|
1
|
Zhang JH, Lin AP, Zhang L, Ruan DD, Gao MZ, Chen Q, Yu HP, Liao LS, Lin XF, Fang ZT, Lin F, Lu SY, Luo JW, Zheng XL, Chen MS. Pedigree Analysis of Nonclassical Cholesteryl Ester Storage Disease with Dominant Inheritance in a LIPA I378T Heterozygous Carrier. Dig Dis Sci 2024; 69:2109-2122. [PMID: 38564148 DOI: 10.1007/s10620-024-08395-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Accepted: 03/17/2024] [Indexed: 04/04/2024]
Abstract
BACKGROUND Cholesterol ester storage disorder (CESD; OMIM: 278,000) was formerly assumed to be an autosomal recessive allelic genetic condition connected to diminished lysosomal acid lipase (LAL) activity due to LIPA gene abnormalities. CESD is characterized by abnormal liver function and lipid metabolism, and in severe cases, liver failure can occur leading to death. In this study, one Chinese nonclassical CESD pedigree with dominant inheritance was phenotyped and analyzed for the corresponding gene alterations. METHODS Seven males and eight females from nonclassical CESD pedigree were recruited. Clinical features and LAL activities were documented. Whole genome Next-generation sequencing (NGS) was used to screen candidate genes and mutations, Sanger sequencing confirmed predicted mutations, and qPCR detected LIPA mRNA expression. RESULTS Eight individuals of the pedigree were speculatively thought to have CESD. LAL activity was discovered to be lowered in four living members of the pedigree, but undetectable in the other four deceased members who died of probable hepatic failure. Three of the four living relatives had abnormal lipid metabolism and all four had liver dysfunctions. By liver biopsy, the proband exhibited diffuse vesicular fatty changes in noticeably enlarged hepatocytes and Kupffer cell hyperplasia. Surprisingly, only a newly discovered heterozygous mutation, c.1133T>C (p. Ile378Thr) on LIPA, was found by gene sequencing in the proband. All living family members who carried the p.I378T variant displayed reduced LAL activity. CONCLUSIONS Phenotypic analyses indicate that this may be an autosomal dominant nonclassical CESD pedigree with a LIPA gene mutation.
Collapse
Affiliation(s)
- Jian-Hui Zhang
- Department of Traditional Chinese Medicine, Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, China
| | - Ai-Ping Lin
- Department of Traditional Chinese Medicine, Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, China
- Department of Digestive, Fujian Provincial Hospital, Fuzhou, China
| | - Li Zhang
- Department of Traditional Chinese Medicine, Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, China
- Department of Nephrology, Fujian Provincial Hospital, Fuzhou, China
| | - Dan-Dan Ruan
- Department of Traditional Chinese Medicine, Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, China
| | - Mei-Zhu Gao
- Department of Traditional Chinese Medicine, Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, China
- Department of Nephrology, Fujian Provincial Hospital, Fuzhou, China
| | - Qian Chen
- Department of Traditional Chinese Medicine, Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, China
| | - Hong-Ping Yu
- Department of Traditional Chinese Medicine, Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, China
| | - Li-Sheng Liao
- Department of Traditional Chinese Medicine, Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, China
- Department of Hematology, Fujian Provincial Hospital, Fuzhou, China
| | - Xin-Fu Lin
- Department of Traditional Chinese Medicine, Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, China
- Department of Pediatrics, Fujian Provincial Hospital, Fuzhou, China
| | - Zhu-Ting Fang
- Department of Traditional Chinese Medicine, Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, China
| | - Fan Lin
- Department of Traditional Chinese Medicine, Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, China
- Department of Geriatric Medicine, Fujian Provincial Center for Geriatrics, Fujian Provincial Hospital, Fuzhou, China
| | - Shi-Yun Lu
- Department of Traditional Chinese Medicine, Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, China
- Department of Digestive, Fujian Provincial Hospital, Fuzhou, China
| | - Jie-Wei Luo
- Department of Traditional Chinese Medicine, Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, China.
- Department of Traditional Chinese Medicine, Fujian Provincial Hospital, Fuzhou, China.
| | - Xiao-Ling Zheng
- Department of Traditional Chinese Medicine, Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, China
- Department of Digestive Endoscopy, Fujian Provincial Hospital, Fuzhou, China
| | - Meng-Shi Chen
- Department of Traditional Chinese Medicine, Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, China
- Department of Digestive, Fujian Provincial Hospital, Fuzhou, China
| |
Collapse
|
|
2
|
Quaglia A, Roberts EA, Torbenson M. Developmental and Inherited Liver Disease. MACSWEEN'S PATHOLOGY OF THE LIVER 2024:122-294. [DOI: 10.1016/b978-0-7020-8228-3.00003-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
|
|
3
|
Guerreiro G, Deon M, Vargas CR. Evaluation of biochemical profile and oxidative damage to lipids and proteins in patients with lysosomal acid lipase deficiency. Biochem Cell Biol 2023; 101:294-302. [PMID: 37042460 DOI: 10.1139/bcb-2022-0330] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/13/2023] Open
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.
Collapse
Affiliation(s)
- Gilian Guerreiro
- Faculdade de Farmácia, UFRGS, Porto Alegre 90610-000, RS, Brasil
- Serviço de Genética Médica, HCPA, UFRGS, Rua Ramiro Barcelos, Porto Alegre, 90035-903, RS, Brasil
| | - Marion Deon
- Faculdade de Farmácia, UFRGS, Porto Alegre 90610-000, RS, Brasil
- Serviço de Genética Médica, HCPA, UFRGS, Rua Ramiro Barcelos, Porto Alegre, 90035-903, RS, Brasil
| | - Carmen Regla Vargas
- Faculdade de Farmácia, UFRGS, Porto Alegre 90610-000, RS, Brasil
- Serviço de Genética Médica, HCPA, UFRGS, Rua Ramiro Barcelos, Porto Alegre, 90035-903, RS, Brasil
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, UFRGS, Rua Ramiro Barcelos, Porto Alegre, 90035-000, RS, Brasil
- Programa de Pós-Graduação em Ciências Farmacêuticas, UFRGS, Porto Alegre, 90610-000, RS, Brasil
| |
Collapse
|
|
4
|
Sen Sarma M, Tripathi PR. Natural history and management of liver dysfunction in lysosomal storage disorders. World J Hepatol 2022; 14:1844-1861. [PMID: 36340750 PMCID: PMC9627439 DOI: 10.4254/wjh.v14.i10.1844] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2021] [Revised: 04/21/2022] [Accepted: 09/21/2022] [Indexed: 02/06/2023] Open
Abstract
Lysosomal storage disorders (LSD) are a rare group of genetic disorders. The major LSDs that cause liver dysfunction are disorders of sphingolipid lipid storage [Gaucher disease (GD) and Niemann-Pick disease] and lysosomal acid lipase deficiency [cholesteryl ester storage disease and Wolman disease (WD)]. These diseases can cause significant liver problems ranging from asymptomatic hepatomegaly to cirrhosis and portal hypertension. Abnormal storage cells initiate hepatic fibrosis in sphingolipid disorders. Dyslipidemia causes micronodular cirrhosis in lipid storage disorders. These disorders must be keenly differentiated from other chronic liver diseases and non-alcoholic steatohepatitis that affect children and young adults. GD, Niemann-Pick type C, and WD also cause neonatal cholestasis and infantile liver failure. Genotype and liver phenotype correlation is variable in these conditions. Patients with LSD may survive up to 4-5 decades except for those with neonatal onset disease. The diagnosis of all LSD is based on enzymatic activity, tissue histology, and genetic testing. Enzyme replacement is possible in GD and Niemann-Pick types A and B though there are major limitations in the outcome. Those that progress invariably require liver transplantation with variable outcomes. The prognosis of Niemann-Pick type C and WD is universally poor. Enzyme replacement therapy has a promising role in cholesteryl ester storage disease. This review attempts to outline the natural history of these disorders from a hepatologist’s perspective to increase awareness and facilitate better management of these rare disorders.
Collapse
Affiliation(s)
- Moinak Sen Sarma
- Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India
| | - Parijat Ram Tripathi
- Department of Pediatric Gastroenterology, Ankura Hospital for Women and Children, Hyderabad 500072, India
| |
Collapse
|
|
5
|
Ghanem M, Lewis GF, Xiao C. Recent advances in cytoplasmic lipid droplet metabolism in intestinal enterocyte. Biochim Biophys Acta Mol Cell Biol Lipids 2022; 1867:159197. [PMID: 35820577 DOI: 10.1016/j.bbalip.2022.159197] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Revised: 06/03/2022] [Accepted: 06/14/2022] [Indexed: 11/30/2022]
Abstract
Processing of dietary fats in the intestine is a highly regulated process that influences whole-body energy homeostasis and multiple physiological functions. Dysregulated lipid handling in the intestine leads to dyslipidemia and atherosclerotic cardiovascular disease. In intestinal enterocytes, lipids are incorporated into lipoproteins and cytoplasmic lipid droplets (CLDs). Lipoprotein synthesis and CLD metabolism are inter-connected pathways with multiple points of regulation. This review aims to highlight recent advances in the regulatory mechanisms of lipid processing in the enterocyte, with particular focus on CLDs. In-depth understanding of the regulation of lipid metabolism in the enterocyte may help identify therapeutic targets for the treatment and prevention of metabolic disorders.
Collapse
Affiliation(s)
- Murooj Ghanem
- Department of Anatomy, Physiology and Pharmacology, College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada
| | - Gary F Lewis
- Departments of Medicine and Physiology, University of Toronto, and University Health Network, Toronto, ON, Canada
| | - Changting Xiao
- Department of Anatomy, Physiology and Pharmacology, College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada.
| |
Collapse
|
|
6
|
Witeck CDR, Schmitz AC, de Oliveira JMD, Porporatti AL, De Luca Canto G, Pires MMDS. Lysosomal acid lipase deficiency in pediatric patients: a scoping review. J Pediatr (Rio J) 2022; 98:4-14. [PMID: 33964214 PMCID: PMC9432115 DOI: 10.1016/j.jped.2021.03.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 02/24/2021] [Accepted: 03/01/2021] [Indexed: 02/07/2023] Open
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.
