Lysosomal Acid Lipase Deficiency Research Articles

Molecular markers of brain cholesterol homeostasis are unchanged despite a smaller brain mass in a mouse model of cholesteryl ester storage disease.

Lysosomal acid lipase (LAL), encoded by the gene LIPA, facilitates the intracellular processing of lipids by hydrolyzing cholesteryl esters and triacylglycerols present in newly internalized lipoproteins. Loss-of-function mutations in LIPA result in cholesteryl ester storage disease (CESD) or Wolman disease when mutations cause complete loss of LAL activity. Although the phenotype of a mouse CESD model has been extensively characterized, there has not been a focus on the brain at different stages of disease progression. In the current studies, whole-brain mass and the concentrations of cholesterol in both the esterified (EC) and unesterified (UC) fractions were measured in Lal-/- and matching Lal+/+ mice (FVB-N strain) at ages ranging from 14 up to 280 days after birth. Compared to Lal+/+ controls at 50, 68-76, 140-142, and 230-280 days of age, Lal-/- mice had brain weights that averaged approximately 6%, 7%, 18%, and 20% less, respectively. Brain EC levels were higher in the Lal-/- mice at every age, being elevated 27-fold at 230-280 days. Brain UC concentrations did not show a genotypic difference at any age. The elevated brain EC levels in the Lal-/- mice did not reflect EC in residual blood. An mRNA expression analysis for an array of genes involved in the synthesis, catabolism, storage, and transport of cholesterol in the brains of 141-day old mice did not detect any genotypic differences although the relative mRNA levels for several markers of inflammation were moderately elevated in the Lal-/- mice. The possible sites of EC accretion in the central nervous system are discussed.

S2581 LAL-D: A Rare Liver Disease

Introduction: Lysosomal acid lipase deficiency (LAL-D) is an autosomal recessive disease associated with abnormal liver enzyme elevation. Mutations in the LIPA gene cause lysosomal acid lipase deficiency with the inability to break down cholesteryl esters in the body. Cholesteryl ester storage disease is associated with an abnormal accumulation of cholesteryl ester and triglycerides in various organs, including the liver, spleen, intestinal mucosa, and lymph nodes, to name a few. There are very few cases of LAL-D reported in the adult population. Case Description/Methods: An 18-year-old male with no significant medical history presented to the outpatient hepatology clinic for evaluation of elevated liver enzymes. The physical exam was unremarkable. Further work-up revealed leukopenia, lymphocytopenia, and elevated INR. The lipid profile was unremarkable. Ultrasound of the liver revealed mild hepatomegaly, splenomegaly, and porta hepatis lymphadenopathy. CT of the abdomen with contrast revealed diffuse hypodense liver suggesting fatty liver disease, massive splenomegaly. Liver biopsy performed and revealed glycogenic hepatopathy with periportal and focal bridging fibrosis. The patient also underwent an esophagogastroduodenoscopy with biopsy, which showed clear foamy appearing cytoplasm that contains PAS-positive and diastase-resistant material. Chronic liver disease work-up was unrevealing except for positivity for alpha-1-antitrypsin deficiency carrier (MZ phenotype). Measurement of liposomal acid lipase in the leukocytes from the blood sample was zero (0) with genetic testing confirmation of LAL-D. The patient was referred to the transplant center to initiate the lysosomal acid lipase infusion treatment with close follow-up. Discussion: Liver damage in cholesteryl ester storage disease may progress to hepatocellular failure along with fibrosis and micronodular cirrhosis. Commonly, patients are misdiagnosed with non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, cryptogenic cirrhosis, heterozygous familial hypercholesterolemia. It is imperative that gastroenterologists are familiar with the diagnostic and therapeutic approaches for this rare illness termed lysosomal acid lipase deficiency.

Defective Lysosomal Lipolysis Causes Prenatal Lipid Accumulation and Exacerbates Immediately after Birth.

