448 results on '"Lysosomal acid lipase deficiency"'
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2. Evaluation of 73 Enlisted Patients for Liver Transplant with Unknown Etiology Reveals a Late-Diagnosed Case of Lysosomal Acid Lipase Deficiency.
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Bastos, Karina Lucio de Medeiros, Stephan, Bruno de Oliveira, Linnenkamp, Bianca Domit Werner, Costa, Larissa Athayde, Lima, Fabiana Roberto, Carvalho, Laura Machado Lara, Honjo, Rachel Sayuri, Tannuri, Uenis, Tannuri, Ana Cristina Aoun, and Kim, Chong Ae
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GENETIC counseling , *LIVER transplantation , *LIVER enzymes , *LIVER failure , *GENETIC testing - Abstract
Lysosomal acid lipase deficiency (LALD) varies from a severe infantile-onset form (Wolman disease) to a late-onset form known as cholesteryl ester storage disease (CESD), both of which are autosomal recessive disorders caused by biallelic LIPA pathogenic variants. We evaluated seventy-three patients enlisted for liver transplant (LT) at Instituto da Criança (HCFMUSP—Brazil) who were subjected to LAL activity measurement and LIPA Sanger sequencing analysis, resulting in a positive LALD diagnosis for only one of these individuals. This LALD patient presented recurrent diarrhea, failure to thrive, hepatomegaly, and dyslipidemia at the age of 4 months and liver failure by the age of 13 years. The LALD diagnosis confirmation was conducted at 24 years old due to low levels of LAL enzyme activity. The causal homozygous variant LIPA(NM_000235.4):c.266T>C(p.Leu89Pro) was identified, but the patient had already undergone his first LT at 18 years with several rejection episodes. Despite beginning treatment with sebelipase alfa at 26 years old (total of five infusions), this patient died at 28 years from complications after his second liver transplant. LALD is an important differential diagnosis in cases presenting with hepatomegaly, elevated liver enzymes, and dyslipidemia. Detecting low/absent LAL activity and identifying the LIPA causal variant are essential for diagnosis and specific treatment, as well as for appropriate genetic counseling. Early diagnosis, along with sebelipase alfa therapy, may improve the prognosis of affected patients. [ABSTRACT FROM AUTHOR]
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- 2024
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3. The Liver and Lysosomal Storage Diseases: From Pathophysiology to Clinical Presentation, Diagnostics, and Treatment.
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Lipiński, Patryk and Tylki-Szymańska, Anna
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LYSOSOMAL storage diseases , *SYMPTOMS , *GLYCOGEN storage disease type II , *NIEMANN-Pick diseases , *GAUCHER'S disease , *LIVER - Abstract
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. [ABSTRACT FROM AUTHOR]
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- 2024
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4. Lanifibranor Reduces Inflammation and Improves Dyslipidemia in Lysosomal Acid Lipase-Deficient Mice
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Ivan Bradić, Nemanja Vujić, Katharina B. Kuentzel, Hansjörg Habisch, Anita Pirchheim, Alena Akhmetshina, John D. Henderson, Tobias Madl, Atul S. Deshmukh, and Dagmar Kratky
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LAL ,Lysosomal Acid Lipase Deficiency ,Liver Inflammation ,Lipoproteins ,Pan-PPAR Agonist ,Diseases of the digestive system. Gastroenterology ,RC799-869 - Abstract
Background and Aims: Recent studies showed that patients suffering from lysosomal acid lipase deficiency (LAL-D) benefit from enzyme replacement therapy; however, liver histopathology improved in some but not all patients. We hypothesized that the pan-peroxisome proliferator-activated receptor 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. Methods: Female 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. Results: Lanifibranor 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. Conclusion: Lanifibranor treatment positively affected liver inflammation and dyslipidemia in Lal−/− mice. These findings suggest the necessity of a further combined study of lanifibranor with enzyme replacement therapy 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.
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- 2024
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5. Evaluation of 73 Enlisted Patients for Liver Transplant with Unknown Etiology Reveals a Late-Diagnosed Case of Lysosomal Acid Lipase Deficiency
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Karina Lucio de Medeiros Bastos, Bruno de Oliveira Stephan, Bianca Domit Werner Linnenkamp, Larissa Athayde Costa, Fabiana Roberto Lima, Laura Machado Lara Carvalho, Rachel Sayuri Honjo, Uenis Tannuri, Ana Cristina Aoun Tannuri, and Chong Ae Kim
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lysosomal acid lipase deficiency ,LIPA gene testing ,liver transplant ,genetic counseling ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Lysosomal acid lipase deficiency (LALD) varies from a severe infantile-onset form (Wolman disease) to a late-onset form known as cholesteryl ester storage disease (CESD), both of which are autosomal recessive disorders caused by biallelic LIPA pathogenic variants. We evaluated seventy-three patients enlisted for liver transplant (LT) at Instituto da Criança (HCFMUSP—Brazil) who were subjected to LAL activity measurement and LIPA Sanger sequencing analysis, resulting in a positive LALD diagnosis for only one of these individuals. This LALD patient presented recurrent diarrhea, failure to thrive, hepatomegaly, and dyslipidemia at the age of 4 months and liver failure by the age of 13 years. The LALD diagnosis confirmation was conducted at 24 years old due to low levels of LAL enzyme activity. The causal homozygous variant LIPA(NM_000235.4):c.266T>C(p.Leu89Pro) was identified, but the patient had already undergone his first LT at 18 years with several rejection episodes. Despite beginning treatment with sebelipase alfa at 26 years old (total of five infusions), this patient died at 28 years from complications after his second liver transplant. LALD is an important differential diagnosis in cases presenting with hepatomegaly, elevated liver enzymes, and dyslipidemia. Detecting low/absent LAL activity and identifying the LIPA causal variant are essential for diagnosis and specific treatment, as well as for appropriate genetic counseling. Early diagnosis, along with sebelipase alfa therapy, may improve the prognosis of affected patients.
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- 2024
- Full Text
- View/download PDF
6. Clinical guidelines for the management of children with lysosomal acid lipase deficiency
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Inga V. Anisimova, Marina B. Albegova, Madlena E. Bagaeva, Galina V. Baidakova, Aleksandr A. Baranov, Nato D. Vashakmadze, Elena A. Vishneva, Olga S. Gundobina, Anna V. Degtiareva, Marat V. Ezhov, Maria S. Zharkova, Nataliia V. Zhurkova, Ekaterina Yu. Zaharova, Vladimir T. Ivashkin, Elena A. Kamenets, Sergey I. Kutzev, Alla E. Lavrova, Irina A. Matinian, Svetlana V. Mikhailova, Leyla S. Namazova-Baranova, Irina E. Pashkova, Elena E. Petriaykina, Tatiana M. Pervunina, Nataliia L. Pechatnikova, Nelia S. Pogosian, Svetlana A. Repina, Lilia R. Selimzianova, Tamara A. Skvortsova, Tatiana V. Strokova, Dmitriy M. Subbotin, Andrey N. Surkov, Elena L. Tumanova, and Ekaterina G. Tzimbalova
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lysosomal acid lipase deficiency ,wolman disease ,cholesterol ester storage disease ,diagnostics ,management ,enzyme replacement therapy ,children ,Pediatrics ,RJ1-570 ,Therapeutics. Pharmacology ,RM1-950 - Abstract
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.
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- 2023
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7. First LIPA Mutational Analysis in Egyptian Patients Reveals One Novel Variant: Wolman Disease.
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Elaraby, Nesma M., Galal, Eman Reda, Abdel-Hamid, Mohamed, Elbendary, Hasnaa M., Elbadry, Mohamed, Mekkawy, Mona K., Ashaat, Neveen A., Mounir, Samir M., and Ashaat, Engy A.
- Abstract
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. [ABSTRACT FROM AUTHOR]
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- 2023
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8. A novel variant in the LIPA gene associated with distinct phenotype
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Sarajlija A., Armengol L., Maver A., Kitic I., Prokic D., Cehic M., Djuricic M.S., and Peterlin B.
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lipa ,lysosomal acid lipase deficiency ,variant of uncertain significance ,Genetics ,QH426-470 - Abstract
Deficiency of lysosomal acid lipase (LAL-D) is caused by biallelic pathogenic variants in the LIPA gene. Spectrum of LAL-D ranges from early onset of hepatosplenomegaly and psychomotor regression (Wolman disease) to a more chronic course (cholesteryl ester storage disease - CESD). The diagnosis is based on lipid and biomarker profiles, specific liver histopathology, enzyme deficiency, and identification of causative genetic variants. Biomarker findings are a useful for diagnostics of LAL-D, including high plasma concentration of chitotriosidase as well as elevated oxysterols. Current treatment options include enzyme replacement therapy (sebelipase-alpha), statins, liver transplantation, and stem cell transplantation.
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- 2023
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9. A Case of Lysosomal Acid Lipase Deficiency Confirmed by Response to Sebelipase Alfa Therapy.
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Shen, Joseph J, Davis, Jessica L, Hong, Xinying, Laningham, Fred H, Gelb, Michael H, and Kim, Grace E
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Humans ,Cholesterol Ester Storage Disease ,Wolman Disease ,Female ,Sterol Esterase ,2.1 Biological and endogenous factors ,Aetiology ,cholesterol ester storage disease ,lysosomal acid lipase deficiency ,LIPA gene ,pathogenic variant ,sebelipase alfa ,variant of uncertain significance ,Medical and Health Sciences ,Gastroenterology & Hepatology - Abstract
Lysosomal acid lipase (LAL) deficiency, or cholesterol ester storage disease, is a disorder affecting the breakdown of cholesterol esters and triglycerides within lysosomes. Clinical findings include hepatomegaly, hepatic dysfunction, and dyslipidemia with a wide range of phenotypic variability and age of onset. The available clinical and molecular information of the patient presented herein was consistent with a diagnosis of LAL deficiency, but her LAL activity assay repeatedly showed normal or borderline low results. Her response to enzyme replacement therapy and demonstrable deficiency on a newer specific enzymatic assay ultimately confirmed her diagnosis of LAL deficiency.
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- 2020
10. Distinguishing Lysosomal Acid Lipase Deficiency From Familial Hypercholesterolemia
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Sohum Sheth, BS, Peter P. Toth, MD, PhD, Seth J. Baum, MD, and Monica Aggarwal, MD
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familial hypercholesterolemia ,low-density lipoprotein cholesterol ,lysosomal acid lipase deficiency ,sebelipase alfa ,Diseases of the circulatory (Cardiovascular) system ,RC666-701 - Abstract
Lysosomal acid lipase deficiency (LAL-D) is underrecognized because it manifests clinically with lipid and lipoprotein values similar to those observed in heterozygous familial hypercholesterolemia (FH). Although LAL-D is uncommon, understanding the differences between the 2 diseases has significant management implications. We present a case of LAL-D that masqueraded as FH. (Level of Difficulty: Advanced.)