Collapse
Affiliation(s)
- Camila da Rosa Witeck
- Universidade Federal de Santa Catarina, Programa de Pós-Graduação em Ciências Médicas, Florianópolis, SC, Brazil.
| | - Anne Calbusch Schmitz
- Universidade Federal de Santa Catarina, Programa de Pós-Graduação em Ciências Médicas, Florianópolis, SC, Brazil
| | - Júlia Meller Dias de Oliveira
- Universidade Federal de Santa Catarina, Centro Brasileiro de Pesquisas Baseadas em Evidências, Florianópolis, SC, Brazil
| | - André Luís Porporatti
- Universidade Federal de Santa Catarina, Centro Brasileiro de Pesquisas Baseadas em Evidências, Florianópolis, SC, Brazil
| | - Graziela De Luca Canto
- Universidade Federal de Santa Catarina, Centro Brasileiro de Pesquisas Baseadas em Evidências, Florianópolis, SC, Brazil
| | - Maria Marlene de Souza Pires
- Universidade Federal de Santa Catarina, Programa de Pós-Graduação em Ciências Médicas, Florianópolis, SC, Brazil; Universidade Federal de Santa Catarina, Laboratório de Pesquisa Clínica e Experimental- MENULab, Florianópolis, SC, Brazil; Universidade Federal de Santa Catarina, Departamento de Pediatria, Florianópolis, SC, Brazil
| |
Collapse
|
|
7
|
Yoo HW. Diverse etiologies, diagnostic approach, and management of primary adrenal insufficiency in pediatric age. Ann Pediatr Endocrinol Metab 2021; 26:149-157. [PMID: 34610702 PMCID: PMC8505038 DOI: 10.6065/apem.2142150.075] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Accepted: 08/11/2021] [Indexed: 12/02/2022] Open
Abstract
Primary adrenal insufficiency (PAI) in pediatric age is a rare, but potentially fatal condition caused by diverse etiologies including biochemical defects of steroid biosynthesis, developmental abnormalities of the adrenal gland, or reduced responsiveness to adrenocorticotropic hormone. Compared to adult PAI, pediatric PAI is more often the result of genetic (monogenic, syndromic disorders) than acquired conditions. During the past decade, rare monogenic disorders associated with PAI have helped unravel the underlying novel molecular genetic mechanism. The diagnosis of adrenal insufficiency in children and young infancy is often challenging, usually based on clinical suspicion and endocrine laboratory findings. Pediatric endocrinologists sometimes encounter therapeutic difficulty in finding the balance between undertreatment and overtreatment, determining how to optimize the dose over the patient's lifetime, and maximizing mimicry of normal cortisol secretion with glucocorticoid replacement therapy.
Collapse
Affiliation(s)
- Han-Wook Yoo
- Department of Pediatrics, Asan Medical Center Children’s Hospital, University of Ulsan College of Medicine, Seoul, Korea,Address for correspondence: Han-Wook Yoo Department of Pediatrics, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympicro 43-gil, Songpa-gu, Seoul 05505, Korea
| |
Collapse
|
|
8
|
Ben Hlima H, Dammak M, Karray A, Drira M, Michaud P, Fendri I, Abdelkafi S. Molecular and Structural Characterizations of Lipases from Chlorella by Functional Genomics. Mar Drugs 2021; 19:70. [PMID: 33525674 PMCID: PMC7910983 DOI: 10.3390/md19020070] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2020] [Revised: 01/24/2021] [Accepted: 01/26/2021] [Indexed: 11/16/2022] Open
Abstract
Microalgae have been poorly investigated for new-lipolytic enzymes of biotechnological interest. In silico study combining analysis of sequences homologies and bioinformatic tools allowed the identification and preliminary characterization of 14 putative lipases expressed by Chlorella vulagaris. These proteins have different molecular weights, subcellular localizations, low instability index range and at least 40% of sequence identity with other microalgal lipases. Sequence comparison indicated that the catalytic triad corresponded to residues Ser, Asp and His, with the nucleophilic residue Ser positioned within the consensus GXSXG pentapeptide. 3D models were generated using different approaches and templates and demonstrated that these putative enzymes share a similar core with common α/β hydrolases fold belonging to family 3 lipases and class GX. Six lipases were predicted to have a transmembrane domain and a lysosomal acid lipase was identified. A similar mammalian enzyme plays an important role in breaking down cholesteryl esters and triglycerides and its deficiency causes serious digestive problems in human. More structural insight would provide important information on the enzyme characteristics.
Collapse
Affiliation(s)
- Hajer Ben Hlima
- Laboratoire de Génie Enzymatique et de Microbiologie, Equipe de Biotechnologie des Algues, Ecole Nationale d’Ingénieurs de Sfax, Université de Sfax, Sfax 3038, Tunisia; (H.B.H.); (M.D.)
| | - Mouna Dammak
- Laboratoire de Génie Enzymatique et de Microbiologie, Equipe de Biotechnologie des Algues, Ecole Nationale d’Ingénieurs de Sfax, Université de Sfax, Sfax 3038, Tunisia; (H.B.H.); (M.D.)
| | - Aida Karray
- Laboratoire de Biochimie et de Génie Enzymatique des Lipases, Ecole Nationale d’Ingénieurs de Sfax, Université de Sfax, Sfax 3038, Tunisia;
| | - Maroua Drira
- Laboratoire de Biotechnologie Végétale Appliquée à l’Amélioration des Cultures, Faculté des Sciences de Sfax, Université de Sfax, Sfax 3038, Tunisia; (M.D.); (I.F.)
| | - Philippe Michaud
- CNRS, SIGMA Clermont, Institut Pascal, Université Clermont-Auvergne, F-63000 Clermont-Ferrand, France
| | - Imen Fendri
- Laboratoire de Biotechnologie Végétale Appliquée à l’Amélioration des Cultures, Faculté des Sciences de Sfax, Université de Sfax, Sfax 3038, Tunisia; (M.D.); (I.F.)
| | - Slim Abdelkafi
- Laboratoire de Génie Enzymatique et de Microbiologie, Equipe de Biotechnologie des Algues, Ecole Nationale d’Ingénieurs de Sfax, Université de Sfax, Sfax 3038, Tunisia; (H.B.H.); (M.D.)
| |
Collapse
|
|
9
|
Vijay S, Brassier A, Ghosh A, Fecarotta S, Abel F, Marulkar S, Jones SA. Long-term survival with sebelipase alfa enzyme replacement therapy in infants with rapidly progressive lysosomal acid lipase deficiency: final results from 2 open-label studies. Orphanet J Rare Dis 2021; 16:13. [PMID: 33407676 PMCID: PMC7789691 DOI: 10.1186/s13023-020-01577-4] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Accepted: 10/13/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND If symptomatic in infants, the autosomal recessive disease lysosomal acid lipase deficiency (LAL-D; sometimes called Wolman disease or LAL-D/Wolman phenotype) is characterized by complete loss of LAL enzyme activity. This very rare, rapidly progressive form of LAL-D results in severe manifestations leading to failure to thrive and death, usually by 6 months of age. We report results from 2 open-label studies of enzyme replacement therapy with sebelipase alfa, a recombinant human LAL, in infants with LAL-D: the phase 2/3 Survival of LAL-D Infants Treated With Sebelipase Alfa (VITAL) study (NCT01371825) and a phase 2 dose-escalation study (LAL-CL08 [CL08]; NCT02193867). In both, infants received once-weekly intravenous infusions of sebelipase alfa. RESULTS The analysis population contained 19 patients (9 in VITAL; 10 in CL08). Kaplan-Meier estimates of survival to 12 months and 5 years of age were 79% and 68%, respectively, in the combined population, and the median age of surviving patients was 5.2 years in VITAL and 3.2 years in CL08. In both studies, median weight-for-age, length-for-age, and mid-upper arm circumference-for-age z scores increased from baseline to end of study. Decreases in median liver and spleen volume over time were noted in both studies. Short-term transfusion-free hemoglobin normalization was achieved by 100% of patients eligible for assessment in VITAL, in an estimated median (95% confidence interval [CI]) time of 4.6 (0.3-16.6) months. In CL08, short-term transfusion-free hemoglobin normalization was achieved by 70% of patients eligible for assessment, in an estimated median (95% CI) time of 5.5 (3.7-19.6) months. No patient discontinued treatment because of treatment-emergent adverse events. Most infusion-associated reactions (94% in VITAL and 88% in CL08) were mild or moderate in severity. CONCLUSIONS The findings of these 2 studies of infants with rapidly progressive LAL-D demonstrated that enzyme replacement therapy with sebelipase alfa prolonged survival with normal psychomotor development, improved growth, hematologic parameters, and liver parameters, and was generally well tolerated, with an acceptable safety profile.
Collapse
Affiliation(s)
- Suresh Vijay
- Birmingham Children's Hospital NHS Foundation Trust, Steelhouse Lane, Birmingham, B4 6NH, UK.
| | | | - Arunabha Ghosh
- Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, St. Mary's Hospital, Manchester, UK
| | | | | | | | - Simon A Jones
- Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, St. Mary's Hospital, Manchester, UK
| |
Collapse
|
|
10
|
Bertholf RL. Disorders of the adrenal gland. HANDBOOK OF DIAGNOSTIC ENDOCRINOLOGY 2021:103-156. [DOI: 10.1016/b978-0-12-818277-2.00004-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
|
|
11
|
Rajamohan F, Reyes AR, Tu M, Nedoma NL, Hoth LR, Schwaid AG, Kurumbail RG, Ward J, Han S. Crystal structure of human lysosomal acid lipase and its implications in cholesteryl ester storage disease. J Lipid Res 2020; 61:1192-1202. [PMID: 32482718 PMCID: PMC7397744 DOI: 10.1194/jlr.ra120000748] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Revised: 05/18/2020] [Indexed: 11/20/2022] Open
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.
Collapse
Affiliation(s)
| | | | - Meihua Tu
- Pfizer Worldwide Research, Cambridge, MA 02139
| | | | | | | | | | | | | |
Collapse
|
|
12
|
García-Macia M, Santos-Ledo A, Caballero B, Rubio-González A, de Luxán-Delgado B, Potes Y, Rodríguez-González SM, Boga JA, Coto-Montes A. Selective autophagy, lipophagy and mitophagy, in the Harderian gland along the oestrous cycle: a potential retrieval effect of melatonin. Sci Rep 2019; 9:18597. [PMID: 31819084 PMCID: PMC6901547 DOI: 10.1038/s41598-019-54743-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2019] [Accepted: 11/07/2019] [Indexed: 12/14/2022] Open
Abstract
Sexual dimorphism has been reported in many processes. However, sexual bias in favour of the use of males is very present in science. One of the main reasons is that the impact of hormones in diverse pathways and processes such as autophagy have not been properly addressed in vivo. The Harderian gland is a perfect model to study autophagic modulation as it exhibits important changes during the oestrous cycle. The aim of this study is to identify the main processes behind Harderian gland differences under oestrous cycle and their modulator. In the present study we show that redox-sensitive transcription factors have an essential role: NF-κB may activate SQSTM1/p62 in oestrus, promoting selective types of autophagy: mitophagy and lipophagy. Nrf2 activation in dioestrus, leads the retrieval phase and restoration of mitochondrial homeostasis. Melatonin’s receptors show higher expression in dioestrus, leading to decreases in pro-inflammatory mediators and enhanced Nrf2 expression. Consequently, autophagy is blocked, and porphyrin release is reduced. All these results point to melatonin as one of the main modulators of the changes in autophagy during the oestrous cycle.
