impaired autophagy, whereas, under starved conditions, they showed normal autophagy. The cause underlying the differential autophagic activity was increased sensitivity of LIPAKO cells to ammonia which was produced from L-glutamine in the medium. Further investigation revealed that ammonia did not affect upstream signals involved in autophagy induction, autophagosome-lysosome fusion, and hydrolytic enzyme activities in LIPAKO cells. On the other hand, LIPAKO cells showed defective lysosomal acidity upon ammonia loading. Microscopic analyses revealed that lysosomes of LIPAKO cells enlarged, whereas the amount of lysosomal proton pump V-ATPase did not proportionally increase. Since the enlargement of lysosomes in LIPAKO cells was not normalized under starved conditions, this is the primary change that occurred in the LIPAKO cells, and autophagy was affected by impaired lysosomal function under the specific conditions. These findings expand our comprehension of the pathogenesis of Wolman's disease, which is caused by a defect in the LIPA gene, and suggest that conditions, such as hyperlipidemia, may easily disrupt lysosomal functions.

Liver-directed AAV gene therapy corrects disease symptoms in a murine model of lysosomal acid lipase deficiency

Liver-directed AAV gene therapy corrects disease symptoms in a murine model of lysosomal acid lipase deficiency

Wolman’s Disease and GNE Myopathy Frequency to Religion

Complete absence or deficiency of Lysosomal acid lipase (LAL) leads to the rare infantile disorder Wolman's Disease [1]. Decreased function of GNE can lead to GNE myopathy [2]. Although both pathological phenotypes are rare, LAL deficiency only affects 1 in every 500,000 births and dysfunction of GNE affects 1 in every 1,000,000 births, there is a higher incidence in the religious groups of the Middle East; the incidence is projected to be as high as 1 in every 4,200 births [3,4]. The LIPA gene encodes for LAL while the GNE gene encodes for UDPN- acetylglucosamine (GlcNAc) 2-epimerase/N-acetylmannosamine (ManNAc) kinase [4,5]. LAL catalyzes the hydrolysis of cholesterol esters and triglycerides [6]. GlcNAc and ManNAc are responsible for the biosynthesis of sialic acid [7]. Presence of variations in GNE genes are known to impair the enzymes and lead to pathological phenotypes. This study reports the prevalence of mutations c.260G>T; p.G87V and c.894G>A; E8SJM in the lipase gene (LIPA) and c.2228T>C p.M743T in GNE gene amongst different religions. We sequenced 1,354 samples for the presence of the variations in LIPA exon 4 and 8 along with GNE exon 13(formerly exon 12). The sample population comprised individuals of varying Middle Eastern religions such as Mizrahi Jewish, Muslims, Christians, Baha’i, Catholic, Buddhist and Zoroastrian. The other religions that were not Mizrahi Jewish were classified under “Non-Jewish” to have a more even distribution. LIPA gene exon 4 variation p.G87V had a heterozygous frequency of 22 in 1,354(1.62%) with 20 of 22(90.9%) heterozygotes being Mizrahi Jewish while 2 of 22(9.09%) heterozygotes were Non-Jewish. Exon 8 splice junction mutation E8SJM, G>A transition at position 1 had a frequency of 2 in 1,354 (0.14%) with 2 of 2(100%) heterozygotes being Mizrahi Jewish. GNE exon 13 variation p.M743T (formerly exon 12 p.M712T) had a mutation frequency of 58 in 1,354(4.28%) with 5 of these 58(8.62%) samples being homozygous while 53 of the 58(91.37%) were heterozygous. In 58 samples that yielded a mutation, 54 of them were Mizarhi jewish (93.1%).

Loss of lysosomal acid lipase results in mitochondrial dysfunction and fiber switch in skeletal muscles of mice

ObjectiveLysosomal acid lipase (LAL) is the only enzyme known to hydrolyze cholesteryl esters (CE) and triacylglycerols in lysosomes at an acidic pH. Despite the importance of lysosomal hydrolysis in skeletal muscle (SM), research in this area is limited. We hypothesized that LAL may play an important role in SM development, function, and metabolism as a result of lipid and/or carbohydrate metabolism disruptions. ResultsMice with systemic LAL deficiency (Lal−/−) had markedly lower SM mass, cross-sectional area, and Feret diameter despite unchanged proteolysis or protein synthesis markers in all SM examined. In addition, Lal−/− SM showed increased total cholesterol and CE concentrations, especially during fasting and maturation. Regardless of increased glucose uptake, expression of the slow oxidative fiber marker MYH7 was markedly increased in Lal−/−SM, indicating a fiber switch from glycolytic, fast-twitch fibers to oxidative, slow-twitch fibers. Proteomic analysis of the oxidative and glycolytic parts of the SM confirmed the transition between fast- and slow-twitch fibers, consistent with the decreased Lal−/− muscle size due to the “fiber paradox”. Decreased oxidative capacity and ATP concentration were associated with reduced mitochondrial function of Lal−/− SM, particularly affecting oxidative phosphorylation, despite unchanged structure and number of mitochondria. Impairment in muscle function was reflected by increased exhaustion in the treadmill peak effort test in vivo. ConclusionWe conclude that whole-body loss of LAL is associated with a profound remodeling of the muscular phenotype, manifested by fiber type switch and a decline in muscle mass, most likely due to dysfunctional mitochondria and impaired energy metabolism, at least in mice.