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- 2023
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11. Evaluation of biochemical profile and oxidative damage to lipids and proteins in patients with lysosomal acid lipase deficiency.
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Guerreiro, Gilian, Deon, Marion, and Vargas, Carmen Regla
- Abstract
Lysosomal acid lipase deficiency (LALD) is an inborn error of metabolism that lacks satisfactory treatment, which leads to the development of severe hepatic and cardiac complications and may even lead to death. In this sense, knowledge of the mechanisms involved in the pathophysiology of this disorder becomes essential to allow the search for new therapeutic strategies. There are no studies in the literature investigating the role of reactive species and inflammatory processes in the pathophysiology of this disorder. Therefore, the aim of this work was to investigate parameters of oxidative and inflammatory stress in LALD patients. In this work, we obtained results that demonstrate that LALD patients are susceptible to oxidative stress caused by an increase in the production of free radicals, observed by the increase of 2-7-dihydrodichlorofluorescein. The decrease in sulfhydryl content reflects oxidative damage to proteins, as well as a decrease in antioxidant defenses. Likewise, the increase in urinary levels of di-tyrosine observed also demonstrates oxidative damage to proteins. Furthermore, the determination of chitotriosidase activity in the plasma of patients with LALD was significantly higher, suggesting a pro-inflammatory state. An increase in plasma oxysterol levels was observed in patients with LALD, indicating an important relationship between this disease and cholesterol metabolism and oxidative stress. Also, we observed in LALD patients increased levels of nitrate production. The positive correlation found between oxysterol levels and activity of chitotriosidase in these patients indicates a possible link between the production of reactive species and inflammation. In addition, an increase in lipid profile biomarkers such as total and low-density lipoprotein cholesterol were demonstrated in the patients, which reinforces the involvement of cholesterol metabolism. Thus, we can assume that, in LALD, oxidative and nitrosative damage, in addition to inflammatory process, play an important role in its evolution and future clinical manifestations. In this way, we can suggest that the study of the potential benefit of the use of antioxidant and anti-inflammatory substances as an adjuvant tool in the treatment will be important, which should be associated with the already recommended therapy. [ABSTRACT FROM AUTHOR]
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- 2023
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12. Successful matched unrelated donor hematopoietic stem cell transplantation for infantile Wolman disease
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Indira Jayakumar, Anupama Gude, Murarji Renangi, Soundaram Valliyappan, Venkateswaran Vellaichamy Swaminathan, Satishkumar Meena, Harika Varla, Rumesh Chandar, Ramya Uppuluri, and Revathi Raj
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Wolman disease ,HSCT ,Primary hypoaldosteronism ,Infant ,Lysosomal acid lipase deficiency ,Pediatrics ,RJ1-570 - Abstract
Introduction: Wolman disease is a rare genetic disorder with an autosomal recessive inheritance. A mutation in the LIPA gene causes lysosomal acid lipase (LAL) deficiency results in lipid storage and adrenal insufficiency. Death in early infancy is due to liver failure. Patients and methods: We describe the clinical course of a three-month-old infant diagnosed with Wolman disease. A rapid mutational analysis confirmed a LIPA gene defect. Results: He underwent matched unrelated donor peripheral blood stem cell hematopoietic stem cell transplantation (HSCT) at 3 months of age, with a treosulfan-based conditioning, which resulted in engraftment with donor-derived hematopoietic cells. He required supportive care for sinusoidal obstruction syndrome and mucositis. He was administered low dose prednisolone for grade I skin graft versus host disease, and a complete donor chimerism was documented on several occasions. At one year post HSCT, his growth and development were optimal, and there was no hepatosplenomegaly. He is maintained on glucocorticoid and mineralocorticoid supplements for primary hypoaldosteronism. Conclusion: The case emphasizes the timely diagnosis and the potential for successful treatment of Wolman disease by HSCT.
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- 2023
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13. A Form of Metabolic-Associated Fatty Liver Disease Associated with a Novel LIPA Variant.
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Anushiravani, Amir, Khamirani, Hossein Jafari, Mohamadkhani, Ashraf, Mani, Arya, Dianatpour, Mehdi, and Malekzadeh, Reza
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SEQUENCE analysis , *GENETIC mutation , *NON-alcoholic fatty liver disease , *CIRRHOSIS of the liver , *LYSOSOMAL storage diseases , *HYPERLIPIDEMIA , *CHOLESTEROL , *DISEASE complications - Abstract
Background: The LIPA gene on chromosome 10q23.31 contains 10 exons and encodes lipase A, the lysosomal acid lipase (LAL) containing 399 amino acids. Pathogenic variants in the LIPA result in autosomal recessive Wolman disease and cholesteryl ester storage disease (CESD). Here, we report a novel missense variant (NM_001127605.3:c.928T > A, p.Trp310Arg) of LIPA in an Iranian family with fatty liver disease identified by whole-exome sequencing and confirmed by Sanger sequencing. Methods: A 28-year-old woman referred with lean NASH cirrhosis and extremely high cholesterol levels. Fatty liver disease was found in six of her family members using vibration-controlled transient elastography (VCTE). Baseline routine laboratory tests were performed and whole-exome sequencing and confirmation by Sanger sequencing were done. Results: The index case had severe dyslipidemia and cirrhosis despite a body mass index of 21.09 kg/m². Six other family members had dyslipidemia and fatty liver or cirrhosis. A homozygous missense variant (NM_001127605.3:c.928T > A, p.Trp310Arg) of LIPA which caused LAL-D was found to be associated with fatty liver disease and/or cirrhosis. Conclusion: A homozygous missense variant (NM_001127605.3:c.928T > A, p.Trp310Arg) of the LIPA gene which caused LAL-D was found to be associated with dyslipidemia, fatty liver disease and/or cirrhosis in six members of an Iranian family. These results should be confirmed by functional studies and extending the study to at least three families. [ABSTRACT FROM AUTHOR]
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- 2023
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14. Rare diseases presenting with hemophagocytic lymphohistiocytosis.
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Kanegane, Hirokazu, Noguchi, Atsuko, Yamada, Yuki, and Yasumi, Takahiro
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IMMUNOLOGICAL deficiency syndrome complications , *HEMOPHAGOCYTIC lymphohistiocytosis , *MEMBRANE transport proteins , *INBORN errors of metabolism , *RHO(D) immune globulin , *MITOGEN-activated protein kinases , *RARE diseases , *DISEASE complications - Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a potentially fatal hyperinflammatory disorder characterized by hypercytokinemia caused by excessive activation of cytotoxic T cells and macrophages. HLH is caused by a variety of factors and is classified into primary and secondary HLH. Familial HLH (FHL) types 1–5, X‐linked lymphoproliferative syndrome types 1 and 2, and FHL syndrome with hypopigmentation are all examples of primary HLH. Secondary HLH, on the other hand, is linked to infections, malignant tumors, autoimmune diseases, and other diseases. The causes of HLH vary, and finding the underlying disease is critical for diagnosis and treatment. The majority of HLH is caused by the aforementioned conditions; however, approximately 10% of cases are caused by rare diseases such as inborn errors of immunity (IEI) and inborn errors of metabolism (IEM). Novel IEI, such as RhoG, MAP kinase activating death domain, TIM3, and ZNFX1 deficiencies, have recently been identified as causes of HLH. IEM patients are rarely associated with HLH. Surprisingly, children with lysinuric protein intolerance and lysosomal acid lipase deficiency (Wolman disease) frequently develop HLH. This review focuses on the most recent knowledge of HLH caused by rare diseases such as IEI and IEM. [ABSTRACT FROM AUTHOR]
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- 2023
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15. Congenital adrenal calcifications as the first clinical indication of sphingosine lyase insufficiency syndrome: A case report and review of the literature.
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Ron, Hayley A., Scobell, Rebecca, Strong, Amy, Salazar, Elizabeth G., and Ganetzky, Rebecca
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Sphingosine Lyase Insufficiency Syndrome (SPLIS) or SGPL1 Deficiency is a newly described entity that is characterized by steroid‐resistant nephrotic syndrome, primary adrenal insufficiency, lymphopenia, ichthyosis, and/or endocrine and neurologic abnormalities. The earliest identification of SGPL1 pathogenic variants in association with this syndrome was reported in 2017. Since then, at least 36 patients have been reported with this pediatric syndrome. Here, we report a new patient with SPLIS who had a prenatal finding of adrenal calcifications, congenital nephrotic syndrome, and abnormal newborn screening concerning for Severe Combined Immunodeficiency. We conclude that SPLIS is a clinically recognizable condition with prenatal onset. This case should increase awareness of SPLIS in the differential diagnosis for adrenal calcifications. We present a case on the severe end of the clinical spectrum of SPLIS, and a review of the literature. [ABSTRACT FROM AUTHOR]
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- 2022
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16. Lysosomal acid lipase deficiency – an underestimated cause of hypercholesterolemia in children
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I. I. Pshenichnikova, I. N. Zakharova, E. V. Skorobogatova, T. I. Bocharova, and Yu. V. Koba
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children ,liver ,lysosomal acid lipase deficiency ,wolman’s disease ,cholesterol ester storage disease ,sebelipase alfa ,clinical observation ,Medicine - Abstract
Lysosomal acid lipase deficiency (LAL-D) is a rare, progressive, autosomal recessive disease, which develops due to impaired degradation and subsequent intra-lysosomal accumulation of triglycerides and cholesterol esters causing dyslipidemia. The clinical manifestations of the disease presumably depend on the residual activity of the enzyme, lysosomal acid lipase. A profound deficiency of the enzyme known as Wolman’s disease has an onset in the first 6 months of life. The disease reveals itself by dyspeptic disorders in the form of vomiting and diarrhea, lack of weight gain, hepatosplenomegaly, and adrenal calcification. If the Wolman’s disease is not treated, children die within the first 6 months as a result of exhaustion caused by malabsorption syndrome combined with progressive deterioration of liver and adrenal glands. Partial deficiency of lysosomal acid lipase manifests itself at a later age and is called cholesterol ester storage disease. Its clinical presentations include hepatosplenomegaly, elevated transaminases, hypercholesterolemia, and, in some cases, hypertriglyceridemia. Liver failure is the main cause of death in the natural course of cholesterol ester storage disease. Delayed diagnosis of the disease leads to its progression causing irreversible liver damage. The implementation of mass screening programs with the determination of cholesterol levels in childhood is critical to identifying asymptomatic patients.The article presents a clinical case of a patient aged 3 years. The molecular genetic testing showed a mutation in exon 8 of the LIPA gene: NM_000235.3:c.894G>A synonymous variant in the homozygous state. It was also found that both parents of the girl had this type of mutation in the heterozygous state. The patient was prescribed sebelipase alfa in a dose of 1 mg/kg once every 14 days. The treatment was well tolerated. Due to the early verification of the diagnosis and timely pathogenetic therapy, the prognosis of the course of LAL-D, the duration and quality of life of the child were considered to be favourable.Raising the awareness of doctors along with the introduction of effective screening programs for the timely detection of dyslipidemia in children contributes to timely diagnosis and early initiation of pathogenetic therapy, which can increase the life expectancy of patients with lysosomal acid lipase deficiency and improve their quality of life.