Collapse
Affiliation(s)
- Marina García-Macia
- Institute of Cellular Medicine, Newcastle University, William Leech Building, NE2 4HH, Newcastle Upon Tyne, UK. .,Instituto de Investigación Biomédica de Salamanca (IBSAL), Neuroenergetics and Metabolism Group, Institute of Functional Biology and Genomics, University of Salamanca-CSIC, Zacarias Gonzalez, 2, 37007, Salamanca, Spain.
| | - Adrián Santos-Ledo
- Institute of Genetic Medicine, Newcastle University, International Centre for Life Central Parkway, NE1 3BZ, Newcastle Upon Tyne, UK
| | - Beatriz Caballero
- Departamento de Morfología y Biología Celular, Área de Biología Celular, Facultad de Medicina, Universidad de Oviedo, Julián Clavería s/n, 33006, Oviedo, Spain
| | - Adrian Rubio-González
- Departamento de Morfología y Biología Celular, Área de Biología Celular, Facultad de Medicina, Universidad de Oviedo, Julián Clavería s/n, 33006, Oviedo, Spain
| | - Beatriz de Luxán-Delgado
- Departamento de Morfología y Biología Celular, Área de Biología Celular, Facultad de Medicina, Universidad de Oviedo, Julián Clavería s/n, 33006, Oviedo, Spain.,Barts Cancer Institute-Queen Mary, University of London, Centre for Tumour biology, John Vane Science Centre, Charterhouse Square, London, EC1M 6BQ, UK
| | - Yaiza Potes
- Departamento de Morfología y Biología Celular, Área de Biología Celular, Facultad de Medicina, Universidad de Oviedo, Julián Clavería s/n, 33006, Oviedo, Spain
| | - Susana Mª Rodríguez-González
- Departamento de Morfología y Biología Celular, Área de Biología Celular, Facultad de Medicina, Universidad de Oviedo, Julián Clavería s/n, 33006, Oviedo, Spain
| | - José Antonio Boga
- Servicio de Microbiología, Hospital Universitario Central de Asturias, Avenida de Roma s/n., 33011, Oviedo, Spain
| | - Ana Coto-Montes
- Departamento de Morfología y Biología Celular, Área de Biología Celular, Facultad de Medicina, Universidad de Oviedo, Julián Clavería s/n, 33006, Oviedo, Spain.
| |
Collapse
|
|
13
|
Genes Potentially Associated with Familial Hypercholesterolemia. Biomolecules 2019; 9:biom9120807. [PMID: 31795497 PMCID: PMC6995538 DOI: 10.3390/biom9120807] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Revised: 11/24/2019] [Accepted: 11/26/2019] [Indexed: 12/21/2022] Open
Abstract
This review addresses the contribution of some genes to the phenotype of familial hypercholesterolemia. At present, it is known that the pathogenesis of this disease involves not only a pathological variant of low-density lipoprotein receptor and its ligands (apolipoprotein B, proprotein convertase subtilisin/kexin type 9 or low-density lipoprotein receptor adaptor protein 1), but also lipids, including sphingolipids, fatty acids, and sterols. The genetic cause of familial hypercholesterolemia is unknown in 20%–40% of the cases. The genes STAP1 (signal transducing adaptor family member 1), CYP7A1 (cytochrome P450 family 7 subfamily A member 1), LIPA (lipase A, lysosomal acid type), ABCG5 (ATP binding cassette subfamily G member 5), ABCG8 (ATP binding cassette subfamily G member 8), and PNPLA5 (patatin like phospholipase domain containing 5), which can cause aberrations of lipid metabolism, are being evaluated as new targets for the diagnosis and personalized management of familial hypercholesterolemia.
Collapse
|
|
14
|
Kuloglu Z, Kansu A, Selbuz S, Kalaycı AG, Şahin G, Kirsaclioglu CT, Demirören K, Dalgıç B, Kasırga E, Önal Z, İşlek A. The Frequency of Lysosomal Acid Lipase Deficiency in Children With Unexplained Liver Disease. J Pediatr Gastroenterol Nutr 2019; 68:371-376. [PMID: 30540705 DOI: 10.1097/mpg.0000000000002224] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
OBJECTIVES Evidence suggests that lysosomal acid lipase deficiency (LAL-D) is often underdiagnosed because symptoms may be nonspecific. We aimed to investigate the prevalence of LAL-D in children with unexplained liver disease and to identify demographic and clinical features with a prospective, multicenter, cross-sectional study. METHODS Patients (aged 3 months-18 years) who had unexplained transaminase elevation, unexplained hepatomegaly or hepatosplenomegaly, obesity-unrelated liver steatosis, biopsy-proven cryptogenic fibrosis and cirrhosis, or liver transplantation for cryptogenic cirrhosis were enrolled. A Web-based electronic data collection system was used. LAL activity (nmol/punch/h) was measured using the dried blood spot method and classified as LAL-D (<0.02), intermediate (0.02-0.37) or normal (> 0.37). A second dried blood spot sample was obtained from patients with intermediate LAL activity for confirmation of the result. RESULTS A total of 810 children (median age 5.6 years) from 795 families were enrolled. The reasons for enrollment were unexplained transaminase elevation (62%), unexplained organomegaly (45%), obesity-unrelated liver steatosis (26%), cryptogenic fibrosis and cirrhosis (6%), and liver transplantation for cryptogenic cirrhosis (<1%). LAL activity was normal in 634 (78%) and intermediate in 174 (21%) patients. LAL-D was identified in 2 siblings aged 15 and 6 years born to unrelated parents. Dyslipidemia, liver steatosis, and mild increase in aminotransferases were common features in these patients. Moreover, the 15-year-old patient showed growth failure and microvesicular steatosis, portal inflammation, and bridging fibrosis in the liver biopsy. Based on 795 families, 2 siblings in the same family were identified as LAL-D cases, making the prevalence of LAL-D in this study population, 0.1% (0.125%-0.606%). In the repeated measurement (76/174), LAL activity remained at the intermediate level in 38 patients. CONCLUSIONS Overall, the frequency of LAL-D patients in this study (0.1%) suggests that LAL-D seems to be rare even in the selected high-risk population.
Collapse
Affiliation(s)
- Zarife Kuloglu
- Department of Pediatric Gastroenterology, Hepatology and Nutrition, Ankara University School of Medicine, Ankara
| | - Aydan Kansu
- Department of Pediatric Gastroenterology, Hepatology and Nutrition, Ankara University School of Medicine, Ankara
| | - Suna Selbuz
- Department of Pediatric Gastroenterology, Hepatology and Nutrition, Ankara University School of Medicine, Ankara
| | - Ayhan G Kalaycı
- Department of Pediatric Gastroenterology, Hepatology and Nutrition, Ondokuz Mayıs University, School of Medicine, Samsun
| | - Gülseren Şahin
- Department of Pediatric Gastroenterology, Hepatology and Nutrition, Dr. Sami Ulus Children's Hospital, Ankara
| | - Ceyda Tuna Kirsaclioglu
- Department of Pediatric Gastroenterology, Hepatology and Nutrition, Turkish Republic Health Ministry, Ankara Child Health Diseases, Haematology Oncology Training and Research Hospital, Ankara
| | - Kaan Demirören
- Department of of Pediatric Gastroenterology, Hepatology and Nutrition, Yuzuncu Yıl University, Faculty of Medicine, Van
| | - Buket Dalgıç
- Department of Pediatric Gastroenterology, Hepatology and Nutrition, Gazi University University, Faculty of Medicine, Ankara
| | - Erhun Kasırga
- Department of Pediatric Gastroenterology, Hepatology and Nutrition, Celal Bayar University Faculty of Medicine, Manisa
| | - Zerrin Önal
- Department of Pediatric Gastroenterology, Hepatology and Nutrition, University of Medical Sciences, Bakırkoy Dr Sadi Konuk Research and Training Center, İstanbul
| | - Ali İşlek
- Department of Pediatric Gastroenterology, Hepatology and Nutrition, Atatürk University, Faculty of Medicine, Erzurum, Turkey
| |
Collapse
|
|
15
|
Carter A, Brackley SM, Gao J, Mann JP. The global prevalence and genetic spectrum of lysosomal acid lipase deficiency: A rare condition that mimics NAFLD. J Hepatol 2019; 70:142-150. [PMID: 30315827 DOI: 10.1016/j.jhep.2018.09.028] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2018] [Revised: 09/13/2018] [Accepted: 09/27/2018] [Indexed: 12/16/2022]
Abstract
BACKGROUND & AIMS Lysosomal acid lipase deficiency (LAL-D) is an autosomal recessive condition that may present in a mild form (cholesteryl ester storage disease [CESD]), which mimics non-alcoholic fatty liver disease (NAFLD). It has been suggested that CESD may affect 1 in 40,000 and is under-diagnosed in NAFLD clinics. Therefore, we aimed to estimate the prevalence of LAL-D using analysis of genetic variation in LIPA. METHODS MEDLINE and EMBASE were systematically searched for previously reported disease variants and prevalence estimates. Previous prevalence estimates were meta-analysed. Disease variants in LIPA were annotated with allele frequencies from gnomAD and combined with unreported major functional variants found in humans. Pooled ethnicity-specific prevalences for LAL-D and CESD were calculated using the Hardy-Weinberg equation. RESULTS Meta-analysis of existing genetic studies estimated the prevalence of LAL-D as 1 per 160,000 (95% CI 1 per 65,025-761,652) using the allele frequency of c.894G>A in LIPA. A total of 98 previously reported disease variants in LIPA were identified, of which 32/98 were present in gnomAD, giving a prevalence of 1 per 307,482 (95% CI 257,672-366,865). Wolman disease was associated with more loss-of-function variants than CESD. When this was combined with 22 previously unreported major functional variants in LIPA identified in humans, the pooled prevalence of LAL-D was 1 per 177,452 (95% CI 149,467-210,683) with a carrier frequency of 1 per 421. The prevalence is lowest in those of East Asian, South Asian, and Finnish ancestry. CONCLUSION Using 120 disease variants in LIPA, these data can reassure clinicians that LAL-D is an ultra-rare disorder. Given the therapeutic capability of sebelipase alpha, investigation for LAL-D might be included in second-line metabolic screening in NAFLD. LAY SUMMARY Lysosomal Acid Lipase Deficiency (LAL-D) is a rare genetic condition that can cause severe liver disease, but it is difficult to diagnose and sometimes can look like simple fatty liver. It was not clear how common LAL-D was and whether many cases were being missed. To study this, we searched for all genetic mutations that could cause LAL-D, calculated how common those mutations were, and added them up. This let us estimate that LAL-D affects roughly 1 in 175,000 people. We conclude that LAL-D is a very rare condition, but it is treatable so may be included in a 'second-line' of tests for causes of fatty liver.
