Lysosomal Acid Lipase Deficiency Research Articles

Lysosomal Acid Lipase Deficiency: A Report of Two Cases and a Review of the Literature

Lysosomal Acid Lipase Deficiency: A Report of Two Cases and a Review of the Literature

From LAL-D to MASLD: Insights into the role of LAL and Kupffer cells in liver inflammation and lipid metabolism

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent liver pathology worldwide, closely associated with obesity and metabolic disorders. Increasing evidence suggests that macrophages play a crucial role in the development of MASLD. Several human studies have shown an inverse correlation between circulating lysosomal acid lipase (LAL) activity and MASLD. LAL is the sole enzyme known to degrade cholesteryl esters (CE) and triacylglycerols in lysosomes. Consequently, these substrates accumulate when their enzymatic degradation is impaired due to LAL deficiency (LALD). This study aimed to investigate the role of hepatic LAL activity and liver-resident macrophages (i.e., Kupffer cells (KC)) in MASLD. To this end, we analyzed lipid metabolism in hepatocyte-specific (hep)Lal−/− mice and depleted KC with clodronate treatment. When fed a high-fat/high-cholesterol diet (HF/HCD), hepLal−/− mice exhibited CE accumulation and an increased number of macrophages in the liver and significant hepatic inflammation. KC were depleted upon clodronate administration, whereas infiltrating/proliferating CD68-expressing macrophages were less affected. This led to exacerbated hepatic CE accumulation and dyslipidemia, as evidenced by increased LDL-cholesterol concentrations. Along with proteomic analysis of liver tissue, these findings indicate that hepatic LAL-D in HF/HCD-fed mice leads to macrophage infiltration into the liver and that KC depletion further exacerbates hepatic CE concentrations and dyslipidemia.

Дефицит лизосомной кислой липазы: клиническая патофизиология и возможности ферментозаместительной терапии

Lysosomal acid lipase deficiency (LALD) is a rare disease of lysosomal storage inherited in an autosomal recessive manner and caused by damaging mutations in the LIPA gene encoding the synthesis of the enzyme lysosomal acid lipase (LAL). Authors represent basic information about LALD, describe its typical clinical and laboratory manifestations, features of enzyme replacement therapy with Sebelipase alfa (sold under the brand name KANUMA®), which is a recombinant form of the enzyme LAL, outcomes and prognosis of the disease in children. Modern methods for the LALD detection and an algorithm for diagnosing the disease in patients with hypertransaminasemia are discussed as well. A clinical case report of LALD with proven effectiveness of treatment with Sebelipase alfa (KANUMA®) in a pediatric patient are given.

Limited Alleviation of Lysosomal Acid Lipase Deficiency by Deletion of Matrix Metalloproteinase 12.

Lysosomal acid lipase (LAL) is the only known enzyme that degrades cholesteryl esters and triglycerides at an acidic pH. In LAL deficiency (LAL-D), dysregulated expression of matrix metalloproteinase 12 (MMP-12) has been described. The overexpression of MMP-12 in myeloid lineage cells causes an immune cell dysfunction resembling that of Lal knockout (Lal KO) mice. Both models develop progressive lymphocyte dysfunction and expansion of myeloid-derived suppressor (CD11b+ Gr-1+) cells. To study whether MMP-12 might be a detrimental contributor to the pathology of LAL-D, we have generated Lal/Mmp12 double knockout (DKO) mice. The phenotype of Lal/Mmp12 DKO mice closely resembled that of Lal KO mice, while the weight and morphology of the thymus were improved in Lal/Mmp12 DKO mice. Cytological examination of blood smears showed a mildly reversed lymphoid-to-myeloid shift in DKO mice. Despite significant decreases in CD11b+ Ly6G+ cells in the peripheral blood, bone marrow, and spleen of Lal/Mmp12 DKO mice, the hematopoietic bone marrow progenitor compartment and markers for neutrophil chemotaxis were unchanged. Since the overall severity of LAL-D remains unaffected by the deletion of Mmp12, we conclude that MMP-12 does not represent a viable target for treating the inflammatory pathology in LAL-D.

7524 Cholesterol ester storage disease

7524 Cholesterol ester storage disease

Frequency of rs1051338 and rs116928232 Variants in Individuals from Northwest Mexico.