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- 2022
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17. Lysosomal acid lipase deficiency in pediatric patients: a scoping review
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Camila da Rosa Witeck, Anne Calbusch Schmitz, Júlia Meller Dias de Oliveira, André Luís Porporatti, Graziela De Luca Canto, and Maria Marlene de Souza Pires
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Pediatrics ,Lysosomal acid lipase deficiency ,Wolman disease ,Cholesteryl ester storage disease ,RJ1-570 - Abstract
Objective: Lysosomal acid lipase deficiency (LAL-D) is an underdiagnosed autosomal recessive disease with onset between the first years of life and adulthood. Early diagnosis is crucial for effective therapy and long-term survival. The objective of this article is to recognize warning signs among the clinical and laboratory characteristics of LAL-D in pediatric patients through a scope review. Sources: Electronic searches in the Embase, PubMed, Livivo, LILACS, Web of Science, Scopus, Google Scholar, Open Gray, and ProQuest Dissertations and Theses databases. The dataset included observational studies with clinical and laboratory characteristics of infants, children and adolescents diagnosed with lysosomal acid lipase deficiency by enzyme activity testing or analysis of mutations in the lysosomal acid lipase gene (LIPA). The reference selection process was performed in two stages. The references were selected by two authors, and the data were extracted in June 2020. Summary of the findings: The initial search returned 1593 studies, and the final selection included 108 studies from 30 countries encompassing 206 patients, including individuals with Wolman disease and cholesteryl ester storage disease (CESD). The most prevalent manifestations in both spectra of the disease were hepatomegaly, splenomegaly, anemia, dyslipidemia, and elevated transaminases. Conclusions: Vomiting, diarrhea, jaundice, and splenomegaly may be correlated, and may serve as a starting point for investigating LAL-D. Familial lymphohistiocytosis should be part of the differential diagnosis with LAL-D, and all patients undergoing upper gastrointestinal endoscopy should be submitted to intestinal biopsy.
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- 2022
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18. Survival in infants treated with sebelipase Alfa for lysosomal acid lipase deficiency: an open-label, multicenter, dose-escalation study
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Jones, Simon A, Rojas-Caro, Sandra, Quinn, Anthony G, Friedman, Mark, Marulkar, Sachin, Ezgu, Fatih, Zaki, Osama, Gargus, J Jay, Hughes, Joanne, Plantaz, Dominique, Vara, Roshni, Eckert, Stephen, Arnoux, Jean-Baptiste, Brassier, Anais, Le Quan Sang, Kim-Hanh, and Valayannopoulos, Vassili
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Biomedical and Clinical Sciences ,Cardiovascular Medicine and Haematology ,Clinical Trials and Supportive Activities ,Pediatric ,Liver Disease ,Digestive Diseases ,Clinical Research ,6.1 Pharmaceuticals ,Evaluation of treatments and therapeutic interventions ,Good Health and Well Being ,Female ,Humans ,Infant ,Male ,Sterol Esterase ,Survival Analysis ,Wolman Disease ,Lysosomal acid lipase deficiency ,Wolman disease ,Sebelipase alfa ,Survival ,Hemophagocytic lymphohistiocytosis ,Other Medical and Health Sciences ,Genetics & Heredity ,Genetics ,Clinical sciences - Abstract
BackgroundInfants 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.ResultsNine patients were enrolled; median age at baseline was 3.0 months (range 1.1-5.8 months). Sixty-seven percent (exact 95% CI 30%-93%) of sebelipase alfa-treated infants survived to 12 months of age compared with 0% (exact 95% CI 0%-16%) for a historical control group (n = 21). Patients who survived to age 12 months exhibited improvements in weight-for-age, reductions in markers of liver dysfunction and hepatosplenomegaly, and improvements in anemia and gastrointestinal symptoms. Three deaths occurred early (first few months of life), two patients died because of advanced disease, and a third patient died following complications of non-protocol-specified abdominal paracentesis. A fourth death occurred at 15 months of age and was related to other clinical conditions. The five surviving patients have survived to age ≥24 months with continued sebelipase alfa treatment; all have displayed marked improvement in growth parameters and liver function. Serious adverse events considered related to sebelipase alfa were reported in one of the nine infants (infusion reaction: tachycardia, pallor, chills, and pyrexia). Most infusion-associated reactions were mild and non-serious.ConclusionSebelipase alfa markedly improved survival with substantial clinically meaningful improvements in growth and other key disease manifestations in infants with rapidly progressive lysosomal acid lipase deficiency TRIAL REGISTRATION: Clinicaltrials.gov NCT01371825 . Registered 9 June 2011.
- Published
- 2017
19. Wolman Disease with a Low Cholesterol Level: An Unusual Laboratory Finding
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Phawin Kor-anantakul, Thipwimol Tim-Aroon, and Somchit Jaruratanasirikul
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lipa gene ,lysosomal acid lipase deficiency ,wolman disease ,Medicine - Abstract
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.
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- 2021
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20. Early Discovery of Children With Lysosomal Acid Lipase Deficiency With the Universal Familial Hypercholesterolemia Screening Program.
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Sustar, Ursa, Groselj, Urh, Podkrajsek, Katarina Trebusak, Mlinaric, Matej, Kovac, Jernej, Thaler, Martin, Torkar, Ana Drole, Skarlovnik, Ajda, Battelino, Tadej, and Hovnik, Tinka
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FAMILIAL hypercholesterolemia ,LIPASES ,LYSOSOMAL storage diseases ,CHILD patients ,HEPATOMEGALY ,ASPARTATE aminotransferase - Abstract
Lysosomal acid lipase deficiency (LAL-D) is an autosomal recessive lysosomal storage disorder, caused by homozygous or compound heterozygous pathogenic variants in the LIPA gene. Clinically, LAL-D is under- and misdiagnosed, due to similar clinical and laboratory findings with other cholesterol or liver misfunctions. As a part of the Slovenian universal familial hypercholesterolemia (FH) screening, LAL-D is screened as a secondary condition among other rare dyslipidemias manifesting with hypercholesterolemia. Out of 669 children included, three were positive for a homozygous disease-causing splicing variant NM_000235.4: c.894G > A (NP_000226.2:p. Gln298Gln) in the LIPA gene (NG_008194.1). The mean age by the diagnosis of LAL-D was 9.8 ± 0.9 years. Moreover, all three LAL-D-positive children had an important elevation of transaminases and decreased activity of the lysosomal acid lipase enzyme. Abdominal MRI in all children detected an enlarged liver but a normal-sized spleen. In conclusion, universal FH screening algorithms with the confirmatory genetic analysis in the pediatric population enable also rare dyslipidemia detection at an early age. An important clinical criterion for differentiation between FH and the LAL-D-positive children has elevated transaminase levels (AST and ALT). In all three LAL-D positive children, an improvement in cholesterol and transaminase levels and steatosis of the liver has been seen after early treatment initiation. [ABSTRACT FROM AUTHOR]
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- 2022
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- View/download PDF
21. Could lysosomal acid lipase enzyme activity be used for clinical follow-up in cryptogenic cirrhosis?
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KÖSE, Engin, ÇAĞATAY, Elçin, YARAŞ, Tutku, TEKE KISA, Pelin, GÜLER, Seminay, ARSLAN GÜLTEN, Zümrüt, AKARSU, Mesut, OKTAY, Yavuz, AYAR KAYALI, Hülya, and ARSLAN, Nur
- Subjects
- *
LYSOSOMES , *PLATELET count , *LEUKOCYTE count , *CIRRHOSIS of the liver , *LIPASES , *ENZYME deficiency , *LOGISTIC regression analysis - Abstract
Background/aim: Cholesterol ester storage disease (CESD) is one of the rare causes that should be kept in mind in the etiology of cirrhosis. Recent studies detected that significantly reduced lysosomal acid lipase deficiency enzyme (LAL) in patients with cryptogenic cirrhosis (CC). Moreover, studies have evaluated that LAL activity is as effective as scoring systems in assessing the severity of cirrhosis. In this study, we aimed to investigate the CESD with LAL level and mutation analysis of LIPA gene in patients diagnosed with CC and to compare LAL activities between patients with CC and healthy volunteers. Materials and methods: Laboratory parameters and cirrhosis stage (CHILD and MELD) were recorded for the patient group included in the study. In addition, blood samples were taken from each case included in the study for LAL activity determination and LIPA gene analysis. Results: A statistically significant decrease in LAL activity was found in patients diagnosed with CC compared to the healthy group. LIPA gene analysis did not detect CESD in any patient group. Correlation analysis showed a positive correlation between LAL activity and white blood cell and platelet counts in both healthy volunteers and CC patient groups. In the univariate and multivariate logistic regression analysis of the parameters associated with the MELD of ≥10 in patients with CC, significant relationship was found between the MELD of ≥10 and the LAL activity. Conclusions: In our study, LAL activity was significantly lower in CC patients than in the normal population. LAL activity level appears to be a parameter that can be used to assess the severity of cirrhosis. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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22. A novel variant in the LIPA gene associated with distinct phenotype.
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Sarajlija, A., Armengol, L., Maver, A., Kitic, I., Prokic, D., Cehic, M., Djuricic, M.S., and Peterlin, B.