Collapse
Affiliation(s)
- Anna Carter
- Manchester University Foundation Trust, Manchester, United Kingdom
| | - Simon Mark Brackley
- University of Cambridge, School of Clinical Medicine, Cambridge, United Kingdom
| | - Jiali Gao
- University of Cambridge, School of Clinical Medicine, Cambridge, United Kingdom
| | - Jake Peter Mann
- University of Cambridge, Department of Paediatrics, Cambridge, United Kingdom; University of Cambridge, Institute of Metabolic Science-Metabolic Research Laboratories, Cambridge, United Kingdom.
| |
Collapse
|
|
16
|
Wang J, Xu W, Yang Z, Yan Y, Xie X, Qu N, Wang Y, Wang C, Hua J. New Diketopyrrolopyrrole-Based Ratiometric Fluorescent Probe for Intracellular Esterase Detection and Discrimination of Live and Dead Cells in Different Fluorescence Channels. ACS APPLIED MATERIALS & INTERFACES 2018; 10:31088-31095. [PMID: 30129745 DOI: 10.1021/acsami.8b11365] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/08/2023]
Abstract
A new diketopyrrolopyrrole-based fluorescent probe (DPP-AM) was designed and synthesized for ratiometric detection of esterase and for imaging of live and dead cells in different modes. DPP-AM showed red fluorescence because of the intramolecular charge transfer (ICT) process from the DPP moiety to the pyridinium cation and gave remarkable ratio changes (about 70 folds), with the fluorescence changing from red to yellow, after treating with esterase because of the broken ICT process. Besides, the detection limit of DPP-AM toward esterase in vitro was 9.51 × 10-5 U/mL. After pretreating with H2O2 and ultraviolet light radiation, the health status of TPC1 cells was successfully imaged. More importantly, DPP-AM showed yellow fluorescence in live cells and a red fluorescent signal in dead cells, indicating that DPP-AM has great potential applications for assessing esterase activity as well as for discriminating live and dead cells.
Collapse
Affiliation(s)
- Jian Wang
- Key Laboratory for Advanced Materials & Institute of Fine Chemicals, College of Chemistry and Molecular Engineering , East China University of Science and Technology , 130 Meilong Road , Shanghai 200237 , China
| | - Weibo Xu
- Department of Oncology , Shanghai Medical College, Fudan University , Shanghai 200032 , China
- Department of Head and Neck Surgery , Fudan University Shanghai Cancer Center , Shanghai 200032 , China
| | - Zhicheng Yang
- Key Laboratory for Advanced Materials & Institute of Fine Chemicals, College of Chemistry and Molecular Engineering , East China University of Science and Technology , 130 Meilong Road , Shanghai 200237 , China
| | - Yongchao Yan
- Key Laboratory for Advanced Materials & Institute of Fine Chemicals, College of Chemistry and Molecular Engineering , East China University of Science and Technology , 130 Meilong Road , Shanghai 200237 , China
| | - Xiaoxu Xie
- Key Laboratory for Advanced Materials & Institute of Fine Chemicals, College of Chemistry and Molecular Engineering , East China University of Science and Technology , 130 Meilong Road , Shanghai 200237 , China
| | - Ning Qu
- Department of Oncology , Shanghai Medical College, Fudan University , Shanghai 200032 , China
- Department of Head and Neck Surgery , Fudan University Shanghai Cancer Center , Shanghai 200032 , China
| | - Yu Wang
- Department of Oncology , Shanghai Medical College, Fudan University , Shanghai 200032 , China
- Department of Head and Neck Surgery , Fudan University Shanghai Cancer Center , Shanghai 200032 , China
| | - Chengyun Wang
- Key Laboratory for Advanced Materials & Institute of Fine Chemicals, College of Chemistry and Molecular Engineering , East China University of Science and Technology , 130 Meilong Road , Shanghai 200237 , China
| | - Jianli Hua
- Key Laboratory for Advanced Materials & Institute of Fine Chemicals, College of Chemistry and Molecular Engineering , East China University of Science and Technology , 130 Meilong Road , Shanghai 200237 , China
| |
Collapse
|
|
17
|
Bernstein DL, Lobritto S, Iuga A, Remotti H, Schiano T, Fiel MI, Balwani M. Lysosomal acid lipase deficiency allograft recurrence and liver failure- clinical outcomes of 18 liver transplantation patients. Mol Genet Metab 2018; 124:11-19. [PMID: 29655841 DOI: 10.1016/j.ymgme.2018.03.010] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2018] [Revised: 03/21/2018] [Accepted: 03/22/2018] [Indexed: 12/20/2022]
Abstract
Lysosomal acid lipase deficiency (LAL-D) results in progressive microvesicular hepatosteatosis, fibrosis, cirrhosis, dyslipidemia, and vascular disease. Interventions available prior to enzyme replacement therapy development, including lipid lowering medications, splenectomy, hematopoietic stem cell and liver transplantation were unsuccessful at preventing multi-systemic disease progression, and were associated with significant morbidity and mortality. We report two sisters, diagnosed in infancy, who succumbed to LAL-D with accelerated disease progression following splenectomy and liver transplantation. The index patient died one year after hematopoietic stem cell transplant and liver transplantation. Her younger sister survived five years post liver-transplantation, complicated by intermittent, acute rejection. Typical LAL-D hepatopathology, including progressive, microvesicular steatosis, foamy macrophage aggregates, vacuolated Kupffer cells, advanced fibrosis and micronodular cirrhosis recurred in the liver allograft. She died before a second liver transplant could occur for decompensated liver failure. Neither patient received sebelipase alfa enzyme replacement therapy, human, recombinant, lysosomal acid lipase enzyme, FDA approved in 2015. Here are reviewed 18 LAL-D post-liver transplantation cases described in the literature. Multi-systemic LAL-D progression occurred in 11 patients (61%) and death in six (33%). These reports demonstrate that liver transplantation may be necessary for LAL-D-associated liver failure, but is not sufficient to prevent disease progression, or liver disease recurrence, since the pathophysiology is predominantly mediated by deficient enzyme activity in bone marrow-derived monocyte-macrophages. Enzyme replacement therapy addresses systemic disease and hepatopathology, potentially improving liver-transplantation outcomes. This is the first systematic review of liver transplantation for LAL-D, and the first account of liver allograft LAL-D-associated hepatopathology recurrence.
Collapse
Affiliation(s)
- Donna Lee Bernstein
- GenoPheno, LLC, New York, NY, United States; Mount Sinai Hospital and Icahn School of Medicine at Mount Sinai, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Steven Lobritto
- New York-Presbyterian Columbia University Morgan Stanley Children's Hospital, Center for Liver Disease and Transplantation, New York, NY, United States
| | - Alina Iuga
- New York-Presbyterian Columbia University Hospital, Department of Pathology and Cell Biology, New York, NY, United States
| | - Helen Remotti
- New York-Presbyterian Columbia University Hospital, Department of Pathology and Cell Biology, New York, NY, United States
| | - Thomas Schiano
- Recanati/Miller Transplantation Institute/Division of Liver Diseases, Mount Sinai Medical Center, New York, NY, United States
| | - Maria Isabel Fiel
- Anatomic and Clinical Pathology Laboratories, Mount Sinai Hospital and Icahn School of Medicine at Mount Sinai, United States
| | - Manisha Balwani
- Mount Sinai Hospital and Icahn School of Medicine at Mount Sinai, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States.
| |
Collapse
|
|
18
|
Hannah-Shmouni F, Stratakis CA. An overview of inborn errors of metabolism manifesting with primary adrenal insufficiency. Rev Endocr Metab Disord 2018; 19:53-67. [PMID: 29956047 PMCID: PMC6204320 DOI: 10.1007/s11154-018-9447-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Primary adrenal insufficiency (PAI) results from an inability to produce adequate amounts of steroid hormones from the adrenal cortex. The most common causes of PAI are autoimmune adrenalitis (Addison's disease), infectious diseases, adrenalectomy, neoplasia, medications, and various rare genetic syndromes and inborn errors of metabolism that typically present in childhood although late-onset presentations are becoming increasingly recognized. The prevalence of PAI in Western countries is approximately 140 cases per million, with an incidence of 4 per 1,000,000 per year. Several pitfalls in the genetic diagnosis of patients with PAI exist. In this review, we provide an in-depth discussion and overview on the inborn errors of metabolism manifesting with PAI, including genetic diagnosis, genotype-phenotype relationships and counseling of patients and their families with a focus on various enzymatic deficiencies of steroidogenesis.
Collapse
Affiliation(s)
- Fady Hannah-Shmouni
- Section on Endocrinology & Genetics, The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Building 10, CRC, Room 1-3330, 10 Center Dr., MSC1103, Bethesda, MD, 20892, USA
| | - Constantine A Stratakis
- Section on Endocrinology & Genetics, The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Building 10, CRC, Room 1-3330, 10 Center Dr., MSC1103, Bethesda, MD, 20892, USA.
| |
Collapse
|
|
19
|
Impact, Characterization, and Rescue of Pre-mRNA Splicing Mutations in Lysosomal Storage Disorders. Genes (Basel) 2018; 9:genes9020073. [PMID: 29415500 PMCID: PMC5852569 DOI: 10.3390/genes9020073] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2017] [Revised: 01/19/2018] [Accepted: 01/31/2018] [Indexed: 11/16/2022] Open
Abstract
Lysosomal storage disorders (LSDs) represent a group of more than 50 severe metabolic diseases caused by the deficiency of specific lysosomal hydrolases, activators, carriers, or lysosomal integral membrane proteins, leading to the abnormal accumulation of substrates within the lysosomes. Numerous mutations have been described in each disease-causing gene; among them, about 5-19% affect the pre-mRNA splicing process. In the last decade, several strategies to rescue/increase normal splicing of mutated transcripts have been developed and LSDs represent excellent candidates for this type of approach: (i) most of them are inherited in an autosomic recessive manner and patients affected by late-onset (LO) phenotypes often retain a fair amount of residual enzymatic activity; thus, even a small recovery of normal splicing may be beneficial in clinical settings; (ii) most LSDs still lack effective treatments or are currently treated with extremely expensive approaches; (iii) in few LSDs, a single splicing mutation accounts for up to 40-70% of pathogenic alleles. At present, numerous preclinical studies support the feasibility of reverting the pathological phenotype by partially rescuing splicing defects in LSDs. This review provides an overview of the impact of splicing mutations in LSDs and the related therapeutic approaches currently under investigation in these disorders.