Cholesterol and fatty acids are essential lipids that are critical for membrane biosynthesis and fetal organ development. Cholesteryl esters (CE) are degraded by hormone-sensitive lipase (HSL) in the cytosol and by lysosomal acid lipase (LAL) in the lysosome. Impaired LAL or HSL activity causes rare pathologies in humans, with HSL deficiency presenting less severe clinical manifestations. The infantile form of LAL deficiency, a lysosomal lipid storage disorder, leads to premature death. However, the importance of defective lysosomal CE degradation and its consequences during early life are incompletely understood. We therefore investigated how defective CE catabolism affects fetus and infant maturation using Lal and Hsl knockout (-/-) mouse models. This study demonstrates that defective lysosomal but not neutral lipolysis alters placental and fetal cholesterol homeostasis and exhibits an initial disease pathology already in utero as Lal-/- fetuses accumulate hepatic lysosomal lipids. Immediately after birth, LAL deficiency exacerbates with massive hepatic lysosomal lipid accumulation, which continues to worsen into young adulthood. Our data highlight the crucial role of LAL during early development, with the first weeks after birth being critical for aggravating LAL deficiency.

Effect of a common missense variant in LIPA gene on fatty liver disease and lipid phenotype: New perspectives from a single-center observational study.

Lysosomal acid lipase deficiency (LAL‐D) is an autosomal recessive disease characterized by hypoalphalipoproteinemia, mixed hyperlipemia, and fatty liver (FL) due to mutations in LIPAse A, lysosomal acid type (LIPA) gene. The rs1051338 single‐nucleotide polymorphism (SNP) in LIPA gene, in vitro, could adversely affect the LAL activity (LAL‐A). Nonalcoholic fatty liver disease (NAFLD) is often associated with metabolic syndrome, and the diagnosis requires the exclusion of excess of alcohol intake and other causes of hepatic disease. The aim of the study was to evaluate the impact of rs1051338 rare allele on lipid phenotype, severity of FL, and LAL‐A in patients suffering from dyslipidemia associated with NAFLD. We selected 74 subjects with hypoalphalipoproteinemia or mixed hyperlipemia and evaluated transaminases, liver assessment with controlled attenuation parameter (CAP), LAL‐A, rs1051338 SNP genotype. The presence of rare allele caused higher levels of triglycerides and hepatic transaminase and lower levels of high‐density lipoprotein cholesterol (HDL‐C). Multivariate analysis highlighted independent association between rare allele and FL severity in subjects with NAFLD. The rs1051338 SNP may modulate FL severity and atherogenic dyslipidemia in patients suffering from NAFLD.

O-8 THE IMPORTANCE OF LYSOSOMAL ACID LIPASE DEFICIENCY IN THE ETIOLOGICAL INVESTIGATION OF CRYPTOGENIC LIVER DISEASE IN ADULTS: A MULTICENTER STUDY

Lysosomal acid lipase deficiency (LAL-D) is a rare genetic disease associated with lipid metabolism deregulation leading to atherosclerosis, dyslipidemia, and hepatic steatosis, with potential progression to cirrhosis. Investigation of LAL-D in patients with chronic liver disease is not routinely performed in most centers. The aim of this study was to evaluate whether it is worthwhile to investigate LAL-D in patients with liver disease of unknown etiology, and if there is any particular population that this search should be focused. This was a multicenter cross-sectional study in 295 patients followed with presumed cryptogenic liver disease from four tertiary centers in Brazil. Clinical, demographic and laboratory data from participants were assessed, with the exclusion of all known causes of liver disease. All patients were submitted to the investigation of LAL enzyme activity. The exams were collected on dried blood spot (DBS). A total of 135 patients were included in the study. Three patients (2.22%) presented values of LAL below the reference limit, compatible with LAL-D. The mean age of these patients was 43.9±10.1 years, of which 2 were females. The mean BMI was 24.3±0.7 and mean serum glycemia was 89.7±3.2 mg/dL. The mean serum HDL and triglycerides were 21.7±3.2 mg/dL and 206.7±25.5 mg/dL, respectively. Despite being a rare disease, also in our study population, LAL-D investigation may be considered in those individuals without overweight with reduced serum HDL and elevated triglycerides levels and chronic liver disease of unknown etiology.