- Subjects
- *
GENETIC variation , *ENZYME replacement therapy , *HETEROZYGOSITY , *STEM cell transplantation , *PHENOTYPES , *ENZYME deficiency - Abstract
Deficiency of lysosomal acid lipase (LAL-D) is caused by biallelic pathogenic variants in the LIPA gene. Spectrum of LAL-D ranges from early onset of hepatosplenomegaly and psychomotor regression (Wolman disease) to a more chronic course (cholesteryl ester storage disease - CESD). The diagnosis is based on lipid and biomarker profiles, specific liver histopathology, enzyme deficiency, and identification of causative genetic variants. Biomarker findings are a useful for diagnostics of LAL-D, including high plasma concentration of chitotriosidase as well as elevated oxysterols. Current treatment options include enzyme replacement therapy (sebelipase-alpha), statins, liver transplantation, and stem cell transplantation. We present two pairs of siblings from Serbia with a distinctive phenotype resembling LAL-D with a novel variant of unknown significance (VUS) detected in the LIPA gene and residual LAL activity. All patients presented with hepatosplenomegaly at early childhood. In siblings from family 1, compound heterozygosity for a pathogenic c.419G>A (p.Trp140Ter) variant and a novel VUS c.851C>T (p.Ser284Phe) was detected. Patients from family 2 were homozygous for c.851C>T VUS and both have typical histopathologic findings for LAL-D in the liver. Enzyme activity of LAL was tested in three patients and reported as sufficient, and therefore enzyme replacement therapy could not be approved. When confronted with a challenge of diagnosing an inherited metabolic disorder, several aspects are taken into consideration: clinical manifestations, specific biomarkers, enzyme assay results, and molecular genetic findings. This report brings cases to light which have a considerable discrepancy between those aspects, namely the preserved LAL enzyme activity in presence of clinical manifestations and rare variants in the LIPA gene. [ABSTRACT FROM AUTHOR]
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- 2022
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23. Early Discovery of Children With Lysosomal Acid Lipase Deficiency With the Universal Familial Hypercholesterolemia Screening Program
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Ursa Sustar, Urh Groselj, Katarina Trebusak Podkrajsek, Matej Mlinaric, Jernej Kovac, Martin Thaler, Ana Drole Torkar, Ajda Skarlovnik, Tadej Battelino, and Tinka Hovnik
- Subjects
cholesterol ester storage disease ,CESD ,lysosomal acid lipase deficiency ,LAL-D ,LIPA gene ,hypercholesterolemia ,Genetics ,QH426-470 - Abstract
Lysosomal acid lipase deficiency (LAL-D) is an autosomal recessive lysosomal storage disorder, caused by homozygous or compound heterozygous pathogenic variants in the LIPA gene. Clinically, LAL-D is under- and misdiagnosed, due to similar clinical and laboratory findings with other cholesterol or liver misfunctions. As a part of the Slovenian universal familial hypercholesterolemia (FH) screening, LAL-D is screened as a secondary condition among other rare dyslipidemias manifesting with hypercholesterolemia. Out of 669 children included, three were positive for a homozygous disease-causing splicing variant NM_000235.4: c.894G > A (NP_000226.2:p. Gln298Gln) in the LIPA gene (NG_008194.1). The mean age by the diagnosis of LAL-D was 9.8 ± 0.9 years. Moreover, all three LAL-D-positive children had an important elevation of transaminases and decreased activity of the lysosomal acid lipase enzyme. Abdominal MRI in all children detected an enlarged liver but a normal-sized spleen. In conclusion, universal FH screening algorithms with the confirmatory genetic analysis in the pediatric population enable also rare dyslipidemia detection at an early age. An important clinical criterion for differentiation between FH and the LAL-D-positive children has elevated transaminase levels (AST and ALT). In all three LAL-D positive children, an improvement in cholesterol and transaminase levels and steatosis of the liver has been seen after early treatment initiation.
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- 2022
- Full Text
- View/download PDF
24. Lysosomal acid lipase deficiency in a 6-year-old child: case report
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Oleksandra SHULHAI, Anna KABAKOVA, and Anna-Mariia SHULHAI
- Subjects
lysosomal acid lipase deficiency ,cholesteryl ester storage disease ,children ,lipid metabolism disorders ,Medicine ,Medicine (General) ,R5-920 - Abstract
Introduction. Cholesteryl ester storage disease or lysosomal acid lipase deficiency is a rare severe congenital enzyme pathology of lysosomal storage disorders. This pathology is linked with LIPA gene impairing mutations on chromosome 10 in locus 10q24-q25, coding lysosomal acid lipase enzyme (cholesterol ester hydrolase). The lysosomal acid lipase enzyme is involved in cellular fat metabolism, thus causing hepatic, vascular, nervous system, and adrenal glands damage. Case presentation. We report the case of a six-year-old boy with cholesteryl ester storage disease, who was admitted to the hospital with physical retardation, hepatosplenomegaly, impaired lipid profile, revealing an increased very-low-density lipoprotein cholesterol level and decreased high-density lipoprotein cholesterol level, dyslipidaemia, and hypercholesterolemia with highly increased atherogenic index, elevated bilirubin and aminotransferases. Conclusions. Severe hepatic impairment may occur in patients with cholesteryl ester storage disease in the absence of replacement therapy with acid lipase fermentation. The possibility of a timely diagnosis raises the likelihood of a quality treatment and prolongation of life in patients with lysosomal storage diseases.
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- 2020
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25. Rapid progression and mortality of lysosomal acid lipase deficiency presenting in infants
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Jones, Simon A, Valayannopoulos, Vassili, Schneider, Eugene, Eckert, Stephen, Banikazemi, Maryam, Bialer, Martin, Cederbaum, Stephen, Chan, Alicia, Dhawan, Anil, Di Rocco, Maja, Domm, Jennifer, Enns, Gregory M, Finegold, David, Gargus, J Jay, Guardamagna, Ornella, Hendriksz, Christian, Mahmoud, Iman G, Raiman, Julian, Selim, Laila A, Whitley, Chester B, Zaki, Osama, and Quinn, Anthony G
- Subjects
Clinical Research ,Pediatric ,Transplantation ,Disease Progression ,Female ,Hematopoietic Stem Cell Transplantation ,Humans ,Infant ,Infant ,Newborn ,Kaplan-Meier Estimate ,Male ,Sterol Esterase ,Treatment Outcome ,Wolman Disease ,cholesteryl ester storage disease ,infants ,lysosomal acid lipase deficiency ,natural history ,Wolman disease ,Genetics ,Clinical Sciences ,Genetics & Heredity - Abstract
PurposeThe purpose of this study was to enhance understanding of lysosomal acid lipase deficiency (LALD) in infancy.MethodsInvestigators reviewed medical records of infants with LALD and summarized data for the overall population and for patients with and without early growth failure (GF). Kaplan-Meier survival analyses were conducted for the overall population and for treated and untreated patients.ResultsRecords for 35 patients, 26 with early GF, were analyzed. Prominent symptom manifestations included vomiting, diarrhea, and steatorrhea. Median age at death was 3.7 months; estimated probability of survival past age 12 months was 0.114 (95% confidence interval (CI): 0.009-0.220). Among patients with early GF, median age at death was 3.5 months; estimated probability of survival past age 12 months was 0.038 (95% CI: 0.000-0.112). Treated patients (hematopoietic stem cell transplant (HSCT), n = 9; HSCT and liver transplant, n = 1) in the overall population and the early GF subset survived longer than untreated patients, but survival was still poor (median age at death, 8.6 months).ConclusionsThese data confirm and expand earlier insights on the progression and course of LALD presenting in infancy. Despite variations in the nature, onset, and severity of clinical manifestations, and treatment attempts, clinical outcome was poor.Genet Med 18 5, 452-458.
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- 2016
26. Lysosomal acid lipase deficiency in pediatric patients: a scoping review.
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Witeck, Camila da Rosa, Schmitz, Anne Calbusch, Dias de Oliveira, Júlia Meller, Luís Porporatti, André, De Luca Canto, Graziela, and de Souza Pires, Maria Marlene
- Subjects
GENETIC disorders ,WOLMAN disease ,LIPIDOSES ,BLOOD protein disorders ,BLOOD diseases - Abstract
Objective: Lysosomal acid lipase deficiency (LAL-D) is an underdiagnosed autosomal recessive disease with onset between the first years of life and adulthood. Early diagnosis is crucial for effective therapy and long-term survival. The objective of this article is to recognize warning signs among the clinical and laboratory characteristics of LAL-D in pediatric patients through a scope review. Sources: Electronic searches in the Embase, PubMed, Livivo, LILACS, Web of Science, Scopus, Google Scholar, Open Gray, and ProQuest Dissertations and Theses databases. The dataset included observational studies with clinical and laboratory characteristics of infants, children and adolescents diagnosed with lysosomal acid lipase deficiency by enzyme activity testing or analysis of mutations in the lysosomal acid lipase gene (LIPA). The reference selection process was performed in two stages. The references were selected by two authors, and the data were extracted in June 2020. Summary of the findings: The initial search returned 1593 studies, and the final selection included 108 studies from 30 countries encompassing 206 patients, including individuals with Wolman disease and cholesteryl ester storage disease (CESD). The most prevalent manifestations in both spectra of the disease were hepatomegaly, splenomegaly, anemia, dyslipidemia, and elevated transaminases. Conclusions: Vomiting, diarrhea, jaundice, and splenomegaly may be correlated, and may serve as a starting point for investigating LAL-D. Familial lymphohistiocytosis should be part of the differential diagnosis with LAL-D, and all patients undergoing upper gastrointestinal endoscopy should be submitted to intestinal biopsy. [ABSTRACT FROM AUTHOR]
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- 2022
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27. Crystal structure of human lysosomal acid lipase and its implications in cholesteryl ester storage disease[S]
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Francis Rajamohan, Allan R. Reyes, Meihua Tu, Nicole L. Nedoma, Lise R. Hoth, Adam G. Schwaid, Ravi G. Kurumbail, Jessica Ward, and Seungil Han
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lysosomal acid lipase deficiency ,Wolman's disease ,lipid metabolism ,protein aggregation ,molecular dynamic simulations ,Biochemistry ,QD415-436 - Abstract
Lysosomal acid lipase (LAL) is a serine hydrolase that hydrolyzes cholesteryl ester (CE) and TGs delivered to the lysosomes into free cholesterol and fatty acids. LAL deficiency due to mutations in the LAL gene (LIPA) results in accumulation of TGs and cholesterol esters in various tissues of the body leading to pathological conditions such as Wolman's disease and CE storage disease (CESD). Here, we present the first crystal structure of recombinant human LAL (HLAL) to 2.6 Å resolution in its closed form. The crystal structure was enabled by mutating three of the six potential glycosylation sites. The overall structure of HLAL closely resembles that of the evolutionarily related human gastric lipase (HGL). It consists of a core domain belonging to the classical α/β hydrolase-fold family with a classical catalytic triad (Ser-153, His-353, Asp-324), an oxyanion hole, and a “cap” domain, which regulates substrate entry to the catalytic site. Most significant structural differences between HLAL and HGL exist at the lid region. Deletion of the short helix, 238NLCFLLC244, at the lid region implied a possible role in regulating the highly hydrophobic substrate binding site from self-oligomerization during interfacial activation. We also performed molecular dynamic simulations of dog gastric lipase (lid-open form) and HLAL to gain insights and speculated a possible role of the human mutant, H274Y, leading to CESD.