Protein profiles in the transfected oviductal secreting cells of laying hen (Gallus gallus domesticus)

Due to the intensive development of novel biopharming applications, there is a need for the in vitro verification models prior to in vivo testing. Laying hen has been already applied as an animal bioreactor to produce the therapeutical enzyme in a rare disease called lysosomal acid lipase deficiency. In this study, we aimed to verify how the proteome of the transfected oviduct epithelial cells would be affected by genetic nonviral modification with the human exogene. The study was based on a previously developed method to cultivate chicken oviduct epithelial cells (COEC). The typical characteristics of the COEC epithelial cells were retained across the experiments. The mean efficiency of nucleofection ranged from 2.6 to 19.7% depending on the cells' isolation and location in the oviduct (upper, infundibulum site, or magnum). The PCR confirmed the incorporation of human interferon alpha2a (hIFNα2a) exogene into the nucleofected COEC but, the production of hIFNα2a protein did not exceed the detection level in this study. The ovalbumin protein was detected in the nontransfected and transfected COEC, which confirmed the normal secreting functions of the cells subject to modification. Proteomic analysis revealed an increase in abundance of the cell adhesion molecules and collagen molecules after introducing gene under ovalbumin promoter. According to the bioinformatic analyses there was a limited negative impact of transfection on cells, and the normal biochemical pathways were not severely disordered. In conclusion, the observations provide new knowledge about the proteomic profile of the manipulated COEC with regard to the retained normal functionality of the cells, which can be informative for avian biopharma research.

Dissecting cell type–specific impact in lysosomal acid lipase deficiency–associated disorders

Dissecting cell type–specific impact in lysosomal acid lipase deficiency–associated disorders

Lysosomal Acid Lipase Deficiency in the Etiological Investigation of Cryptogenic Liver Disease in Adults: A Multicenter Brazilian Study

Background: Lysosomal acid lipase deficiency (LAL-D) is a rare genetic disease associated with the deregulation of lipid metabolism, leading to atherosclerosis, dyslipidemia, and hepatic steatosis, with potential progression to cirrhosis. Our study aims to assess the role of LAL-D in the setting of cryptogenic liver disease. Methods: A large multicenter cross-sectional study was conducted, which included 135 patients with cryptogenic liver disease from four liver centers in Brazil. All patients were submitted to the investigation of LAL enzyme activity on dried blood spots. Results: Three patients (two female) presented levels of LAL below the reference limit, compatible with LAL-D (2.2%). They had a mean age of 43.9 ± 10.1 years and a mean body-mass index (BMI) of 23.1 ± 1.7 kg/m2. The mean serum levels of glucose, HDL-cholesterol, and triglycerides were 89.7 ± 3.2, 21.7 ± 3.2, and 206.7 ± 25.5 mg/dL, respectively. All patients had duodenal polyposis with xanthomatous macrophages. LAL-D investigation should be considered for individuals with chronic liver disease of an unknown etiology, especially with a normal BMI, high triglycerides, and low-HDL-cholesterol levels. The identification of LAL-D patients is extremely important since enzyme replacement therapy with Sebelipase Alfa significantly increases their survival.