Hepatic lysosomal acid lipase drives the autophagy-lysosomal response and alleviates cholesterol metabolic disorder in ApoE deficient mice

Lysosomal acid lipase (LAL)-dependent lipolysis degrades cholesteryl ester (CE) and triglyceride in the lysosome. LAL deficiency in human and mice leads to hypercholesterolemia, hepatic CE deposition, and atherosclerosis. Despite its hepatocyte-specific deficiency leads to CE accumulation, the regulation of LAL in cholesterol metabolic disease remains elusive. For the in vitro study, the target gene Lipa was transfected with recombinant shRNA or lentiviral vector in Hepa1-6 cells. It was found that LAL silencing in cells affected lysosomal function by reducing LAL activity and proteolytic activity, and altered the expression of genes related to cholesterol metabolism and autophagy, leading to cholesterol accumulation; whereas LAL overexpression improved the above effects. To explore the impacts of hepatic LAL on cholesterol metabolic disease in vivo, apolipoprotein E deficient (ApoE−/−) mice were intravenously injected with lentivirus to achieve hepatic LAL overexpression and fed a Western diet for 16 weeks. The results showed that hepatic LAL overexpression significantly reduced plasma lipid levels, alleviated inflammation and oxidative status in plasma and liver, and attenuated hepatic steatosis and fibrosis in ApoE−/− mice. Mechanically, hepatic LAL promoted cholesterol transport and biliary excretion by increasing liver X receptor alpha (LXRα) and its downstream genes, and modulated the compliance of the autophagy-lysosomal pathway. Our data provide the original evidence of the validity of hepatic LAL in controlling cholesterol metabolism and liver homeostasis, suggesting that targeting hepatic LAL may provide a promising approach to rescue cholesterol metabolic disorders, such as hypercholesterolemia and liver disease.

A combination of cardiovascular and hepatocellular disease in a patient with a late diagnosis of lysosomal acid lipase deficiency.

Background and Aims: Lysosomal acid lipase deficiency (LAL-D) is a lysosomal storage disease due to mutations in the LIPA gene encoding lysosomal acid lipase (LAL). Decrease in activity results in accumulation of cholesteryl esters and triglycerides in various organs. Clinical presentation varies from a rapidly progressive, fatal infantile disease to a less severe, more variable clinical course in older children and adults. Prevalence is estimated at 1 in 40,000-300,000. Many cases remain undiagnosed.

Cholesterol ester storage disorder (CESD) in pediatric age: The effect of ezetimibe treatment and the radiological evaluation of steatosis in three patients

Background and Aims: Cholesterol ester storage disorder (CESD) is a variant of Lysosomal Acid Lipase deficiency (LAL-D) and usually presents with dyslipidemia and liver involvement. No formal treatment guidelines exist. We present the effects of ezetimibe treatment and the radiological evaluation of steatosis in pediatric patients.

Disturbance of lipid homeostasis in lysosomal lipase deficiency – pathomechanism, diagnosis and treatment

Lysosomal acid lipase (LAL) plays a key role in lipid metabolism through the hydrolysis of cholesteryl esters and triglycerides in lysosomes. LAL deficiency is a rare autosomal recessive lysosomal storage disease caused by deleterious mutations in the LIPA gene. In the case of LAL deficiency, cholesteryl esters and triglycerides accumulate within the lysosomes. The up-regulation of endogenous cholesterol production, increased synthesis of apolipoprotein B (ApoB) and increased production of very-low-density lipoprotein cholesterol (VLDL-C) is observed. The diagnosis is easy due to the currently available method of testing the enzyme activity in a dry blood spot. Molecular analysis is necessary to verify the clinical and biochemical diagnosis and to analyze the genotype-phenotype correlation. Sebelipase alfa is a recombinant human lysosomal lipase intended for use in enzyme replacement therapy in patients with LAL deficiency.