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- 2020
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28. Persistent dyslipidemia in treatment of lysosomal acid lipase deficiency
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Amanda Barone Pritchard, Alanna Strong, and Can Ficicioglu
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Lysosomal acid lipase deficiency ,Sebelipase alfa ,Hypercholesterolemia ,Enzyme replacement therapy ,Medicine - Abstract
Abstract Background Lysosomal acid lipase deficiency (LALD) is an autosomal recessive inborn error of lipid metabolism characterized by impaired lysosomal hydrolysis and consequent accumulation of cholesteryl esters and triglycerides. The phenotypic spectrum is diverse, ranging from severe, neonatal onset failure to thrive, hepatomegaly, hepatic fibrosis, malabsorption and adrenal insufficiency to childhood-onset hyperlipidemia, hepatomegaly, and hepatic fibrosis. Sebelipase alfa enzyme replacement has been approved by the Food and Drug Administration for use in LALD after demonstrating dramatic improvement in transaminitis and dyslipidemia with initiation of enzyme replacement therapy. Methods A chart review was performed on 2 patients with childhood-onset, symptomatic LALD with persistent dyslipidemia despite appropriate enzyme replacement therapy to identify biological pathways and risk factors for incomplete response to therapy. Results Two patients with attenuated, symptomatic LALD had resolution of transaminitis on enzyme replacement therapy without concomitant effect on dyslipidemia despite dose escalation and no evidence of antibody response to enzyme. Conclusion Enzyme replacement therapy does not universally resolve all complications of LALD. Persistent dyslipidemia remains a clinically significant issue, likely related to the complex metabolic pathways implicated in LALD pathogenesis. We discuss the possible mechanistic basis for this unexpected finding and the implications for curative LALD therapy.
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- 2020
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29. Fatty Liver and Systemic Atherosclerosis in a Young, Lean Patient: Rule Out Lysosomal Acid Lipase Deficiency
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Maria Zharkova, Tatiana Nekrasova, Vladimir Ivashkin, Marina Maevskaya, and Tatyana Strokova
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fatty liver disease ,hepatosplenomegaly ,lysosomal acid lipase deficiency ,sebelipase alfa ,Diseases of the digestive system. Gastroenterology ,RC799-869 - Abstract
Lysosomal acid lipase deficiency (LALD) is a rare genetic disease characterized by the accumulation of cholesteryl esters and triglycerides in many organs, including the liver, spleen, lymph nodes, bone marrow, and vascular endothelium. Patients with LALD can appear asymptomatic until liver failure or premature sudden death from coronary artery disease, stroke, and aneurysm, which lead to the diagnosis. Herein, we present a diagnostic workup in a young 17-year-old female patient who manifested hepatosplenomegaly, elevated liver enzymes, severe dyslipidemia, and systemic atherosclerosis. Liver biopsy demonstrated over 90% diffuse microvesicular steatosis, lipid accumulation in Kupffer cells, and birefringent cholesteryl ester crystals. The diagnosis of LALD was proven by the decrease of lysosomal acid lipase activity in dried blood spots and by the detection of two compound heterozygous mutations in the LIPA gene: nonsense mutation G796T (Gly266Term) and splicing site mutation G894A (E8SJM). The patient started enzyme replacement therapy with sebelipase alfa. Following the 1-year treatment, the patient remained asymptomatic, her serum aminotransferase levels were normal, liver density increased due to lipid resorption, and plaque-associated stenosis of carotid artery regressed. Moreover, liver biopsy showed a decrease of cholesteryl ester crystals in Kupffer cells.
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- 2019
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30. Lanifibranor Reduces Inflammation and Improves Dyslipidemia in Lysosomal Acid Lipase-Deficient Mice.
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Bradić I, Vujić N, Kuentzel KB, Habisch H, Pirchheim A, Akhmetshina A, Henderson JD, Madl T, Deshmukh AS, and Kratky D
- Abstract
Background and Aims: Recent studies showed that patients suffering from lysosomal acid lipase deficiency (LAL-D) benefit from enzyme replacement therapy; however, liver histopathology improved in some but not all patients. We hypothesized that the pan-peroxisome proliferator-activated receptor 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., Methods: Female 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., Results: Lanifibranor 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., Conclusion: Lanifibranor treatment positively affected liver inflammation and dyslipidemia in Lal-/- mice. These findings suggest the necessity of a further combined study of lanifibranor with enzyme replacement therapy 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., (© 2024 The Authors.)
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- 2024
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31. Fatty liver in a child: Looking beyond nonalcoholic fatty liver disease
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Jaya Agarwal, Ajmal Hasan, Mayank Mehrotra, and Rashmi Kapoor
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cholesteryl ester storage disease ,dyslipidemia ,lysosomal acid lipase deficiency ,nonalcoholic fatty liver disease ,Pediatrics ,RJ1-570 - Abstract
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.
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- 2021
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32. Zaburzenie homeostazy lipidowej w deficycie lizosomalnej lipazy – patomechanizm, diagnostyka i leczenie.
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Lipiński, Patryk and Tylki-Szymańska, Anna
- Abstract
Copyright of Advances in Biochemistry / Postepy Biochemii is the property of Polish Biochemical Society / Acta Biochimica Polonica and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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- 2021
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33. Early diagnosis of infantile-onset lysosomal acid lipase deficiency in the advent of available enzyme replacement therapy
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Jennifer L. Cohen, Jessica Burfield, Karen Valdez-Gonzalez, Angela Samuels, Arianna K. Stefanatos, Marc Yudkoff, Helio Pedro, and Can Ficicioglu
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Wolman disease ,Enzyme replacement therapy ,Lysosomal acid lipase deficiency ,Diet ,Adrenal insufficiency ,Medicine - Abstract
Abstract Background Lysosomal acid lipase deficiency (LAL-D) is an autosomal recessive disorder that can present as a severe, infantile form also known as Wolman disease. We sought to determine the outcomes and clinical needs of infants diagnosed with LAL-D, treated with enzyme replacement therapy (ERT). Methods A chart review was conducted on two infantile-onset LAL-D patients to determine clinical outcomes based on laboratory results, abdominal imaging, growth and dietary records, cardiology, endocrinology, ophthalmology, hematology, and neurocognitive evaluations. Results Two patients, both diagnosed and treated before 6 months old, demonstrated clinical improvement following weekly ERT. They required dosage increases to optimize growth and symptomatology. Both received a formula low in long chain triglycerides and high in medium chain triglycerides, an intervention that allowed significant catch-up growth. Patient 1 required treatment for partial adrenal insufficiency and hypothyroidism. Both patients demonstrated reduction in liver and spleen size and varying degrees of improved liver function. Neither experienced serious adverse reactions to ERT. Conclusion ERT has led to longer and healthier survival of affected infants. It is imperative that dietary interventions and systemic clinical care become integral to the management. Continued evidence of survival and clinical improvement in this population, coupled with available mass spectrometry enzyme assay from dried blood spots, raises the question of this rare and possibly underdiagnosed disorder’s candidacy for newborn screening.
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- 2019
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34. Mutations identified in a cohort of Mexican patients with lysosomal acid lipase deficiency
- Author
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Alejandra Consuelo-Sánchez, Rodrigo Vázquez-Frias, Alejandra Reyes-De La Rosa, Carlos P. Acosta-Rodríguez-Bueno, María P. Ortal-Vite, and Jorge J. Cebolla
- Subjects
Lysosomal acid lipase deficiency ,LIPA gene ,Pediatrics ,Lysosomal disease ,Liver ,Specialties of internal medicine ,RC581-951 - Abstract
Introduction and Objectives: Lysosomal acid lipase deficiency (LAL-D) is an autosomal recessive disease caused by mutations in the LIPA gene, located on the long arm of chromosome 10 (10q23.31). Up until now, more than 59 mutations have been described and which are the cause of a very wide clinical spectrum. The goal of this study was to identify the mutations present in Mexican pediatric patients with a diagnosis of LAL-D. Materials and methods: A cross-sectional study was carried out which included all the pediatric patients with LAL-D treated in a tertiary hospital in Mexico from January 2000 to June 2017. Results: Sixteen patients with LAL-D were identified with a disease phenotype marked by the accumulation of cholesteryl esters. Eight distinct variants in the LIPA gene sequence were found, four pathogenic variants and four probably pathogenic. In six individuals, the variants were found in the homozygous state and ten were compound heterozygous. The eight variants were inverted, with five found on exon 4 and the others on exons 2, 8 and 10. The variant c.386A>G;p.His129Arg was the most common, being found in six of the 16 individuals (37.5%), making it much more frequent than what had previously been reported in the literature in proportion to the rest of the variants. The mutation known as E8SJM, which has been the mostly frequently found at the international level, was not the most common among this group of Mexican patients.In conclusion, Mexican patients present a different frequency of mutations associated with LAL-D in comparison to European populations.
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- 2019
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35. Pediatric patients with lysosomal acid lipase deficiency
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Maria M. Rojas-Rojas, Jacqueline Mugnier-Quijano, David A. Suarez-Zamora, Felipe Ordoñez-Guerrero, and Rocío del Pilar López-Panqueva
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medicine.medical_specialty ,business.industry ,Cholesterol ,Microvesicular Steatosis ,Cathepsin D ,Enzyme replacement therapy ,Lysosomal acid lipase deficiency ,medicine.disease ,Pathology and Forensic Medicine ,Transaminase ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Endocrinology ,chemistry ,Fibrosis ,030220 oncology & carcinogenesis ,Internal medicine ,Cholesteryl ester ,medicine ,030211 gastroenterology & hepatology ,business - Abstract
Lysosomal acid lipase (LAL) deficiency is a rare, autosomal recessive disease caused by mutations in the LIPA gene, which produces cholesteryl ester and triglyceride accumulation predominantly in hepatocytes, adrenal glands, and gastrointestinal tract. We describe two new cases occurring in siblings, aged 5 and 7 years, who presented with hepatomegaly, dyslipidemia, and abnormal liver function. Percutaneous liver biopsy revealed portal inflammation, hypertrophic Kupffer cells with a foamy appearance and microvesicular steatosis with fibrosis. Immunostaining for lysosomal markers, cathepsin D and LAMP1 reflected the lysosomal nature of the lipid vacuoles. After enzymatic confirmation, enzyme replacement therapy was initiated for both siblings. Follow-up transaminase levels and lipid profiles showed a notable decrease in AST and ALT and a slight increase in HDL cholesterol. It is crucial to increase awareness of this rare condition among clinicians and pathologists. The expression of lysosomal markers around the lipid vacuoles might help diagnose LAL deficiency in pediatric patients.