Collapse
|
|
20
|
Vinje T, Wierød L, Leren TP, Strøm TB. Prevalence of cholesteryl ester storage disease among hypercholesterolemic subjects and functional characterization of mutations in the lysosomal acid lipase gene. Mol Genet Metab 2018; 123:169-176. [PMID: 29196158 DOI: 10.1016/j.ymgme.2017.11.008] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2017] [Revised: 11/21/2017] [Accepted: 11/21/2017] [Indexed: 12/14/2022]
Abstract
Lysosomal acid lipase hydrolyzes cholesteryl esters and triglycerides contained in low density lipoprotein. Patients who are homozygous or compound heterozygous for mutations in the lysosomal acid lipase gene (LIPA), and have some residual enzymatic activity, have cholesteryl ester storage disease. One of the clinical features of this disease is hypercholesterolemia. Thus, patients with hypercholesterolemia who do not carry a mutation as a cause of autosomal dominant hypercholesterolemia, may actually have cholesteryl ester storage disease. In this study we have performed DNA sequencing of LIPA in 3027 hypercholesterolemic patients who did not carry a mutation as a cause of autosomal dominant hypercholesterolemia. Functional analyses of possibly pathogenic mutations and of all mutations in LIPA listed in The Human Genome Mutation Database were performed to determine the pathogenicity of these mutations. For these studies, HeLa T-REx cells were transiently transfected with mutant LIPA plasmids and Western blot analysis of cell lysates was performed to determine if the mutants were synthesized in a normal fashion. The enzymatic activity of the mutants was determined in lysates of the transfected cells using 4-methylumbelliferone-palmitate as the substrate. A total of 41 mutations in LIPA were studied, of which 32 mutations were considered pathogenic by having an enzymatic activity <10% of normal. However, none of the 3027 hypercholesterolemic patients were homozygous or compound heterozygous for a pathogenic mutation. Thus, cholesteryl ester storage disease must be a very rare cause of hypercholesterolemia in Norway.
Collapse
Affiliation(s)
- Terje Vinje
- Unit for Cardiac and Cardiovascular Genetics, Department of Medical Genetics, Oslo University Hospital, Oslo, Norway
| | - Lene Wierød
- Unit for Cardiac and Cardiovascular Genetics, Department of Medical Genetics, Oslo University Hospital, Oslo, Norway
| | - Trond P Leren
- Unit for Cardiac and Cardiovascular Genetics, Department of Medical Genetics, Oslo University Hospital, Oslo, Norway
| | - Thea Bismo Strøm
- Unit for Cardiac and Cardiovascular Genetics, Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
| |
Collapse
|
|
21
|
Quaglia A, Roberts EA, Torbenson M. Developmental and Inherited Liver Disease. MACSWEEN'S PATHOLOGY OF THE LIVER 2018:111-274. [DOI: 10.1016/b978-0-7020-6697-9.00003-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
|
|
22
|
Abstract
INTRODUCTION With the growing obesity epidemic, nonalcoholic fatty liver disease (NAFLD) is rapidly becoming one of the leading causes of liver disease worldwide. Although obesity is a main risk factor for the development of NAFLD, it can also develop in lean subjects and can be encountered in different clinical setting and in association with an array of genetic, metabolic, nutritional, infectious and drug-induced disorders. Areas covered: This article discusses causes of fatty liver in non-obese subjects focusing on Lysosomal acid lipase deficiency (LAL-D), a commonly overlooked disorder reviewing its prevalence, genetics, pathogenesis, clinical features, diagnosis and treatment. It will also review other causes of non-alcoholic fatty liver disease, which can be encountered in the absence of obesity and metabolic syndrome. Expert commentary: Although the prevalence of LAL-D has been estimated in the range of 1 in 40,000 and 1 in 300,000, this estimate is much more than the identified cases reported in the literature, which suggests that that the disease may be considerably under-diagnosed. There is a pressing need to educate clinicians about the disease, especially with the development of new promising therapeutic modalities.
Collapse
Affiliation(s)
- Hassan H A-Kader
- a Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics , The University of Arizona , Tucson , AZ , USA
| |
Collapse
|
|
23
|
Pisciotta L, Tozzi G, Travaglini L, Taurisano R, Lucchi T, Indolfi G, Papadia F, Di Rocco M, D'Antiga L, Crock P, Vora K, Nightingale S, Michelakakis H, Garoufi A, Lykopoulou L, Bertolini S, Calandra S. Molecular and clinical characterization of a series of patients with childhood-onset lysosomal acid lipase deficiency. Retrospective investigations, follow-up and detection of two novel LIPA pathogenic variants. Atherosclerosis 2017; 265:124-132. [PMID: 28881270 DOI: 10.1016/j.atherosclerosis.2017.08.021] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2017] [Revised: 08/05/2017] [Accepted: 08/22/2017] [Indexed: 11/22/2022]
Abstract
BACKGROUND AND AIMS Childhood/Adult-onset Lysosomal Acid Lipase Deficiency (LAL-D) is a recessive disorder due to loss of function variants of LAL, the enzyme which hydrolyses cholesteryl esters, derived from internalized apoB containing lipoproteins. The disease is characterized by multi-organ involvement including the liver, spleen, intestine and cardiovascular system. The aim of this study was the clinical and molecular characterization of 14 (13 unrelated) previously unreported patients with childhood-onset LAL-D. METHODS Data collected included clinical and laboratory investigations, liver imaging, liver biopsy and LIPA gene analysis. The response to lipid-lowering medications, liver transplantation and enzyme replacement therapy (ERT) was reported for some patients. RESULTS LAL-D was suspected at 4.4 ± 3.3 years of age for the presence of hepatomegaly, elevated serum transaminases and hypercholesterolemia, and was confirmed by liver biopsy/imaging and LAL assay. The follow up period ranged from 3 to 40 years (mean 7.8 ± 4.0 years in 13 cases). Patients treated with statins with or without ezetimibe showed 28% reduction of plasma LDL-cholesterol without a tangible effect on liver enzymes; some patients receiving ERT showed normalized lipoprotein profile and transaminase levels. The common c.894G > A variant was observed in homozygosity or compound heterozygosity in 10 patients. We found seven previously reported variants: p.(Trp140*), p.(Arg218*), p.(Gly266*), p.(Thr288Ile), p.(Leu294Ser), p.(His295Tyr) and p.(Gly342Arg) and two novel variants: p.(Asp345Asn), affecting the LAL catalytic triad, and c.229+3A > C, affecting splicing. Homozygosity for p.(Thr288Ile) or c.229+3A > C was associated with a severe phenotype. CONCLUSIONS This study provides additional data on the features of childhood-onset LAL-D and describes two novel pathogenic variants of the LIPA gene.
Collapse
Affiliation(s)
| | - Giulia Tozzi
- Laboratory of Molecular Medicine, Unit of Neuromuscular and Neurodegenerative Disorders, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Lorena Travaglini
- Laboratory of Molecular Medicine, Unit of Neuromuscular and Neurodegenerative Disorders, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Roberta Taurisano
- Metabolism Division, Department of Pediatrics Specialist, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Tiziano Lucchi
- Department of Internal Medicine and Medical Specialities, IRCSS Ca' Granda, Milan, Italy
| | - Giuseppe Indolfi
- Paediatric and Liver Unit, Meyer Children's University-Hospital, Florence, Italy
| | - Francesco Papadia
- University Pediatric Hospital Giovanni XXIII, O.U. Metabolic and Genetic Diseases, Bari, Italy
| | - Maja Di Rocco
- IRCCS Institute Giannina Gaslini, Department of Pediatrics, Unit of Rare Diseases, Genoa, Italy
| | - Lorenzo D'Antiga
- Pediatric Department, Hospital Papa Giovanni XXIII, Bergamo, Italy
| | - Patricia Crock
- John Hunter Children Hospital, Discipline of Paediatrics and Child Health, University of Newcastle, Newcastle, Australia
| | - Komal Vora
- John Hunter Children Hospital, Discipline of Paediatrics and Child Health, University of Newcastle, Newcastle, Australia
| | - Scott Nightingale
- John Hunter Children Hospital, Discipline of Paediatrics and Child Health, University of Newcastle, Newcastle, Australia
| | - Helen Michelakakis
- Department of Enzymology and Cellular Function, Institute of Child Health, Athens, Greece
| | - Anastasia Garoufi
- 2nd Department of Pediatrics, National and Kapodistrian University of Athens, "P. & A. Kyriakou" Children's Hospital, Athens, Greece
| | - Lilia Lykopoulou
- 1st Department of Pediatrics, University of Athens, Aghia Sofia Children's Hospital, Athens, Greece
| | | | - Sebastiano Calandra
- Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Italy.
| |
Collapse
|
|
24
|
Pericleous M, Kelly C, Wang T, Livingstone C, Ala A. Wolman's disease and cholesteryl ester storage disorder: the phenotypic spectrum of lysosomal acid lipase deficiency. Lancet Gastroenterol Hepatol 2017; 2:670-679. [PMID: 28786388 DOI: 10.1016/s2468-1253(17)30052-3] [Citation(s) in RCA: 94] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2016] [Revised: 02/02/2017] [Accepted: 02/07/2017] [Indexed: 02/07/2023]
Abstract
Lysosomal acid lipase deficiency is a rare, autosomal recessive condition caused by mutations in the gene encoding lysosomal acid lipase (LIPA) that result in reduced or absent activity of this essential enzyme. The severity of the resulting disease depends on the nature of the underlying mutation and magnitude of its effect on enzymatic function. Wolman's disease is a severe disorder that presents during infancy, resulting in failure to thrive, hepatomegaly, and hepatic failure, and an average life expectancy of less than 4 months. Cholesteryl ester storage disorder arises later in life and is less severe, although the two diseases share many common features, including dyslipidaemia and transaminitis. The prevalence of these diseases has been estimated at one in 40 000 to 300 000, but many cases are undiagnosed and unreported, and awareness among clinicians is low. Lysosomal acid lipase deficiency-which can be diagnosed using dry blood spot testing-is often misdiagnosed as non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), hereditary dyslipidaemia, or cryptogenic cirrhosis. There are no formal guidelines for treatment of these patients, and treatment options are limited. In this Review we appraise the existing literature on Wolman's disease and cholesteryl ester storage disease, and discuss available treatments, including enzyme replacement therapy, oral lipid-lowering therapy, stem-cell transplantation, and liver transplantation.