Fatty Liver in a Child

Background: Cholesteryl ester storage disease (CESD) is a rare genetic condition caused due to deficiency of the enzyme lysosomal acid lipase (LAL). The condition is characterized by poor growth, dyslipidemia, and fatty liver. There is currently no data on the prevalence of this condition in the Indian population. It can easily be confused with nonalcoholic fatty liver disease (NAFLD). Clinical Description: We report the case of 4-year-old boy who presented to a pediatrician with poor growth. He was born to a nonconsanguineous couple with an uneventful perinatal period. The parents felt that the child was not growing well for 2 years. At presentation, he was hemodynamically stable and anthropometrically normal. He had pallor and hepatosplenomegaly. Rest of the examination was within normal limits. Preliminary workup showed persistent transaminitis. Further evaluation revealed dyslipidemia and hepatic steatosis in the liver fibroscan. The workup for other common causes of chronic liver disease was negative, and the clinical features were suggestive of CESD. Enzyme testing is required for the confirmation of this diagnosis, which was not available at our center or any outsourcing labs. Management: The diagnosis of cholesteryl ester storage disease was confirmed by next-generation sequencing (NGS) with multigene panel targeting the condition. At present, this child is in process to get registered for enzyme replacement therapy. Conclusions: LAL deficiency is a rare and difficult to diagnose entity. It should be considered as a differential diagnosis in children presenting with chronic liver disease with dyslipidemia and in lean children with NAFLD. For rare disorders where enzyme testing is not available, NGS can be utilized for diagnosis.

Lysosomal Acid Lipase Is a Potential Therapeutic Target for Controlling Gvhd after Allogeneic Hematopoietic Cell Transplantation in Mice

Graft-versus-host disease (GVHD) is a main barrier for the success of allogenic hematopoietic cell transplantation (allo-HCT). Lysosomal acid lipase (LAL) mediated cell-intrinsic lipolysis to generate free fatty acids and cholesterol in the cells. It plays an essential role in the development, proliferation and function of T cells. LAL deficiency decreases Th1 and Th2 differentiation while inducing the generation of myeloid-derived suppressor cells (MDSC) and regulatory T cells (Tregs). Treg and MDSC are suppressive and Th1/Th2/memory CD8 cells are pathogenic in GVHD. LAL is also required for CD8 memory T cells development. Due to its importance in alloreactive T cell metabolism, we hypothesize that LAL is a valid potential target for the control of GVHD.Using murine models of allo-HCT, we show here that transfer of reconstituted donor LAL-/- T-cells is associated with significantly less GVHD, compared with LAL+/+ donors in MHC-mismatched (B6->BALB/c or FVB->B6) (Figure 1A) and haploidentical (B6->BDF1) model (Figure 1B). To investigate the effect of pharmacologic LAL inhibition, Orlistat, a specific LAL inhibitor was chosen. Oral treatment of transplanted recipients with Orlistat significantly reduced GVHD severity and improves mortality of recipient mice in B6-BDF1 model. Mechanistically, LAL-/- donor T cells significantly reduced proliferation in allogeneic recipients compared to WT counterpart. Furthermore, LAL deficiency in donor T cells also reduced T cell activation and Th1 differentiation after transplantation. Strikingly, we observed that LAL-/- T-cells or Orlistat treatment largely preserved graft-versus-leukemia (GVL) activity against P815 mastocytoma in B6->BDF1 model (Figure 1, C&D).Taken all together, our current study provides evidences that LAL can be a valid target for the treatment of GVHD while maintaining GVL effect. Lipid lipase inhibitors could be a potential pharmacological agents for treating GVHD. Our findings thus explore a novel therapeutic strategy for the control of GVHD by altering lipid metabolism in donor T cells.*Hung Nguyen and Sandeepkumar Kuril contributed equally to this work [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Enzyme replacement therapy and hematopoietic stem cell transplant: a new paradigm of treatment in Wolman disease