- Published
- 2023
36. Serum protein profile analysis in lysosomal storage disorders patients.
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López de Frutos, Laura, García-González, Elena, García-Rodríguez, Beatriz, González-Irazabal, Yolanda, Lahoz, Carlos, Irún, Pilar, Cebolla, Jorge J., and Giraldo, Pilar
- Subjects
- *
BLOOD proteins , *LYSOSOMAL storage diseases , *PROTEIN analysis , *BLOOD protein electrophoresis , *CAPILLARY electrophoresis , *ALKALOIDS , *LYSOSOMES , *ERGOT alkaloids - Abstract
• Gammopathy is not more frequent on LDSs' patients at diagnosis than in general population. • SPE can be useful to simplify new LSDs' marker discovery projects. Serum protein electrophoresis (SPE) is a well-established technique to identify alterations in plasma protein profiles, caused by diseases as multiple myeloma (MM). In addition, it could be a cost-effective technique to discover new plasma biomarkers. Relation between MM and lysosomal storage diseases (LSDs) as Gaucher disease has been set out but, it has not been evaluated on other LSDs nor the utility of the SPE as first step on LSDs biomarkers discovery projects. Stored plasma samples at diagnosis from several LSDs patients underwent analysis. Quality control was checked prior to the SPE was analyzed by capillary electrophoresis. The analysis for monoclonal spikes and the differences between each fraction on patients' samples vs the control data previously published, were evaluated. Furthermore, immunoprotein quantification and free light chains ratio were done by nephelometry and turbidimetry. Seventy-five samples of LSD patients at diagnosis, were assessed. The frequency of the MGUS on LSDs patients was not higher than in general population whereas one lysosomal acid lipase deficiency infant showed increased IgA and kappa deviation. Regarding to the usefulness of SPE in biomarkers discovery, statistically significant differences were observed on SPE fractions between LSDs and healthy population. The evaluation of SPE fractions can be a useful tool to understand pathophysiologic aspects in LDSs and, to simplify new marker discovery projects. In some of them, the MGUS appearance is a risk factor for the MM development despite its frequency is not increased on the studied LSDs at diagnosis. [ABSTRACT FROM AUTHOR]
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- 2020
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37. Progressive macrophage accumulation in lysosomal acid lipase deficiency
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Patryk Lipiński, Joanna Cielecka-Kuszyk, Anna Bożkiewicz-Kasperczyk, Barbara Perkowska, Elżbieta Jurkiewicz, and Anna Tylki-Szymańska
- Subjects
Lysosomal acid lipase ,Lysosomal acid lipase deficiency ,Macrophage ,Lymphadenitis ,CD68 ,Medicine (General) ,R5-920 ,Biology (General) ,QH301-705.5 - Abstract
Lysosomal acid lipase (LAL) deficiency (LAL-D) is a lysosomal lipid storage disorder in which the accumulation of cholesteryl esters and triglycerides predominantly in hepatocytes and cells of the macrophage-monocyte system is observed. The disturbance in the synthesis and trafficking of cholesterol and other lipids (triglycerides as well as phospholipids) as well as the systemic lipoprotein dysregulation, reflects the pathophysiology of LAL-D.The aim of this study was to present the occurrence of macrophage derived structures in LAL-D patient, and to provide an overview on underlying mechanisms, as the literature about the presence of such cluster cells in LAL deficiency is sparse.We describe the case of LAL-D patient diagnosed at 3 years of age, in whom the massive macrophage accumulation resulting in the abdominal lymphadenopathy, subcutaneous papules and hepatosplenomegaly, have been observed within 4 years since diagnosis. Histopathological examination of the excised lymph nodes and subcutaneous papules revealed them to be diffusely infiltrated by lipid-overloaded histiocytes. The immunohistochemistry revealed the macrophages to be CD68-positive.This study comprises one of the first reports of accumulation of lipid-laden macrophages throughout the body in the course of LAL-D.
- Published
- 2020
- Full Text
- View/download PDF
38. THE DISEASE IS THE ACCUMULATION OF CHOLESTEROL ESTERS DUE TO DEFICIT OF LYSOSOMAL ACID LIPASE. CLINICAL CASE OF LYSOSOMAL ACID LIPASE DEFICIENCY IS DESCRIBED IN THIS ARTICLE
- Author
-
S. A. Loskutova, T. V. Belousova, and A. B. Nikulina
- Subjects
lysosomal acid lipase deficiency ,cholesterol ester storage disease ,wolman disease ,sebelipase alfa ,Medicine - Abstract
Lysosomal acid lipase deficiency (LAL D) is an orphan disease connected with accumulation of cholesterol estersin different organs, interest to this disease increased due to the possibility of enzyme replacement therapy. The article presents a clinical case of verification of LAL D in a child 5 years of age.
- Published
- 2018
- Full Text
- View/download PDF
39. Long term substrate reduction therapy with ezetimibe alone or associated with statins in three adult patients with lysosomal acid lipase deficiency
- Author
-
Maja Di Rocco, Livia Pisciotta, Annalisa Madeo, Marta Bertamino, and Stefano Bertolini
- Subjects
Lysosomal acid lipase deficiency ,Ezetimibe ,Substrate reduction therapy ,Medicine - Abstract
Abstract Background Lysosomal acid lipase deficiency is an autosomal recessive metabolic disease with a wide range of severity from Wolman Disease to Cholesterol Ester Storage Disease. Recently enzyme replacement therapy with sebelipase alpha has been approved by drug agencies for treatment of this lysosomal disease. Ezetimibe is an azetidine derivative which blocks Niemann Pick C1-Like 1 Protein; as its consequence, plasmatic concentration of low density lipoproteins and other apoB-containing lipoproteins, that are the substrate of lysosomal acid lipase, are decreased. Furthermore, ezetimibe acts by blocking inflammasome activation which is the cause of liver fibrosis in steatohepatitis and in lysosomal storage diseases. Results Two patients with Cholesterol Ester Storage Disease were treated with ezetimibe for 9 years and a third patients for 10 years. Treatment was supplemented with low dose of atorvastatin in the first two patients during the last 6 years. All patients showed a significant reduction of alanine aminotransferase, cholesterol and triglyceride. Furthermore, no progression of liver fibrosis was demonstrated. Conclusion In this observational case series, ezetimibe is effective, safe, and sustainable treatment for lysosomal acid lipase deficiency. Further studies are warranted to demonstrate that ezetimibe is an alternative therapy to enzyme replacement therapy.
- Published
- 2018
- Full Text
- View/download PDF
40. Mexican consensus on lysosomal acid lipase deficiency diagnosis
- Author
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R. Vázquez-Frias, J.E. García-Ortiz, P.F. Valencia-Mayoral, G.E. Castro-Narro, P.G. Medina-Bravo, Y. Santillán-Hernández, J. Flores-Calderón, R. Mehta, C.A. Arellano-Valdés, L. Carbajal-Rodríguez, J.I. Navarrete-Martínez, M.L. Urbán-Reyes, M.T. Valadez-Reyes, F. Zárate-Mondragón, and A. Consuelo-Sánchez
- Subjects
Lysosomal acid lipase ,Lysosomal acid lipase deficiency ,Hepatomegaly ,Dyslipidemia ,Cholesteryl ester storage disease ,Diseases of the digestive system. Gastroenterology ,RC799-869 - Abstract
Introduction: 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. Methods: The review was designed by a group of Mexican experts and is presented as an orienting algorithm for the pediatrician, internist, gastroenterologist, endocrinologist, geneticist, pathologist, radiologist, and other specialists that could come across this disease in their patients. An up-to-date review of the literature in relation to the clinical manifestations of LAL-D and its diagnosis was performed. The statements were formulated based on said review and were then voted upon. The structured quantitative method employed for reaching consensus was the nominal group technique. Results: A practical algorithm of the diagnostic process in LAL-D patients was proposed, based on clinical and laboratory data indicative of the disease and in accordance with the consensus established for each recommendation. Conclusion: The algorithm provides a sequence of clinical actions from different studies for optimizing the diagnostic process of patients suspected of having LAL-D.
- Published
- 2018
- Full Text
- View/download PDF
41. Frequency of lysosomal acid lipase deficiency in patients with primary hyperlipidemia
- Author
-
Bahri Evren, yilmaz bilgic, Feyza Firat Atay, Ayse Nuransoy Cengiz, and Yasir Furkan Cagin
- Subjects
primary hyperlipidemia ,lysosomal acid lipase deficiency ,Medicine - Abstract
The aim of our study was to investigate the prevalence of LAL (lysosomal acid lipase) deficiency in patients with primary hyperlipidemia. Twenty-four patients with primary hyperlipidemia were included in the study. The gender, age, height, weight, body mass index and waist circumference of the patients were recorded. Lipid profiles, glucose, transaminases and LAL enzyme profiles were evaluated. LAL enzyme deficiency was not detected in patients with primary hyperlipidemia. In our study, when we investigated LAL deficiency in primary hyperlipidemic patients, we could not find a relationship between them. As a result of our study, LAL deficiency was not detected in patients with primary hyperlipidemia. However, in this context, there is a need to work with a large number of patients. [Med-Science 2019; 8(2.000): 260-2]
- Published
- 2019
- Full Text
- View/download PDF
42. AISF update on the diagnosis and management of adult-onset lysosomal storage diseases with hepatic involvement.
- Author
-
Nascimbeni, Fabio, Dionisi Vici, Carlo, Vespasiani Gentilucci, Umberto, Angelico, Francesco, Nobili, Valerio, Petta, Salvatore, and Valenti, Luca
- Abstract
Lysosomal storage diseases (LSDs) are a heterogeneous group of inherited disorders caused by loss-of-function mutations in genes encoding for lysosomal enzymes/proteins. The consequence is a progressive accumulation of substrates in these intracellular organelles, resulting in cellular and tissue damage. The overall incidence is about 1/8000 live births, but is likely underestimated. LSDs are chronic progressive multi-systemic disorders, generally presenting with visceromegaly, and involvement of the central nervous system, eyes, the skeleton, and the respiratory and cardiovascular systems. The age at onset and phenotypic expression are highly variable, according to the specific enzymatic defect and tissues involved, the residual activity, and the disease-causing genotype. Enzyme-replacement therapies and substrate-reduction therapies have recently become available, leading to the improvement in symptoms, disease progression and quality of life of affected individuals. Liver involvement and hepatosplenomegaly are frequent features of LSDs and a hallmark of adult-onset forms, frequently leading to medical attention. LSDs should therefore be considered in the differential diagnosis of liver disease with organomegaly. The present document will provide a short overview of adult-onset LSDs with hepatic involvement, highlighting the specificities and systemic manifestations of the ones most frequently encountered in clinical practice, which may hint at the correct diagnosis and the appropriate treatment. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