LIPA, situated on chromosome 10q23.2-q23.3, encodes the enzyme lysosomal acid lipase (LAL) (EC 3.1.1.13). Genetic alterations in LIPA lead to lysosomal acid lipase deficiency (LALD), an inborn error causing lipid metabolism anomalies and impairing cholesterol and triacylglyceride degradation. Over 40 LIPA variants have been documented, yet this study focuses on just two. The rs1051338 variant (NM_000235:c.46A>C) affects the signal peptide in Exon 2, whereas rs116928232, located in Exon 8, alters the splice site (NM_000235:c.894G>A), impacting lysosomal acid lipase activity. Considering the diverse clinical manifestations of LALD and the rising hepatic steatosis prevalence in Mexican population, mainlydue to diet, these variants were investigated within this demographic to uncover potential contributing factors. This study aimed to reveal the frequency of rs1051338 and rs116928232 among healthy mestizo individuals in Northwest Mexico, marking a significant genetic exploration in this demographic. Three hundred ten healthy mestizo individuals underwent PCR-RFLP analysis for both variants, and Sanger sequencing was performed for variant rs116928232. Bioinformatic analysis was also performed to predict protein changes. Allele frequencies for rs1051338 (FA = 0.39, p value = 0.15) and rs116928232 (FA = 0.0016, p value = 0.49) aligned with reported data, while bioinformatic analysis allowed us to identify the protein alteration observed in both variants; finally, the variants showed no linkage between them (normalized D' = 1.03, p value = 0.56). Allelic frequencies closely matched reported data, and protein structure analysis confirmed variant impacts on LAL enzyme function. Notably, this study marks the first analysis of rs1051338 and rs116928232 in a healthy Mexican mestizo population.

A Rare Case of Neuroacanthocytosis with Predominant Dystonia

Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements, postures, or both. Acanthocytosis is irregular spiky red cells on peripheral blood smears, usually associated with neurological and hematological abnormalities. The different types of neuroacanthocytosis (NA) syndromes include core syndromes like chorea-acanthocytosis, McLeod syndrome, Huntington’s disease-like 2, and Pantothenate kinase-associated neurodegeneration, as well as NA associated with lipoprotein disorders such as abetalipoproteinemia (Bassen–Kornzweig syndrome), familial hypobetalipoproteinemia, Anderson disease, and atypical Wolman disease. Here, we describe a case of a 23-year-old man who presented to this hospital with complaints of choriform movements and abnormal dystonic body posturing since childhood. The peripheral smear revealed acanthocytes, and the brain’s MRI was normal.

Twice weekly dosing with Sebelipase alfa (Kanuma®) rescues severely ill infants with Wolman disease

BackgroundSebelipase alfa (Kanuma®) is approved for patients with Wolman disease (WD) at a dosage of 3–5 mg/kg once weekly. Survival rates in the second of two clinical trials was greater, despite recruiting more severely ill patients, probably related to higher initial and maximal doses. We aimed to evaluate the effective pharmacokinetics and pharmacodynamics of Sebelipase alfa when administered to patients with severe WD at 5 mg/kg twice weekly, an intensive regimen which was not assessed in the trials.MethodsWe recruited 3 patients receiving Sebelipase alfa 5 mg/kg twice weekly. We measured LAL activity in leukocytes and plasma oxysterol concentration in two patients and LAL activity in fibroblasts in one patient. Clinical follow up was also assessed.ResultsAnalyses of LAL activity and oxysterols demonstrate that there is short-lived enzyme activity post-dosing which is associated with the release of stored lipids. Clinical data demonstrate that 5 mg/kg twice weekly dosing is well tolerated and effective.Conclusion5 mg/kg twice weekly dosing with Sebelipase alfa rescues severely ill infants with WD by increasing substrate clearance. There is biologically relevant lipid accumulation in the ‘trough’ periods before the next dosing, even with this intensive regimen.

The Liver and Lysosomal Storage Diseases: From Pathophysiology to Clinical Presentation, Diagnostics, and Treatment.

The liver, given its role as the central metabolic organ, is involved in many inherited metabolic disorders, including lysosomal storage diseases (LSDs). The aim of this manuscript was to provide a comprehensive overview on liver involvement in LSDs, focusing on clinical manifestation and its pathomechanisms. Gaucher disease, acid sphingomyelinase deficiency, and lysosomal acid lipase deficiency were thoroughly reviewed, with hepatic manifestation being a dominant clinical phenotype. The natural history of liver disease in the above-mentioned lysosomal disorders was delineated. The importance of Niemann-Pick type C disease as a cause of cholestatic jaundice, preceding neurological manifestation, was also highlighted. Diagnostic methods and current therapeutic management of LSDs were also discussed in the context of liver involvement.

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.