BackgroundWolman disease is a rare, lysosomal storage disorder in which biallelic variants in the LIPA gene result in reduced or complete lack of lysosomal acid lipase. The accumulation of the substrates; cholesterol esters and triglycerides, significantly impacts cellular function. Untreated patients die within the first 12 months of life. Clinically, patients present severely malnourished, with diarrhoea and hepatosplenomegaly, many have an inflammatory phenotype, including with hemophagocytic lymphohistiocytosis (HLH). Hematopoietic stem cell transplant (HCT) had been historically the only treatment available but has a high procedure-related mortality because of disease progression and disease-associated morbidities. More recently, enzyme replacement therapy (ERT) with dietary substrate reduction (DSR) has significantly improved patient survival. However, ERT is life long, expensive and its utility is limited by anti-drug antibodies (ADA) and the need for central venous access.ResultsWe describe five Wolman disease patients diagnosed in infancy that were treated at Royal Manchester Children's Hospital receiving ERT with DSR then HCT—multimodal therapy. In 3/5 an initial response to ERT was attenuated by ADA with associated clinical and laboratory features of deterioration. 1/5 developed anaphylaxis to ERT and the other patient died post HCT with ongoing HLH. All patients received allogeneic HCT. 4/5 patients are alive, and both disease phenotype and laboratory parameters are improved compared to when they were on ERT alone. The gastrointestinal symptoms are particularly improved after HCT, with reduced diarrhoea and vomiting. This allows gradual structured normalisation of diet with improved tolerance of dietary fat. Histologically there are reduced cholesterol clefts, fewer foamy macrophages and an improved villous structure. Disease biomarkers also show improvement with ERT, immunotherapy and HCT. Three patients have mixed chimerism after HCT, indicating a likely engraftment-defect in this condition.ConclusionWe describe combined ERT, DSR and HCT, multimodal treatment for Wolman disease. ERT and DSR stabilises the sick infant and reduces the formerly described prohibitively high, transplant-associated mortality in this condition. HCT abrogates the problems of ERT, namely attenuating ADA, the need for continuing venous access, and continuing high cost drug treatment. HCT also brings improved efficacy, particularly evident in improved gastrointestinal function and histology. Multimodal therapy should be considered a new paradigm of treatment for Wolman disease patients where there is an attenuated response to ERT, and for all patients where there is a well-matched transplant donor, in order to improve long term gut function, tolerance of a normal diet and quality of life.

Large-scale screening of lipase acid deficiency in at risk population

BackgroundLysosomal acid lipase deficiency (LALD, OMIM#278000) is a rare lysosomal disorder with an autosomal recessive inheritance. The main clinical manifestations are related to a progressive accumulation of cholesteryl esters, triglycerides or both within the lysosome in different organs such as the liver, spleen, and cardiovascular system. A wide range of clinical severity is associated with LALD including a severe very rare antenatal/neonatal/infantile phenotype named Wolman disease and a late-onset form named cholesteryl ester storage disease (CESD). MethodsThis study aimed to investigate a cohort of at-risk patients (4174) presenting with clinical or biological signs consistent with LALD using the assessment of LAL activity on dried blood spots. ResultsLAL activity was lower than 0.05 nmol/punch/L (cut-off: 0.12) in 19 patients including 13 CESD and 6 Wolman. Molecular study has been conducted in 17 patients and succeeded in identifying 34 mutated alleles. Fourteen unique variants have been characterized, 7 of which are novel. ConclusionThis study allowed to identify a series of patients and expanded the molecular spectrum knowledge of LALD. Besides, a new screening criteria grid based on the clinical/biological data from our study and the literature has been proposed in order to enhance the diagnosis rate in at risk populations.

Wolman Disease with a Low Cholesterol Level: An Unusual Laboratory Finding

Wolman disease is a very rare autosomal recessive genetic disorder. The patients have the typical clinical finding of hepatosplenomegaly but with an abnormal lipid profile of high levels of total cholesterol (TC), triglycerides, and low-density lipoprotein cholesterol (LDL-C), but a low level of high-density lipoprotein cholesterol (HDL-C). We report a 1-month-old boy with Wolman disease who had hepatosplenomegaly but with an atypical abnormal lipid profile of low TC level, and very low levels of both LDL-C and HDL-C. The genetic study revealed a compound heterozygous mutation of the LIPA gene, leading to the confirmed diagnosis of Wolman disease.

Loss of function of lysosomal acid lipase (LAL) profoundly impacts osteoblastogenesis and increases fracture risk in humans.