Collapse
Affiliation(s)
- Marinos Pericleous
- Department of Gastroenterology and Hepatology, Royal Surrey County Hospital NHS Foundation Trust, Guildford, Surrey, UK; Department of Clinical and Experimental Medicine, University of Surrey, Guildford, Surrey, UK
| | - Claire Kelly
- Department of Gastroenterology and Hepatology, Royal Surrey County Hospital NHS Foundation Trust, Guildford, Surrey, UK; Department of Clinical and Experimental Medicine, University of Surrey, Guildford, Surrey, UK
| | - Tim Wang
- Department of Clinical Biochemistry, Royal Surrey County Hospital NHS Foundation Trust, Guildford, Surrey, UK; School of Biosciences and Medicine, University of Surrey, Guildford, Surrey, UK
| | - Callum Livingstone
- Department of Clinical Biochemistry, Royal Surrey County Hospital NHS Foundation Trust, Guildford, Surrey, UK; School of Biosciences and Medicine, University of Surrey, Guildford, Surrey, UK
| | - Aftab Ala
- Department of Gastroenterology and Hepatology, Royal Surrey County Hospital NHS Foundation Trust, Guildford, Surrey, UK; Department of Clinical and Experimental Medicine, University of Surrey, Guildford, Surrey, UK.
| |
Collapse
|
|
25
|
Tuohetahuntila M, Molenaar MR, Spee B, Brouwers JF, Wubbolts R, Houweling M, Yan C, Du H, VanderVen BC, Vaandrager AB, Helms JB. Lysosome-mediated degradation of a distinct pool of lipid droplets during hepatic stellate cell activation. J Biol Chem 2017; 292:12436-12448. [PMID: 28615446 DOI: 10.1074/jbc.m117.778472] [Citation(s) in RCA: 56] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2017] [Revised: 06/14/2017] [Indexed: 11/06/2022] Open
Abstract
Activation of hepatic stellate cells (HSCs) is a critical step in the development of liver fibrosis. During activation, HSCs lose their lipid droplets (LDs) containing triacylglycerols (TAGs), cholesteryl esters, and retinyl esters (REs). We previously provided evidence for the presence of two distinct LD pools, a preexisting and a dynamic LD pool. Here we investigate the mechanisms of neutral lipid metabolism in the preexisting LD pool. To investigate the involvement of lysosomal degradation of neutral lipids, we studied the effect of lalistat, a specific lysosomal acid lipase (LAL/Lipa) inhibitor on LD degradation in HSCs during activation in vitro The LAL inhibitor increased the levels of TAG, cholesteryl ester, and RE in both rat and mouse HSCs. Lalistat was less potent in inhibiting the degradation of newly synthesized TAG species as compared with a more general lipase inhibitor orlistat. Lalistat also induced the presence of RE-containing LDs in an acidic compartment. However, targeted deletion of the Lipa gene in mice decreased the liver levels of RE, most likely as the result of a gradual disappearance of HSCs in livers of Lipa-/- mice. Lalistat partially inhibited the induction of activation marker α-smooth muscle actin (α-SMA) in rat and mouse HSCs. Our data suggest that LAL/Lipa is involved in the degradation of a specific preexisting pool of LDs and that inhibition of this pathway attenuates HSC activation.
Collapse
Affiliation(s)
- Maidina Tuohetahuntila
- Department of Biochemistry and Cell Biology, Faculty of Veterinary Medicine, Utrecht University, 3584 CM, Utrecht, The Netherlands
| | - Martijn R Molenaar
- Department of Biochemistry and Cell Biology, Faculty of Veterinary Medicine, Utrecht University, 3584 CM, Utrecht, The Netherlands
| | - Bart Spee
- Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, 3584 CM, Utrecht, The Netherlands
| | - Jos F Brouwers
- Department of Biochemistry and Cell Biology, Faculty of Veterinary Medicine, Utrecht University, 3584 CM, Utrecht, The Netherlands
| | - Richard Wubbolts
- Department of Biochemistry and Cell Biology, Faculty of Veterinary Medicine, Utrecht University, 3584 CM, Utrecht, The Netherlands
| | - Martin Houweling
- Department of Biochemistry and Cell Biology, Faculty of Veterinary Medicine, Utrecht University, 3584 CM, Utrecht, The Netherlands
| | - Cong Yan
- Indiana University School of Medicine, Indianapolis, Indiana 46202
| | - Hong Du
- Indiana University School of Medicine, Indianapolis, Indiana 46202
| | - Brian C VanderVen
- Department of Microbiology and Immunology, Cornell University, C5 181 Veterinary Medicine Center, Ithaca, New York 14853
| | - Arie B Vaandrager
- Department of Biochemistry and Cell Biology, Faculty of Veterinary Medicine, Utrecht University, 3584 CM, Utrecht, The Netherlands
| | - J Bernd Helms
- Department of Biochemistry and Cell Biology, Faculty of Veterinary Medicine, Utrecht University, 3584 CM, Utrecht, The Netherlands.
| |
Collapse
|
|
26
|
de Aguiar Vallim TQ, Lee E, Merriott DJ, Goulbourne CN, Cheng J, Cheng A, Gonen A, Allen RM, Palladino END, Ford DA, Wang T, Baldán Á, Tarling EJ. ABCG1 regulates pulmonary surfactant metabolism in mice and men. J Lipid Res 2017; 58:941-954. [PMID: 28264879 DOI: 10.1194/jlr.m075101] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2017] [Revised: 03/03/2017] [Indexed: 12/27/2022] Open
Abstract
Idiopathic pulmonary alveolar proteinosis (PAP) is a rare lung disease characterized by accumulation of surfactant. Surfactant synthesis and secretion are restricted to epithelial type 2 (T2) pneumocytes (also called T2 cells). Clearance of surfactant is dependent upon T2 cells and macrophages. ABCG1 is highly expressed in both T2 cells and macrophages. ABCG1-deficient mice accumulate surfactant, lamellar body-loaded T2 cells, lipid-loaded macrophages, B-1 lymphocytes, and immunoglobulins, clearly demonstrating that ABCG1 has a critical role in pulmonary homeostasis. We identify a variant in the ABCG1 promoter in patients with PAP that results in impaired activation of ABCG1 by the liver X receptor α, suggesting that ABCG1 basal expression and/or induction in response to sterol/lipid loading is essential for normal lung function. We generated mice lacking ABCG1 specifically in either T2 cells or macrophages to determine the relative contribution of these cell types on surfactant lipid homeostasis. These results establish a critical role for T2 cell ABCG1 in controlling surfactant and overall lipid homeostasis in the lung and in the pathogenesis of human lung disease.
Collapse
Affiliation(s)
- Thomas Q de Aguiar Vallim
- Department of Medicine, University of California Los Angeles, Los Angeles, CA 90095.,Department of Biological Chemistry, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095.,Molecular Biology Institute, University of California Los Angeles, Los Angeles, CA 90095.,Johnson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA 90095
| | - Elinor Lee
- Department of Medicine, University of California Los Angeles, Los Angeles, CA 90095.,Division of Pulmonary and Critical Care Medicine, University of California Los Angeles, Los Angeles, CA 90095
| | - David J Merriott
- Department of Biological Chemistry, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095
| | | | - Joan Cheng
- Department of Biological Chemistry, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095
| | - Angela Cheng
- Department of Biological Chemistry, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095
| | - Ayelet Gonen
- Department of Medicine, University of California San Diego, La Jolla, CA 92093
| | - Ryan M Allen
- Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University, St. Louis, MO 63104
| | - Elisa N D Palladino
- Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University, St. Louis, MO 63104.,Center for Cardiovascular Research, School of Medicine, Saint Louis University, St. Louis, MO 63104
| | - David A Ford
- Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University, St. Louis, MO 63104.,Center for Cardiovascular Research, School of Medicine, Saint Louis University, St. Louis, MO 63104
| | - Tisha Wang
- Department of Medicine, University of California Los Angeles, Los Angeles, CA 90095.,Division of Pulmonary and Critical Care Medicine, University of California Los Angeles, Los Angeles, CA 90095
| | - Ángel Baldán
- Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University, St. Louis, MO 63104
| | - Elizabeth J Tarling
- Department of Medicine, University of California Los Angeles, Los Angeles, CA 90095 .,Molecular Biology Institute, University of California Los Angeles, Los Angeles, CA 90095.,Johnson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA 90095
| |
Collapse
|
|
27
|
Chora JR, Alves AC, Medeiros AM, Mariano C, Lobarinhas G, Guerra A, Mansilha H, Cortez-Pinto H, Bourbon M. Lysosomal acid lipase deficiency: A hidden disease among cohorts of familial hypercholesterolemia? J Clin Lipidol 2017; 11:477-484.e2. [PMID: 28502505 DOI: 10.1016/j.jacl.2016.11.002] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2016] [Revised: 10/18/2016] [Accepted: 11/08/2016] [Indexed: 12/15/2022]
Abstract
BACKGROUND Lysosomal acid lipase deficiency (LALD) is an autosomal recessive disorder and an unrecognized cause of dyslipidemia. Patients usually present with dyslipidemia and altered liver function and mutations in LIPA gene are the underlying cause of LALD. OBJECTIVE The aim of this study was to investigate LALD in individuals with severe dyslipidemia and/or liver steatosis. METHODS Coding, splice regions, and promoter region of LIPA were sequenced by Sanger sequencing in a cohort of mutation-negative familial hypercholesterolemia (FH) patients (n = 492) and in a population sample comprising individuals with several types of dyslipidemia and/or liver steatosis (n = 258). RESULTS This study led to the identification of LALD in 4 children referred to the Portuguese FH Study, all with a clinical diagnosis of FH. Mild liver dysfunction was present at the age of FH diagnosis; however, a diagnosis of LALD was not considered. No adults at the time of referral have been identified with LALD. CONCLUSION LALD is a life-threatening disorder, and early identification is crucial for the implementation of specific treatment to avoid premature mortality. FH cohorts should be investigated to identify possible LALD patients, who will need appropriate treatment. These results highlight the importance of correctly identifying the etiology of the dyslipidemia.