Wolman disease presenting with hemophagocytic lymphohistiocytosis syndrome and a novel LIPA gene variant: a case report and review of the literature 

BackgroundWolman disease is a rare disease caused by the absence of functional liposomal acid lipase due to mutations in LIPA gene. It presents with organomegaly, malabsorption, and adrenal calcifications. The presentations can resemble hemophagocytic lymphohistiocytosis, the life threatening hyperinflammatory disorder. Since the disease is very rare, clinicians might not think of it when a patient presents with hemophagocytic lymphohistiocytosis, and the opportunity to treat it properly can be lost, thus leading to demise of the child.Case presentationWe present a 4.5-month-old Caucasian boy with fever, icterus, and hepatosplenomegaly who was treated according to presumed hemophagocytic lymphohistiocytosis disease. Wolman disease was diagnosed after the death of the child. There are some case reports in the literature presenting patients with Wolman disease primarily diagnosed as hemophagocytic lymphohistiocytosis, which we discuss in this review. The genetic analysis revealed after his demise was compatible with Wolman disease, introducing a novel mutation in LIPA gene: exon 4: NM_001127605: c. G353A (p.G118D), which converts the glycine amino acid to aspartic acid.ConclusionsConsidering the similarities in presentation of Wolman disease and hemophagocytic lymphohistiocytosis, the patient’s life can be saved if special attention is paid to presenting features of a patient with suspected hemophagocytic lymphohistiocytosis, that is special attention to symptoms, findings on physical exams, laboratory values, and radiologic findings, and the proper treatment is urgently initiated. Reporting the novel mutations of Wolman disease can help geneticists interpret the results of their patients’ genetic studies appropriately, leading to correct diagnosis and treatment.

Clinical guidelines for the management of children with lysosomal acid lipase deficiency

Lysosomal acid lipase deficiency is s a rare hereditary enzymopathy. The article presents epidemiological data and features of etiopathogenesis of two phenotypic forms of lysosomal acid lipase deficiency — Wolman disease and cholesterol ester storage disease. Special attention has been given to the key issues of differential diagnostic search, clinical guidelines based on the principles of evidence-based medicine have been given.

Metabolic changes and propensity for inflammation, fibrosis, and cancer in livers of mice lacking lysosomal acid lipase

Lysosomal acid lipase (LAL) is the sole lysosomal enzyme responsible for the degradation of cholesteryl esters and triacylglycerols at acidic pH. Impaired LAL activity leads to LAL deficiency (LAL-D), a severe and fatal disease characterized by ectopic lysosomal lipid accumulation. Reduced LAL activity also contributes to the development and progression of non-alcoholic fatty liver disease (NAFLD). To advance our understanding of LAL-related liver pathologies, we performed comprehensive proteomic profiling of livers from mice with systemic genetic loss of LAL (Lal−/−) and from mice with hepatocyte-specific LAL-D (hepLal−/−). Lal−/− mice exhibited drastic proteome alterations, including dysregulation of multiple proteins related to metabolism, inflammation, liver fibrosis, and cancer. Global loss of LAL activity impaired both acidic and neutral lipase activities and resulted in hepatic lipid accumulation, indicating a complete metabolic shift in Lal−/− livers. Hepatic inflammation and immune cell infiltration were evident, with numerous upregulated inflammation-related gene ontology biological process terms. In contrast, both young and mature hepLal−/− mice displayed only minor changes in the liver proteome, suggesting that loss of LAL solely in hepatocytes does not phenocopy metabolic alterations observed in mice globally lacking LAL. These findings provide valuable insights into the mechanisms underlying liver dysfunction in LAL-D and may help in understanding why decreased LAL activity contributes to NAFLD. Our study highlights the importance of LAL in maintaining liver homeostasis and demonstrates the drastic consequences of its global deficiency on the liver proteome and liver function.

The Current Treatment of Rare Disease, Lysosomal Acid Lipase Deficiency (LAL-D) and Paroxysmal Nocturnal Haemoglobinuria (PNH)

The Paroxysmal Nocturnal Hemoglobinuria (PNH) and Lysosomal acid Lipase Deficiency (LAL-D) are rare disorder disease. Ultomiris and Soliris for PNH and Kanuma for LAL-D are innovative treatments for PNH and LAL-D, respectively. These therapies can treat each ultra-rare condition by alleviating symptoms and lowering mortality rates for both diseases. The aim of this research is to investigate the rare diseases PNH and LAL-D, as well as the existing treatments for both. Each medicine should be safe and have a good therapeutic effect, with a wide range of benefits and few adverse effects. PRISMA (Preferred Reporting Items for Systematic Reviews) was used to evaluate three treatments: Ultomiris and Soliris for PNH and Kanuma for LAL-D. The search was limited to scientific research articles and clinical trials (Publication years between 2007 and 2022). In the analysis, 20 studies were chosen based on their treatment, concentration, population, year of publication, outcomes, and references. Extensive study on the present treatment of PNH and LAL-D was used to draw conclusions on the overall benefits, distribution, efficacy, and safety of the medicines. This study was also utilised to validate the overall improvement in the lives of people with PNH and LAL-D. Ultomiris has an average effect of 96.5% on PNH symptoms, including hemolysis events. Kanuma has a 90% typical impact against LAL-D by reducing symptoms such as LDL-C and normalising Aspartate Aminotransferase (AST) levels (LAL-D symptoms), whilst Soliris has an average 97% effect against PNH, by reducing the presence of lactate dehydrogenase, for example.