Lysosomal acid lipase (LAL) is essential for cholesteryl ester (CE) and triacylglycerol (TAG) hydrolysis in the lysosome. Clinically, an autosomal recessive LIPA mutation causes LAL deficiency (LALD), previously described as Wolman Disease or Cholesteryl Ester Storage Disease (CESD). LAL-D is associated with ectopic lipid accumulation in the liver, small intestine, spleen, adrenal glands, and blood. Considering the importance of unesterified cholesterol and fatty acids in bone metabolism, we hypothesized that LAL is essential for bone formation, and ultimately, skeletal health. To investigate the role of LAL in skeletal homeostasis, we used LAL-deficient (-/-) mice, in vitro osteoblast cultures, and novel clinical data from LAL-D patients. Both male and female LAL-/- mice demonstarted lower trabecular and cortical bone parameters , which translated to reduced biomechanical properties. Further histological analyses revealed that LAL-/- mice had fewer osteoblasts, with no change in osteoclast or marrow adipocyte numbers. In studying the cell-autonomous role of LAL, we observed impaired differentiation of LAL-/- calvarial osteoblasts and in bone marrow stromal cells treated with the LAL inhibitor lalistat. Consistent with LAL's role in other tissues, lalistat resulted in profound lipid puncta accumulation and an altered intracellular lipid profile. Finally, we analyzed a large de-identified national insurance database (i.e. 2016/2017 Optum Clinformatics®) which revealed that adults (≥18years) with CESD (n=3076) had a higher odds ratio (OR=1.21; 95% CI=1.03-1.41) of all-cause fracture at any location compared to adults without CESD (n=13.7M) after adjusting for demographic variables and osteoporosis. These data demonstrate that alterations in LAL have significant clinical implications related to fracture risk and that LAL's modulation of lipid metabolism is a critical for osteoblast function.

Cross-sectional imaging features of unusual adrenal lesions: a radiopathological correlation.

The detection rates of adrenal masses are increasing with the common and widespread use of cross-sectional imaging. Adrenal adenomas, myelolipomas, metastases, pheochromocytomas, and adrenocortical tumors are well-known and relatively common adrenal tumors. However, there are many less-known neoplastic and nonneoplastic adrenal diseases that might affect the adrenal glands in addition to these common lesions. These rare entities include, but are not limited to, hydatid cysts, congenital adrenal hyperplasia, Wolman disease, adrenal tuberculosis, primary adrenal lymphoma. This article aims to present imaging findings of these unusual lesions in accordance with their pathologic characteristics. We think that the simultaneous presentation of the pathological findings with the imaging features may facilitate the learning process and may potentially enhance the recognition of these entities.

A216 CLINICAL MANIFESTATIONS OF LYSOSOMAL ACID LIPASE DEFICIENCY (LAL-D): THE INTERNATIONAL LAL-D REGISTRY

Abstract Background Lysosomal acid lipase deficiency (LAL-D) is a rare, autosomal recessive disease caused by pathogenic variants in the LIPA gene. Lysosomal accumulation of cholesteryl esters and triglycerides leads to cirrhosis and dyslipidemia across a clinical spectrum, and affect both infants and children/adults. Aims An international registry (NCT01633489; Alexion Pharmaceuticals, Inc.; 2013–ongoing) was established to better understand the natural history of lysosomal acid lipase deficiency (LAL-D) and to evaluate long-term treatment outcomes. Methods Baseline findings for patients enrolled through July 1, 2019 are presented. Of 190 patients enrolled, 35 were excluded from this analysis (LIPA carrier, deceased at enrollment, unconfirmed LAL-D diagnosis); 155 patients with confirmed LAL-D diagnosis were included (12 infants, 143 children/adults). LAL enzyme activity analysis was performed for 145/154 patients (94%) and genetic testing for 128/154 patients (83%). Results Of 105 children/adults with reported LIPA mutations, 39 were homozygous and 34 were compound heterozygous for the common LIPA mutation E8SJM (c.894G>A); 6 infants with reported LIPA mutations were homozygotes and 2 were compound heterozygotes. Of the 155 patients, 62% were <18 years, 52% were male, and 85% were white. Median (range) age at clinical onset was 0.2 years (0.0–0.7) among infants and 6.0 years (0.0–41.3) among 133 children/adults with data; median (range) age at diagnosis was 0.2 years (−0.1 to 1.2) among infants and 10.8 years (0.2–53.6) among 135 children/adults with data. Manifestations that raised suspicion of LAL-D were reported in 149/155 patients. Infants (12 with data) presented predominantly with hepatomegaly (75%), splenomegaly (58%), nausea/vomiting (58%), and diarrhea (50%), and 50% had a known family history of LAL-D. Children/adults (n=143) presented predominantly with elevated alanine aminotransferase levels (67%), hepatomegaly (66%), and elevated aspartate aminotransferase levels (65%). Of 74 children/adults with baseline liver biopsy, 58% had microvesicular steatosis, 16% had micro- and macrovesicular steatosis, and 32% had lobular inflammation. Of the 155 patients, 6% had a medical history of cirrhosis. Analyses exploring the genotype-phenotype relationship will be presented. Conclusions Registry data of >150 LAL-D patients demonstrate early symptom onset, variable clinical manifestations, and a significant diagnostic delay in children/adults. Funding Agencies Alexion Pharmaceuticals, Inc.