Cholesterol ester storage disease, own clinical observation of a family case of the disease

Lysosomal acid lipase deficiency is an orphan autosomal recessive disease associated with the presence of mutations in the LIPA gene. Clinical manifestations of lysosomal acid lipase deficiency come in two main forms: Wolman’s disease and cholesterol ester storage disease. The article presents current information about the disease, describes the most characteristic clinical and laboratory signs, features of enzyme replacement therapy, outcomes and prognosis of the disease in children. The article also provides its own clinical observation of the family case of cholesterol ester storage disease in brothers.

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

Lysosomal acid lipase deficiency: features of manifestation in patients of the Moscow region

Lysosomal acid lipase deficiency (LALD) is a rare, chronic, progressive disease based on a defect in the LIPA gene encoding lysosomal acid lipase, early diagnosis of which may be difficult due to the diversity of the clinical picture. The purpose of the study. To evaluate the early clinical and laboratory symptoms of LALD, the timing of manifestation and diagnosis in patients of the Moscow region. Materials and methods. The analysis of the medical documentation of 6 patients with a confirmed diagnosis of lysosomal acid lipase deficiency by the results of enzyme diagnostics and DNA-diagnostics registered in the Moscow region: 5 children aged 2 to 16 years, one patient aged 19 years. Boys - 3, girls - 3. Results. In 3 patients (50%), the first symptoms of the disease were detected before the age of 1 year, in two children (33%) - from 1 to 2 years, in one child - at the age of 5 years. The most common early clinical symptom was cytolysis syndrome and hepatosplenomegaly, less often dyspeptic manifestations (flatulence, diarrhea). The average age of onset of the disease is 1.5 years. The duration of follow-up ranged from 1 year to 14 years. On average, the duration of the diagnostic search was 6.75 years, and the average age of diagnosis was 8.25 years. At the time of diagnosis confirmation, all patients showed signs of hepatosplenomegaly, diffuse changes in liver parenchyma, increased serum transaminases, hypercholesterolemia, increased LDL and decreased HDL. Excess of ALT values up to 2 norms was diagnosed in one child (17%), from 2 to 3 norms - in 3 children (50%), from 3 to 5 norms - in 2 children (33%). AST is less than 2 norms - in 2 children (33%), from 2 to 3 norms - in 3 (50%), in 1 child - 5-6 norms (17%). The absolute majority of patients (83%) had c894G>A mutations in the LIPA gene in a homozygous state. Conclusion. LALD is a rare disease, the diagnosis of which is difficult due to the frequent asymptomatic course or non-specific clinic. In most children, the disease manifests at an early age (up to 3-5 years), and the most common symptoms are increased liver transaminases and hepatosplenomegaly. ALT and AST activity, as a rule, does not exceed 2-3 norms. The signs characteristic of DL are detected randomly during examination for other diseases. Due to the non-specificity of clinical symptoms, the duration of diagnosis varies from several months to several years. The main modern method of diagnosing LALD is enzyme diagnostics and DNA diagnostics. If a child has hepatolienal syndrome, a persistent increase in markers of cytolysis and dyslipidemia, caution should be exercised and the necessary diagnostic examinations should be carried out in a timely manner to exclude LALD.

Lanifibranor Reduces Inflammation and Improves Dyslipidemia in Lysosomal Acid Lipase-Deficient Mice

Background and AimsRecent studies showed that patients suffering from lysosomal acid lipase deficiency (LAL-D) benefit from enzyme replacement therapy (ERT), however, liver histolopathology improved in some but not all patients. We hypothesized that the pan-PPAR agonist lanifibranor may have beneficial effects on liver inflammation in LAL knockout (Lal-/-) mice based on its promising results in alleviating liver inflammation in patients with metabolic dysfunction-associated steatohepatitis. MethodsFemale Lal-/- mice were daily gavaged with lanifibranor or vehicle for 21 days. The effects of the treatment were assessed by measuring body and organ weights, plasma lipids and lipoproteins, as well as hematological parameters, followed by liver proteomics and metabolomics. ResultsLanifibranor treatment slightly altered organ weights without affecting the total body weight of Lal-/- mice. We observed major changes in the proteome, with multiple proteins related to lipid metabolism, peroxisomal, and mitochondrial activities being upregulated and inflammation-related proteins being downregulated in the livers of treated mice. Hepatic lipid levels and histology remained unaltered, whereas plasma triacylglycerol and total cholesterol levels were decreased and the lipoprotein profile of lanifibranor-treated Lal-/- mice improved. ConclusionsLanifibranor treatment positively affected liver inflammation and dyslipidemia in Lal-/- mice. These findings suggest the necessity of a further combined study of lanifibranor with ERT in Lal-/- mice to improve the phenotype. Moreover, there is a compelling rationale for conducting clinical trials to assess the efficacy of lanifibranor as a potential treatment option for LAL-D in humans.

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.