Rare Cause of Liver Cell Failure in Infants: Wolman Disease

Wolman disease is an extremely rare hereditary metabolic lipid storage disorder, characterized by a total deficiency of lysosomal acid lipase (LAL), which leads to the accumulation of cholesteryl esters and triglycerides in the lysosomes, resulting in more or less progressive damage to numerous organs, thus presenting the patient with vomiting, diarrhea, and severe malnutrition. With a fatal outcome in the first months of life if untreated. We present the case of a two-month-old infant admitted for abdominal distension; physical examination revealed jaundice, hepatomegaly, and splenomegaly; biological investigations revealed hepatic cytolysis, anemia, and thrombocytopenia. Imaging studies showed bilateral calcifications of the adrenal glands. The diagnosis of Wolman disease was confirmed by measuring the activity of the collapsed lysosomal acid lipase.

Cryptogenic chronic hepatitis: looking for an ideal diagnostic algorithm

IntroductionCryptogenic chronic hepatitis is a growing cause of liver transplants, affecting 5%–15% of patients with chronic liver diseases. This study aimed to identify underlying causes of cryptogenic liver disease in a Brazilian cohort and propose a new diagnostic algorithm, including investigation for metabolic-dysfunction-associated fatty liver disease (MAFLD) and lysosomal acid lipase deficiency (LAL-D).MethodsA retrospective analysis was conducted on 326 patients with presumed cryptogenic hepatitis.ResultsUsing Czaja’s algorithm, non-alcoholic fatty liver disease was diagnosed in 21.3% of patients, while alpha-1 antitrypsin deficiency, alcoholic liver disease, autoimmune hepatitis, hemochromatosis, biliary-related hepatitis, viral hepatitis, Budd–Chiari syndrome, glycogenosis, drug-induced liver injury, and Wilson’s disease were diagnosed in smaller proportions (< 3.5% each). LAL-D was found in 1% of patients, and 53.6% of patients remained with cryptogenic hepatitis. The etiology of the liver disease in a subset of patients undergoing liver transplantation was updated post hoc based on explant histology, and non-alcoholic steatohepatitis was found in 52.5% of patients. By incorporating the concept of MAFLD, the new algorithm could diagnose 49.1% of patients, reducing the number of individuals without an etiological diagnosis by 11.4%.ConclusionOne-third of patients with initially presumed cryptogenic liver disease were diagnosed with MAFLD. LAL-D should be considered in patients with chronic liver disease of unknown etiology. The updated diagnostic algorithm proposed in this study could improve diagnostic accuracy and aid in the management of patients with cryptogenic hepatitis.

Identification cohort of lysosomal acid lipase deficiency patients through information system

Identification cohort of lysosomal acid lipase deficiency patients through information system

Screening for lysosomal acid lipase deficiency in Japanese patients with suspected familial hypercholesterolemia

Screening for lysosomal acid lipase deficiency in Japanese patients with suspected familial hypercholesterolemia

First LIPA Mutational Analysis in Egyptian Patients Reveals One Novel Variant: Wolman Disease

Lysosomal acid lipase (LAL) is a necessary enzyme for the hydrolysis of both triglycerides (TGs) and cholesteryl esters (CEs) in the lysosome. Deficiency of this enzyme encoded by the lipase A (LIPA) gene leads to LAL deficiency (LAL-D). A severe disease subtype of LAL-D is known as Wolman disease (WD), present with diarrhea, hepatosplenomegaly, and adrenal calcification. Untreated patients do not survive more than a year. The aim of this study was to assess the clinical and molecular characterizations of WD patients in Egypt. A total of seven patients (from five unrelated Egyptian families) were screened by targeted next-generation sequencing (NGS), and the co-segregation of causative variants was analyzed using Sanger sequencing. Furthermore, multiple in silico analyses were performed to assess the pathogenicity of the candidate variants. Overall, we identified three diseases causing variants harbored in the LIPA gene. One of these variants is a novel missense variant (NM_000235.4: c.1122 T > G; p. His374Gln), which was classified as a likely pathogenic variant. All variants were predicted to be disease causing using in silico analyses. Our findings expand the spectrum of variants involved in WD which may help to investigate phenotype-genotype correlation and assist genetic counseling. To the best of our knowledge, this is the first clinico-genetic study carried out on Egyptian patients affected with WD.