Wolman\u2019s disease presenting with secondary hemophagocytic lymphohistiocytosis: a case report from Saudi Arabia and literature review

BackgroundHemophagocytic lymphohistiocytosis (HLH) is a rare and potentially fatal syndrome that is characterized by strong activation of the immune system from hyperinflammatory cytokines. Symptoms of HLH patients include fever, hepatosplenomegaly, cytopenia, and hyperferritinemia. Inherited HLH is classified as primary, whereas secondary HLH (sHLH) occurs when acquired from non-inherited reasons that include severe infection, immune deficiency syndrome, autoimmune disorder, neoplasm, and metabolic disorder. Wolman’s disease (WD) is a rare and fatal infantile metabolic disorder caused by lysosomal acid lipase deficiency, that exhibits similar clinical signs and symptoms as HLH. This paper reports the case of an infant diagnosed with WD and who presented with sHLH.Case presentationA 4-month-old infant presenting with hepatosplenomegaly, failure to thrive, and other abnormalities. WD diagnosis was confirmed by the presence of the LIPA gene homozygous deletion c.(428 + 1_967-1)_(*1_?)del. The infant also met the HLH-2004 diagnostic criteria.ConclusionsMetabolic disorder such as WD should be investigated in infants fulfilling the HLH criteria to diagnose the underlying condition. More studies are needed to understand the link between WD and sHLH and to identify appropriate therapies.

Long-term survival with sebelipase alfa enzyme replacement therapy in infants with rapidly progressive lysosomal acid lipase deficiency: final results from 2 open-label studies

BackgroundIf symptomatic in infants, the autosomal recessive disease lysosomal acid lipase deficiency (LAL-D; sometimes called Wolman disease or LAL-D/Wolman phenotype) is characterized by complete loss of LAL enzyme activity. This very rare, rapidly progressive form of LAL-D results in severe manifestations leading to failure to thrive and death, usually by 6 months of age. We report results from 2 open-label studies of enzyme replacement therapy with sebelipase alfa, a recombinant human LAL, in infants with LAL-D: the phase 2/3 Survival of LAL-D Infants Treated With Sebelipase Alfa (VITAL) study (NCT01371825) and a phase 2 dose-escalation study (LAL-CL08 [CL08]; NCT02193867). In both, infants received once-weekly intravenous infusions of sebelipase alfa.ResultsThe analysis population contained 19 patients (9 in VITAL; 10 in CL08). Kaplan–Meier estimates of survival to 12 months and 5 years of age were 79% and 68%, respectively, in the combined population, and the median age of surviving patients was 5.2 years in VITAL and 3.2 years in CL08. In both studies, median weight-for-age, length-for-age, and mid-upper arm circumference-for-age z scores increased from baseline to end of study. Decreases in median liver and spleen volume over time were noted in both studies. Short-term transfusion-free hemoglobin normalization was achieved by 100% of patients eligible for assessment in VITAL, in an estimated median (95% confidence interval [CI]) time of 4.6 (0.3–16.6) months. In CL08, short-term transfusion-free hemoglobin normalization was achieved by 70% of patients eligible for assessment, in an estimated median (95% CI) time of 5.5 (3.7–19.6) months. No patient discontinued treatment because of treatment-emergent adverse events. Most infusion-associated reactions (94% in VITAL and 88% in CL08) were mild or moderate in severity.ConclusionsThe findings of these 2 studies of infants with rapidly progressive LAL-D demonstrated that enzyme replacement therapy with sebelipase alfa prolonged survival with normal psychomotor development, improved growth, hematologic parameters, and liver parameters, and was generally well tolerated, with an acceptable safety profile.

Lysosomal Acid Lipase Deficiency: rare genetic disease disguised as nonalcoholic fatty liver disease with dyslipidemia

Lysosomal Acid Lipase Deficiency: rare genetic disease disguised as nonalcoholic fatty liver disease with dyslipidemia