43. Persistent dyslipidemia in treatment of lysosomal acid lipase deficiency.
- Author
-
Pritchard, Amanda Barone, Strong, Alanna, and Ficicioglu, Can
- Subjects
- *
INBORN errors of metabolism , *CHOLESTERYL ester transfer protein , *DYSLIPIDEMIA , *HEPATIC fibrosis , *PATHOLOGY , *ADRENAL insufficiency - Abstract
Background: Lysosomal acid lipase deficiency (LALD) is an autosomal recessive inborn error of lipid metabolism characterized by impaired lysosomal hydrolysis and consequent accumulation of cholesteryl esters and triglycerides. The phenotypic spectrum is diverse, ranging from severe, neonatal onset failure to thrive, hepatomegaly, hepatic fibrosis, malabsorption and adrenal insufficiency to childhood-onset hyperlipidemia, hepatomegaly, and hepatic fibrosis. Sebelipase alfa enzyme replacement has been approved by the Food and Drug Administration for use in LALD after demonstrating dramatic improvement in transaminitis and dyslipidemia with initiation of enzyme replacement therapy.Methods: A chart review was performed on 2 patients with childhood-onset, symptomatic LALD with persistent dyslipidemia despite appropriate enzyme replacement therapy to identify biological pathways and risk factors for incomplete response to therapy.Results: Two patients with attenuated, symptomatic LALD had resolution of transaminitis on enzyme replacement therapy without concomitant effect on dyslipidemia despite dose escalation and no evidence of antibody response to enzyme.Conclusion: Enzyme replacement therapy does not universally resolve all complications of LALD. Persistent dyslipidemia remains a clinically significant issue, likely related to the complex metabolic pathways implicated in LALD pathogenesis. We discuss the possible mechanistic basis for this unexpected finding and the implications for curative LALD therapy. [ABSTRACT FROM AUTHOR]- Published
- 2020
- Full Text
- View/download PDF
44. Large‐scale functional LIPA variant characterization to improve birth prevalence estimates of lysosomal acid lipase deficiency.
- Author
-
Angel, Guillermo, Hutchinson, Andrew T., Jain, Nina K., Forbes, Chris D., and Reynders, John
- Abstract
Lysosomal acid lipase (LAL) deficiency is an autosomal recessive disorder caused by LIPA gene mutations that disrupt LAL activity. We performed in vitro functional testing of 149 LIPA variants to increase the understanding of the variant effects on LAL deficiency and to improve disease prevalence estimates. Chosen variants had been reported in literature or population databases. Functional testing was done by plasmid transient transfection and LAL activity assessment. We assembled a set of 165 published LAL deficient patient genotypes to evaluate this assay's effectiveness to recapitulate genotype/phenotype relationships. Rapidly progressive LAL deficient patients showed negligible enzymatic activity (<1%), whereas patients with childhood/adult LAL deficiency typically have 1–7% average activity. We benchmarked six in silico variant effect prediction algorithms with these functional data. PolyPhen‐2 was shown to have a superior area under the receiver operating curve performance. We used functional data along with Genome Aggregation Database (gnomAD) allele frequencies to estimate LAL deficiency birth prevalence, yielding a range of 3.45–5.97 cases per million births in European‐ancestry populations. The low estimate only considers functionally assayed variants in gnomAD. The high estimate computes allele frequencies for variants absent in gnomAD, and uses in silico scores for unassayed variants. Prevalence estimates are lower than previously published, underscoring LAL deficiency's rarity. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
45. Enzymes Approved for Therapy
- Author
-
Baldo, Brian A. and Baldo, Brian A.
- Published
- 2016
- Full Text
- View/download PDF
46. Lysosomal acid lipase deficiency, a rare pathology
- Author
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Verónica Botero, Catalina Gómez-Duarte, Gabriel J. Echeverri, Ana M. Aristizabal, Victor H. Garcia, and Harry Pachajoa
- Subjects
medicine.medical_specialty ,Endocrinology ,Chemistry ,Internal medicine ,medicine ,General Medicine ,Lysosomal acid lipase deficiency ,medicine.disease - Published
- 2023
47. Thérapie génique ex vivo pour les β-hémoglobinopathies et les maladies métaboliques
- Author
-
Laurent, Marine, Approches génétiques intégrées et nouvelles thérapies pour les maladies rares (INTEGRARE), Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Généthon, Université Paris-Saclay, and Mario Amendola
- Subjects
Déficience en lipase acide lysosomale ,Therapie genique ,Gene therapy ,[SDV.BIO]Life Sciences [q-bio]/Biotechnology ,[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics ,HBA platform ,Β-Hémoglobinopathies ,[SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology ,Lysosomal acid lipase deficiency ,CRISPR/Cas9 ,Platforme HBA ,Β-Hemoglobinopathies - Abstract
Monogenic disorder are inherited mutation(s) in a single gene that result in abnormal protein synthesis impairing normal cellular homeostasis and organ function that reduces patient life-pan. Recently autologous transplantation of genetically corrected patient's hematopoietic stem cells (HSCs) defined as ex-vivo gene therapy (GT) has emerged as a promising curative approach for such genetic diseases. In ex-vivo GT, targeted integration of a therapeutic transgene into a tolerant and safe locus appears to be a powerful approach to produce the therapeutic protein above physiological level in a broad type of hematopoietic cells using endogenous promoter. Such genome editing strategy relies on DNA double strand break and delivery of a functional copy of the mutated gene in the locus of interest. Here, we exploited the α-globin locus (HBA) as a safe harbor locus for transgene integration to develop a universal platform for expression and secretion of therapeutic proteins into erythroid cells. In HSCs, we induced double strand breaks (DSBs) in HBA locus with CRISPR-Cas9 and delivered a therapeutic transgene using AAV-6 to target integration by homology directed repair. Due to the abundance of erythroid cells in human (5X10^6 RBCs/microliter of blood) and the high HBA expression in erythroid population (around 1,5g/day), the HBA platform would require minimal transgene integration events in HBA locus to provide sufficient amount of therapeutic proteins reducing as consequence the potential off-target and toxicity due to editing and DNA donor delivery. First, we applied the HBA platform for β-thalassemia : a genetic condition impairing the hemoglobin formation and triggering toxic α-globin chain precipitation. The genetic correction of β-thalassemia using our HBA platform results in 1 copy of A-globin gene deletion decreasing the α-globin chain precipitation while α-globin gene integration into HBA locus restore the normal hemoglobin formation. Then, we evaluated the HBA platform for erythroid-specific secretion of therapeutic proteins into bloodstream and, in particular,we focused on a genetic metabolic disorder: lysosomal acid lipase (LAL) deficiency caused by LIPA gene mutation(s) that lead to toxic lipid accumulation especially in liver. We achieved efficient expression and secretion of LAL enzyme that retained enzymatic activity and cross-corrected the lipid accumulation in patients' fibroblasts. We then focused on the optimization of LIPA cDNA transgene using lentiviral vectors (LVVs) to maximize the LAL expression and secretion. The optimized LIPA transgene will serve for LVV-based ex-vivo GT and for our HBA targeted platform in the purpose of enhancing the LAL expression while minimizing the targeting integration events required to fully correct the disorder. Finally, to better characterize LAL-D phenotype and to evaluate the therapeutic potency of our GT strategy, we set-up a multimodal cytometry approach using flow cytometry and image flow cytometry. We evaluated this pipeline on mainly patient's fibroblasts and on peripheral mononuclear blood mononuclear cells (PBMCs) for LAL-D mouse model.; Les maladies monogéniques sont des mutations héréditaires d'un seul gène qui entraînent une synthèse anormale de protéines, altérant l'homéostasie cellulaire normale et la fonction des organes et réduisant la durée de vie des patients. Récemment, la greffe autologue de cellules souches hématopoïétiques (HSCs) de patients génétiquement corrigés appelée thérapie génique (TG) ex-vivo, est apparue comme une approche curative prometteuse pour ces maladies. Dans la TG ex-vivo, l'intégration ciblée d'un transgène thérapeutique dans un locus tolérant apparaît comme une approche puissante pour produire les protéines thérapeutiques à un niveau supérieur au niveau physiologique dans un large type de cellules hématopoïétiques en utilisant un promoteur endogène. Une telle stratégie d'édition du génome repose sur la cassure double brin d'ADN et la livraison d'une copie fonctionnelle du gène muté dans le locus d'intérêt. Ici, nous avons exploité le locus de l'α-globine (HBA) comme un locus tolérant pour l'intégration de transgènes afin de développer une plateforme universelle pour l'expression et la sécrétion de protéines thérapeutiques par les globules rouges (GR). Dans les HSCs, nous avons induit des cassures double brin dans le locus HBA avec CRISPR-Cas9 et délivré un transgène thérapeutique en utilisant un AAV-6 pour cibler l'intégration par réparation dirigée par l'homologie. En raison de l'abondance des globules rouges chez l'homme (5X10^6 globules rouges/microlitre de sang) et de la forte expression de HBA dans cette population (environ 1,5g/jour), la plateforme HBA nécessiterait un minimum d'événement d'intégration du transgène pour fournir une quantité suffisante de protéines thérapeutiques, réduisant ainsi les risques de toxicité et d'édition non spécifique induit par CRISPR-Cas9 ou l'AAV6. Dans un premier temps, nous avons appliqué la plateforme HBA à la β-thalassémie : une condition génétique altérant la formation de l'hémoglobine (composé de 2 α-globine et 2 β-globine) et déclenchant la précipitation toxique de la chaîne α-globine. La correction génétique de la β-thalassémie à l'aide de notre plateforme HBA entraîne la délétion d'une copie du gène de l'α-globine, ce qui diminue la précipitation de cette chaîne, tandis que l'intégration du gène de la β-globine dans le locus HBA rétablit la formation normale d'hémoglobine. Ensuite, nous avons évalué la plateforme HBA pour la sécrétion spécifique de protéines thérapeutiques par les GRs dans la circulation sanguine et, en particulier, nous nous sommes concentrés sur un trouble métabolique génétique : la déficience en lipase acide lysosomale (LAL) causée par une ou plusieurs mutations du gène LIPA qui entraînent une accumulation toxique de lipides, notamment dans le foie. Nous avons obtenu une expression et une sécrétion efficaces de l'enzyme LAL qui a conservé son activité enzymatique et corrigé l'accumulation de lipides dans les fibroblastes des patients. Nous nous sommes ensuite concentrés sur l'optimisation du transgène LIPA en utilisant des vecteurs lentiviraux (LVVs) pour maximiser l'expression et la sécrétion de la LAL. Le transgène LIPA optimisé servira à développer une TG ex-vivo basée sur les LVVs et à notre plateforme ciblée HBA dans le but d'améliorer l'expression de LAL tout en minimisant les événements d'intégration nécessaires pour corriger complètement la maladie. Enfin, pour mieux caractériser le phénotype la déficience en LAL et évaluer le pouvoir thérapeutique de notre stratégie de GT, nous avons mis en place une approche de cytométrie multimodale utilisant la cytométrie en flux et la cytométrie en flux d'images. Nous avons évalué ces techniques principalement sur les fibroblastes du patient et sur les cellules mononucléaires du sang périphérique (PBMCs) provenant de souris déficiente en LAL.