Collapse
Affiliation(s)
- Joana Rita Chora
- Unidade I&D, Grupo de Investigação Cardiovascular, Departamento de Promoção da Saúde e Doenças Não Transmissíveis, Instituto Nacional de Saúde Doutor Ricardo Jorge, Lisboa, Portugal; University of Lisboa, Faculty of Sciences, BioISI-Biosystems & Integrative Sciences Institute, Campo Grande, Lisboa, Portugal
| | - Ana Catarina Alves
- Unidade I&D, Grupo de Investigação Cardiovascular, Departamento de Promoção da Saúde e Doenças Não Transmissíveis, Instituto Nacional de Saúde Doutor Ricardo Jorge, Lisboa, Portugal; University of Lisboa, Faculty of Sciences, BioISI-Biosystems & Integrative Sciences Institute, Campo Grande, Lisboa, Portugal
| | - Ana Margarida Medeiros
- Unidade I&D, Grupo de Investigação Cardiovascular, Departamento de Promoção da Saúde e Doenças Não Transmissíveis, Instituto Nacional de Saúde Doutor Ricardo Jorge, Lisboa, Portugal; University of Lisboa, Faculty of Sciences, BioISI-Biosystems & Integrative Sciences Institute, Campo Grande, Lisboa, Portugal
| | - Cibelle Mariano
- Unidade I&D, Grupo de Investigação Cardiovascular, Departamento de Promoção da Saúde e Doenças Não Transmissíveis, Instituto Nacional de Saúde Doutor Ricardo Jorge, Lisboa, Portugal; University of Lisboa, Faculty of Sciences, BioISI-Biosystems & Integrative Sciences Institute, Campo Grande, Lisboa, Portugal
| | - Goreti Lobarinhas
- Serviço de Pediatria, Hospital de Santa Maria Maior, Barcelos, Portugal
| | - António Guerra
- Serviço de Pediatria, Centro Hospitalar de São João, Porto, Portugal; Centro de Investigação em Tecnologias e Serviços de Saúde (CINTESIS), Faculdade de Medicina, Universidade do Porto, Porto, Portugal
| | - Helena Mansilha
- Serviço de Pediatria/Nutrição Pediátrica, Departamento da Infância e Adolescência, Centro Materno-Infantil do Norte (CMIN), Porto, Portugal
| | - Helena Cortez-Pinto
- Departamento de Gastrenterologia, Laboratório de Nutrição, Hospital Santa Maria, Faculdade de Medicina de Lisboa, Universidade de Lisboa, Portugal
| | - Mafalda Bourbon
- Unidade I&D, Grupo de Investigação Cardiovascular, Departamento de Promoção da Saúde e Doenças Não Transmissíveis, Instituto Nacional de Saúde Doutor Ricardo Jorge, Lisboa, Portugal; University of Lisboa, Faculty of Sciences, BioISI-Biosystems & Integrative Sciences Institute, Campo Grande, Lisboa, Portugal.
| |
Collapse
|
|
28
|
Jones SA, Rojas-Caro S, Quinn AG, Friedman M, Marulkar S, Ezgu F, Zaki O, Gargus JJ, Hughes J, Plantaz D, Vara R, Eckert S, Arnoux JB, Brassier A, Le Quan Sang KH, Valayannopoulos V. Survival in infants treated with sebelipase Alfa for lysosomal acid lipase deficiency: an open-label, multicenter, dose-escalation study. Orphanet J Rare Dis 2017; 12:25. [PMID: 28179030 PMCID: PMC5299659 DOI: 10.1186/s13023-017-0587-3] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2016] [Accepted: 02/04/2017] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Infants presenting with lysosomal acid lipase deficiency have marked failure to thrive, diarrhea, massive hepatosplenomegaly, anemia, rapidly progressive liver disease, and death typically in the first 6 months of life; the only available potential treatment has been hematopoietic stem cell transplantation, which is associated with high morbidity and mortality in this population. The study objective was to evaluate safety and efficacy (including survival) of enzyme replacement with sebelipase alfa in infants with lysosomal acid lipase deficiency. This is an ongoing multicenter, open-label, phase 2/3 study conducted in nine countries. The study enrolled infants with growth failure prior to 6 months of age with rapidly progressive lysosomal acid lipase deficiency; they received once-weekly doses of sebelipase alfa initiated at 0.35 mg/kg with intrapatient dose escalation up to 5 mg/kg. The main outcome of interest is survival to 12 months and survival beyond 24 months of age. RESULTS Nine 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. CONCLUSION Sebelipase 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.
Collapse
Affiliation(s)
- Simon A. Jones
- Manchester Centre for Genomic Medicine, 6th floor, St Mary’s Hospital, Central Manchester Foundation Trust, University of Manchester, Oxford Road, Manchester, M13 9WL UK
| | | | - Anthony G. Quinn
- Synageva BioPharma Corp., 33 Hayden Avenue, Lexington, MA 02421 USA
- Present: IDBioPharm Consulting, LLC, Boston, MA USA
| | - Mark Friedman
- Alexion Pharmaceuticals, Inc., 100 College Street, New Haven, CT 06510 USA
| | - Sachin Marulkar
- Alexion Pharmaceuticals, Inc., 100 College Street, New Haven, CT 06510 USA
| | - Fatih Ezgu
- Gazi University Faculty of Medicine, Gazi Hospital, 10th Floor, Beşevler Ankara, Turkey
| | - Osama Zaki
- Ain Shams University Pediatrics Hospital, 3, Kamal Raslan, Heliopolis, Cairo, 11771 Egypt
| | - J. Jay Gargus
- University of California, Irvine, 2056 Hewitt Hall, 843 Health Sciences Road, Irvine, CA 92697 USA
| | - Joanne Hughes
- Temple Street Children’s University Hospital, 1 Temple Street, Dublin, 1 Ireland
| | - Dominique Plantaz
- Hôpital Couple-Enfant CHU Grenoble, Avenue Maquis du Grésivaudan, 38700 La Tronche, Grenoble, France
| | - Roshni Vara
- Evelina Children’s Hospital, Westminster Bridge Road, London, SE1 7EH UK
| | - Stephen Eckert
- Synageva BioPharma Corp., 33 Hayden Avenue, Lexington, MA 02421 USA
| | - Jean-Baptiste Arnoux
- Hôpital Necker-Enfants Malades and IMAGINE Institute, 149 Rue de Sèvres, 75015 Paris, France
| | - Anais Brassier
- Hôpital Necker-Enfants Malades and IMAGINE Institute, 149 Rue de Sèvres, 75015 Paris, France
| | - Kim-Hanh Le Quan Sang
- Hôpital Necker-Enfants Malades and IMAGINE Institute, 149 Rue de Sèvres, 75015 Paris, France
| | - Vassili Valayannopoulos
- Hôpital Necker-Enfants Malades and IMAGINE Institute, 149 Rue de Sèvres, 75015 Paris, France
- Present: Sanofi Genzyme, Cambridge, MA USA
| |
Collapse
|
|
29
|
Aguisanda F, Thorne N, Zheng W. Targeting Wolman Disease and Cholesteryl Ester Storage Disease: Disease Pathogenesis and Therapeutic Development. Curr Chem Genom Transl Med 2017; 11:1-18. [PMID: 28401034 PMCID: PMC5362971 DOI: 10.2174/2213988501711010001] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2016] [Revised: 09/20/2016] [Accepted: 11/23/2016] [Indexed: 12/13/2022] Open
Abstract
Wolman disease (WD) and cholesteryl ester storage disease (CESD) are lysosomal storage diseases (LSDs) caused by a deficiency in lysosomal acid lipase (LAL) due to mutations in the LIPA gene. This enzyme is critical to the proper degradation of cholesterol in the lysosome. LAL function is completely lost in WD while some residual activity remains in CESD. Both are rare diseases with an incidence rate of less than 1/100,000 births for WD and approximate 2.5/100,000 births for CESD. Clinical manifestation of WD includes hepatosplenomegaly, calcified adrenal glands, severe malabsorption and a failure to thrive. As in CESD, histological analysis of WD tissues reveals the accumulation of triglycerides (TGs) and esterified cholesterol (EC) in cellular lysosomes. However, the clinical presentation of CESD is less severe and more variable than WD. This review is to provide an overview of the disease pathophysiology and the current state of therapeutic development for both of WD and CESD. The review will also discuss the application of patient derived iPSCs for further drug discovery.
Collapse
Affiliation(s)
- Francis Aguisanda
- National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892-3370, USA
| | - Natasha Thorne
- National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892-3370, USA
| | - Wei Zheng
- National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892-3370, USA
| |
Collapse
|
|
30
|
Su K, Donaldson E, Sharma R. Novel treatment options for lysosomal acid lipase deficiency: critical appraisal of sebelipase alfa. Appl Clin Genet 2016; 9:157-167. [PMID: 27799810 PMCID: PMC5074735 DOI: 10.2147/tacg.s86760] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Lysosomal acid lipase deficiency (LAL-D) is a rare disorder of cholesterol metabolism with an autosomal recessive mode of inheritance. The absence or deficiency of the LAL enzyme gives rise to pathological accumulation of cholesterol esters in various tissues. A severe LAL-D phenotype manifesting in infancy is associated with adrenal calcification and liver and gastrointestinal involvement with characteristic early mortality. LAL-D presenting in childhood and adulthood is associated with hepatomegaly, liver fibrosis, cirrhosis, and premature atherosclerosis. There are currently no curative pharmacological treatments for this life-threatening condition. Supportive management with lipid-modifying agents does not ameliorate disease progression. Hematopoietic stem cell transplantation as a curative measure in infantile disease has mixed success and is associated with inherent risks and complications. Sebelipase alfa (Kanuma) is a recombinant human LAL protein and the first enzyme replacement therapy for the treatment of LAL-D. Clinical trials have been undertaken in infants with rapidly progressive LAL-D and in children and adults with later-onset LAL-D. Initial data have shown significant survival benefits in the infant group and improvements in biochemical parameters in the latter. Sebelipase alfa has received marketing authorization in the United States and Europe as long-term therapy for all affected individuals. The availability of enzyme replacement therapy for this rare and progressive disorder warrants greater recognition and awareness by physicians.
Collapse
Affiliation(s)
- Kim Su
- Division of Gastroenterology/Hepatology
| | | | - Reena Sharma
- The Mark Holland Metabolic Unit, Salford Royal Hospital NHS Foundation Trust, Salford, UK
| |
Collapse
|
|
31
|
D'Aquila T, Hung YH, Carreiro A, Buhman KK. Recent discoveries on absorption of dietary fat: Presence, synthesis, and metabolism of cytoplasmic lipid droplets within enterocytes. Biochim Biophys Acta Mol Cell Biol Lipids 2016; 1861:730-47. [PMID: 27108063 DOI: 10.1016/j.bbalip.2016.04.012] [Citation(s) in RCA: 92] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2015] [Revised: 03/16/2016] [Accepted: 04/16/2016] [Indexed: 02/07/2023]
Abstract
Dietary fat provides essential nutrients, contributes to energy balance, and regulates blood lipid concentrations. These functions are important to health, but can also become dysregulated and contribute to diseases such as obesity, diabetes, cardiovascular disease, and cancer. Within enterocytes, the digestive products of dietary fat are re-synthesized into triacylglycerol, which is either secreted on chylomicrons or stored within cytoplasmic lipid droplets (CLDs). CLDs were originally thought to be inert stores of neutral lipids, but are now recognized as dynamic organelles that function in multiple cellular processes in addition to lipid metabolism. This review will highlight recent discoveries related to dietary fat absorption with an emphasis on the presence, synthesis, and metabolism of CLDs within this process.