- Published
- 2023
48. Ex vivo gene therapy for β-hemoglobinpathies and metabolic disorders
- Author
-
Laurent, Marine, Approches génétiques intégrées et nouvelles thérapies pour les maladies rares (INTEGRARE), Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Généthon, Université Paris-Saclay, Mario Amendola, and STAR, ABES
- Subjects
Déficience en lipase acide lysosomale ,[SDV.BIO]Life Sciences [q-bio]/Biotechnology ,HBA platform ,[SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology ,[SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics ,Lysosomal acid lipase deficiency ,[SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology ,Platforme HBA ,[SDV.BIO] Life Sciences [q-bio]/Biotechnology ,Therapie genique ,Gene therapy ,[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics ,Β-Hémoglobinopathies ,CRISPR/Cas9 ,Β-Hemoglobinopathies - Abstract
Monogenic disorder are inherited mutation(s) in a single gene that result in abnormal protein synthesis impairing normal cellular homeostasis and organ function that reduces patient life-pan. Recently autologous transplantation of genetically corrected patient's hematopoietic stem cells (HSCs) defined as ex-vivo gene therapy (GT) has emerged as a promising curative approach for such genetic diseases. In ex-vivo GT, targeted integration of a therapeutic transgene into a tolerant and safe locus appears to be a powerful approach to produce the therapeutic protein above physiological level in a broad type of hematopoietic cells using endogenous promoter. Such genome editing strategy relies on DNA double strand break and delivery of a functional copy of the mutated gene in the locus of interest. Here, we exploited the α-globin locus (HBA) as a safe harbor locus for transgene integration to develop a universal platform for expression and secretion of therapeutic proteins into erythroid cells. In HSCs, we induced double strand breaks (DSBs) in HBA locus with CRISPR-Cas9 and delivered a therapeutic transgene using AAV-6 to target integration by homology directed repair. Due to the abundance of erythroid cells in human (5X10^6 RBCs/microliter of blood) and the high HBA expression in erythroid population (around 1,5g/day), the HBA platform would require minimal transgene integration events in HBA locus to provide sufficient amount of therapeutic proteins reducing as consequence the potential off-target and toxicity due to editing and DNA donor delivery. First, we applied the HBA platform for β-thalassemia : a genetic condition impairing the hemoglobin formation and triggering toxic α-globin chain precipitation. The genetic correction of β-thalassemia using our HBA platform results in 1 copy of A-globin gene deletion decreasing the α-globin chain precipitation while α-globin gene integration into HBA locus restore the normal hemoglobin formation. Then, we evaluated the HBA platform for erythroid-specific secretion of therapeutic proteins into bloodstream and, in particular,we focused on a genetic metabolic disorder: lysosomal acid lipase (LAL) deficiency caused by LIPA gene mutation(s) that lead to toxic lipid accumulation especially in liver. We achieved efficient expression and secretion of LAL enzyme that retained enzymatic activity and cross-corrected the lipid accumulation in patients' fibroblasts. We then focused on the optimization of LIPA cDNA transgene using lentiviral vectors (LVVs) to maximize the LAL expression and secretion. The optimized LIPA transgene will serve for LVV-based ex-vivo GT and for our HBA targeted platform in the purpose of enhancing the LAL expression while minimizing the targeting integration events required to fully correct the disorder. Finally, to better characterize LAL-D phenotype and to evaluate the therapeutic potency of our GT strategy, we set-up a multimodal cytometry approach using flow cytometry and image flow cytometry. We evaluated this pipeline on mainly patient's fibroblasts and on peripheral mononuclear blood mononuclear cells (PBMCs) for LAL-D mouse model., Les maladies monogéniques sont des mutations héréditaires d'un seul gène qui entraînent une synthèse anormale de protéines, altérant l'homéostasie cellulaire normale et la fonction des organes et réduisant la durée de vie des patients. Récemment, la greffe autologue de cellules souches hématopoïétiques (HSCs) de patients génétiquement corrigés appelée thérapie génique (TG) ex-vivo, est apparue comme une approche curative prometteuse pour ces maladies. Dans la TG ex-vivo, l'intégration ciblée d'un transgène thérapeutique dans un locus tolérant apparaît comme une approche puissante pour produire les protéines thérapeutiques à un niveau supérieur au niveau physiologique dans un large type de cellules hématopoïétiques en utilisant un promoteur endogène. Une telle stratégie d'édition du génome repose sur la cassure double brin d'ADN et la livraison d'une copie fonctionnelle du gène muté dans le locus d'intérêt. Ici, nous avons exploité le locus de l'α-globine (HBA) comme un locus tolérant pour l'intégration de transgènes afin de développer une plateforme universelle pour l'expression et la sécrétion de protéines thérapeutiques par les globules rouges (GR). Dans les HSCs, nous avons induit des cassures double brin dans le locus HBA avec CRISPR-Cas9 et délivré un transgène thérapeutique en utilisant un AAV-6 pour cibler l'intégration par réparation dirigée par l'homologie. En raison de l'abondance des globules rouges chez l'homme (5X10^6 globules rouges/microlitre de sang) et de la forte expression de HBA dans cette population (environ 1,5g/jour), la plateforme HBA nécessiterait un minimum d'événement d'intégration du transgène pour fournir une quantité suffisante de protéines thérapeutiques, réduisant ainsi les risques de toxicité et d'édition non spécifique induit par CRISPR-Cas9 ou l'AAV6. Dans un premier temps, nous avons appliqué la plateforme HBA à la β-thalassémie : une condition génétique altérant la formation de l'hémoglobine (composé de 2 α-globine et 2 β-globine) et déclenchant la précipitation toxique de la chaîne α-globine. La correction génétique de la β-thalassémie à l'aide de notre plateforme HBA entraîne la délétion d'une copie du gène de l'α-globine, ce qui diminue la précipitation de cette chaîne, tandis que l'intégration du gène de la β-globine dans le locus HBA rétablit la formation normale d'hémoglobine. Ensuite, nous avons évalué la plateforme HBA pour la sécrétion spécifique de protéines thérapeutiques par les GRs dans la circulation sanguine et, en particulier, nous nous sommes concentrés sur un trouble métabolique génétique : la déficience en lipase acide lysosomale (LAL) causée par une ou plusieurs mutations du gène LIPA qui entraînent une accumulation toxique de lipides, notamment dans le foie. Nous avons obtenu une expression et une sécrétion efficaces de l'enzyme LAL qui a conservé son activité enzymatique et corrigé l'accumulation de lipides dans les fibroblastes des patients. Nous nous sommes ensuite concentrés sur l'optimisation du transgène LIPA en utilisant des vecteurs lentiviraux (LVVs) pour maximiser l'expression et la sécrétion de la LAL. Le transgène LIPA optimisé servira à développer une TG ex-vivo basée sur les LVVs et à notre plateforme ciblée HBA dans le but d'améliorer l'expression de LAL tout en minimisant les événements d'intégration nécessaires pour corriger complètement la maladie. Enfin, pour mieux caractériser le phénotype la déficience en LAL et évaluer le pouvoir thérapeutique de notre stratégie de GT, nous avons mis en place une approche de cytométrie multimodale utilisant la cytométrie en flux et la cytométrie en flux d'images. Nous avons évalué ces techniques principalement sur les fibroblastes du patient et sur les cellules mononucléaires du sang périphérique (PBMCs) provenant de souris déficiente en LAL.
- Published
- 2023
49. Die Lysosomale saure Lipase-Defizienz diagnostizieren und behandeln
- Author
-
Kassner, Ursula, Haberbosch, Linus, and Schumann, Friederike
- Published
- 2022
- Full Text
- View/download PDF
50. Fatty Liver and Systemic Atherosclerosis in a Young, Lean Patient: Rule Out Lysosomal Acid Lipase Deficiency.
- Author
-
Zharkova, Maria, Nekrasova, Tatiana, Ivashkin, Vladimir, Maevskaya, Marina, and Strokova, Tatyana
- Subjects
- *
GLYCOGEN storage disease type II , *FATTY liver , *LIPASES , *GENETIC mutation , *LIVER enzymes , *KUPFFER cells , *ALANINE aminotransferase - Abstract
Lysosomal acid lipase deficiency (LALD) is a rare genetic disease characterized by the accumulation of cholesteryl esters and triglycerides in many organs, including the liver, spleen, lymph nodes, bone marrow, and vascular endothelium. Patients with LALD can appear asymptomatic until liver failure or premature sudden death from coronary artery disease, stroke, and aneurysm, which lead to the diagnosis. Herein, we present a diagnostic workup in a young 17-yearold female patient who manifested hepatosplenomegaly, elevated liver enzymes, severe dyslipidemia, and systemic atherosclerosis. Liver biopsy demonstrated over 90% diffuse microvesicular steatosis, lipid accumulation in Kupffer cells, and birefringent cholesteryl ester crystals. The diagnosis of LALD was proven by the decrease of lysosomal acid lipase activity in dried blood spots and by the detection of two compound heterozygous mutations in the LIPA gene: nonsense mutation G796T (Gly266Term) and splicing site mutation G894A (E8SJM). The patient started enzyme replacement therapy with sebelipase alfa. Following the 1-year treatment, the patient remained asymptomatic, her serum aminotransferase levels were normal, liver density increased due to lipid resorption, and plaque-associated stenosis of carotid artery regressed. Moreover, liver biopsy showed a decrease of cholesteryl ester crystals in Kupffer cells. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
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