Collapse
Affiliation(s)
- Theresa D'Aquila
- Department of Nutrition Science, Purdue University, West Lafayette, IN 47907, USA
| | - Yu-Han Hung
- Department of Nutrition Science, Purdue University, West Lafayette, IN 47907, USA
| | - Alicia Carreiro
- Department of Nutrition Science, Purdue University, West Lafayette, IN 47907, USA
| | - Kimberly K Buhman
- Department of Nutrition Science, Purdue University, West Lafayette, IN 47907, USA.
| |
Collapse
|
|
32
|
Kuranobu N, Murakami J, Okamoto K, Nishimura R, Murayama K, Takamura A, Umeda T, Eto Y, Kanzaki S. Cholesterol ester storage disease with a novel LIPA mutation (L264P) that presented massive hepatomegaly: A case report. Hepatol Res 2016; 46:477-82. [PMID: 26385844 DOI: 10.1111/hepr.12574] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2015] [Revised: 08/11/2015] [Accepted: 08/11/2015] [Indexed: 12/13/2022]
Abstract
Cholesterol ester storage disease (CESD) is an autosomal recessive disorder caused by deficient lysosomal acid lipase (LAL) activity, resulting in cholesteryl ester (CE) accumulation. CESD patients have liver disease associated with mixed dyslipidemia leading to liver failure. We here report the case of an 11-year-old male CESD patient with a novel mutation who had the chief complaint of massive hepatomegaly. The patient's liver reached to his pelvis, and his spleen was 2 cm below the costal margin. The patient had elevated serum liver enzymes and mixed dyslipidemia. The liver biopsy tissue showed characteristic CESD pathology, which included microvesicular steatosis, mild fibrosis and foamy macrophages. Electron microscopy showed a remnant cleft of CE crystals, and dried blood spot testing showed reduced LAL activity. We identified compound heterozygous mutations in the LIPA gene in this patient, namely, c.607G>C and c.791T>C. The former mutation was previously reported only in a Japanese patient, whereas the latter mutation is novel. The findings of this study suggest that LIPA gene mutations in Japanese CESD patients are different from those in Western patients. Although CESD is rare, it is likely that many patients are unrecognized or misdiagnosed, and thus the possibility of CESD should be considered in patients with hepatosplenomegaly and dyslipidemia.
Collapse
Affiliation(s)
- Naomi Kuranobu
- Division of Pediatrics and Perinatology, Tottori University Faculty of Medicine, Yonago, Japan
| | - Jun Murakami
- Division of Pediatrics and Perinatology, Tottori University Faculty of Medicine, Yonago, Japan
| | - Ken Okamoto
- Division of Pediatrics and Perinatology, Tottori University Faculty of Medicine, Yonago, Japan
| | - Rei Nishimura
- Division of Pediatrics and Perinatology, Tottori University Faculty of Medicine, Yonago, Japan
| | - Kei Murayama
- Department of Metabolism, Chiba Children's Hospital, Chiba, Japan
| | - Ayumi Takamura
- Advanced Clinical Research Center, Southern TOHOKU Research Institute for Neuroscience, Fukushima, Japan
| | - Toshiko Umeda
- Advanced Clinical Research Center, Southern TOHOKU Research Institute for Neuroscience, Fukushima, Japan
| | - Yoshikatsu Eto
- Advanced Clinical Research Center, Southern TOHOKU Research Institute for Neuroscience, Fukushima, Japan
| | - Susumu Kanzaki
- Division of Pediatrics and Perinatology, Tottori University Faculty of Medicine, Yonago, Japan
| |
Collapse
|
|
33
|
Rajamohan F, Reyes AR, Ruangsiriluk W, Hoth LR, Han S, Caspers N, Tu M, Ward J, Kurumbail RG. Expression and functional characterization of human lysosomal acid lipase gene (LIPA) mutation responsible for cholesteryl ester storage disease (CESD) phenotype. Protein Expr Purif 2015; 110:22-9. [DOI: 10.1016/j.pep.2014.12.009] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2014] [Revised: 12/15/2014] [Accepted: 12/16/2014] [Indexed: 11/27/2022]
|
|
34
|
Santillán-Hernández Y, Almanza-Miranda E, Xin WW, Goss K, Vera-Loaiza A, Mora MTGDL, Piña-Aguilar RE. Novel LIPA mutations in Mexican siblings with lysosomal acid lipase deficiency. World J Gastroenterol 2015; 21:1001-8. [PMID: 25624737 PMCID: PMC4299316 DOI: 10.3748/wjg.v21.i3.1001] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2014] [Revised: 08/12/2014] [Accepted: 09/29/2014] [Indexed: 02/06/2023] Open
Abstract
Lysosomal acid lipase (LAL) deficiency is an under-recognized lysosomal disease caused by deficient enzymatic activity of LAL. In this report we describe two affected female Mexican siblings with early hepatic complications. At two months of age, the first sibling presented with alternating episodes of diarrhea and constipation, and later with hepatomegaly, elevated transaminases, high levels of total and low-density lipoprotein cholesterol, and low levels of high-density lipoprotein. Portal hypertension and grade 2 esophageal varices were detected at four years of age. The second sibling presented with hepatomegaly, elevated transaminases and mildly elevated low-density lipoprotein and low high-density lipoprotein at six months of age. LAL activity was deficient in both patients. Sequencing of LIPA revealed two previously unreported heterozygous mutations in exon 4: c.253C>A and c.294C>G. These cases highlight the clinical continuum between the so-called Wolman disease and cholesteryl ester storage disease, and underscore that LAL deficiency represents a single disease with a degree of clinical heterogeneity.
Collapse
|
|
35
|
Sebelipase alfa over 52 weeks reduces serum transaminases, liver volume and improves serum lipids in patients with lysosomal acid lipase deficiency. J Hepatol 2014; 61:1135-42. [PMID: 24993530 PMCID: PMC4203712 DOI: 10.1016/j.jhep.2014.06.022] [Citation(s) in RCA: 72] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2014] [Revised: 05/21/2014] [Accepted: 06/23/2014] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Lysosomal acid lipase deficiency is an autosomal recessive enzyme deficiency resulting in lysosomal accumulation of cholesteryl esters and triglycerides. LAL-CL04, an ongoing extension study, investigates the long-term effects of sebelipase alfa, a recombinant human lysosomal acid lipase. METHODS Sebelipase alfa (1mg/kg or 3mg/kg) was infused every-other-week to eligible subjects. Safety and tolerability assessments, including liver function, lipid profiles and liver volume assessment, were carried out at regular intervals. RESULTS 216 infusions were administered to eight adult subjects through week 52 during LAL-CL04. At week 52, mean alanine aminotransferase and aspartate aminotransferase levels were normal with mean change from baseline of -58% and -40%. Mean changes for low-density lipoprotein, total cholesterol, triglyceride and high-density lipoprotein were -60%, -39%, -36%, and +29%, respectively. Mean liver volume by magnetic resonance imaging and hepatic proton density fat fraction decreased (12% and 55%, respectively). Adverse events were mainly mild and unrelated to sebelipase alfa. Infusion-related reactions were uncommon: three events of moderate severity were reported in two subjects; one patient's event was suggestive of a hypersensitivity-like reaction, but additional testing did not confirm this, and the subject has successfully re-started sebelipase alfa. Of samples tested to date, no anti-drug antibodies have been detected. CONCLUSIONS Long-term dosing with sebelipase alfa in lysosomal acid lipase-deficient patients is well tolerated and produces sustained reductions in transaminases, improvements in serum lipid profile and reduction in the hepatic fat fraction. A randomized, placebo-controlled phase 3 trial in children and adults is underway (ARISE: NCT01757184).
Collapse
|
|
36
|
Thelwall PE, Smith FE, Leavitt MC, Canty D, Hu W, Hollingsworth KG, Thoma C, Trenell MI, Taylor R, Rutkowski JV, Blamire AM, Quinn AG. Hepatic cholesteryl ester accumulation in lysosomal acid lipase deficiency: non-invasive identification and treatment monitoring by magnetic resonance. J Hepatol 2013; 59:543-9. [PMID: 23624251 PMCID: PMC3749380 DOI: 10.1016/j.jhep.2013.04.016] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2012] [Revised: 03/26/2013] [Accepted: 04/16/2013] [Indexed: 12/11/2022]
Abstract
BACKGROUND & AIMS Lysosomal Acid Lipase (LAL) deficiency is a rare metabolic storage disease, caused by a marked reduction in activity of LAL, which leads to accumulation of cholesteryl esters (CE) and triglycerides (TG) in lysosomes in many tissues. We used (1)H magnetic resonance (MR) spectroscopy to characterize the abnormalities in hepatic lipid content and composition in patients with LAL deficiency, and in ex vivo liver tissue from a LAL deficiency rat model. Secondly, we used MR spectroscopy to monitor the effects of an enzyme replacement therapy (ERT), sebelipase alfa (a recombinant human lysosomal acid lipase), on hepatic TG and CE content in the preclinical model. METHODS Human studies employed cohorts of LAL-deficient patients and NAFLD subjects. Rat experimental groups comprised ex vivo liver samples of wild type, NAFLD, LAL-deficient, and LAL-deficient rats receiving 4weeks of sebelipase alfa treatment. Hepatic (1)H MR spectroscopy was performed using 3T (human) and 7T (preclinical) MRI scanners to quantify hepatic cholesterol and triglyceride content. RESULTS CE accumulation was identified in LAL deficiency in both human and preclinical studies. A significant decrease in hepatic CE was observed in LAL-deficient rats following treatment with sebelipase alfa. CONCLUSIONS We demonstrate an entirely non-invasive method to identify and quantify the hepatic lipid signature associated with a rare genetic cause of fatty liver. The approach provides a more favorable alternative to repeated biopsy sampling for diagnosis and disease progression / treatment monitoring of patients with LAL deficiency and other disorders characterised by increased free cholesterol and/or cholesteryl esters.
Collapse
Affiliation(s)
- Peter E Thelwall
- Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
| | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
37
|
Scott SA, Liu B, Nazarenko I, Martis S, Kozlitina J, Yang Y, Ramirez C, Kasai Y, Hyatt T, Peter I, Desnick RJ. Frequency of the cholesteryl ester storage disease common LIPA E8SJM mutation (c.894G>A) in various racial and ethnic groups. Hepatology 2013; 58:958-65. [PMID: 23424026 PMCID: PMC3690149 DOI: 10.1002/hep.26327] [Citation(s) in RCA: 77] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2012] [Accepted: 02/06/2013] [Indexed: 12/11/2022]
Abstract
UNLABELLED Cholesteryl ester storage disease (CESD) and Wolman disease are autosomal recessive later-onset and severe infantile disorders, respectively, which result from the deficient activity of lysosomal acid lipase (LAL). LAL is encoded by LIPA (10q23.31) and the most common mutation associated with CESD is an exon 8 splice junction mutation (c.894G>A; E8SJM), which expresses only ∼3%-5% of normally spliced LAL. However, the frequency of c.894G>A is unknown in most populations. To estimate the prevalence of CESD in different populations, the frequencies of the c.894G>A mutation were determined in 10,000 LIPA alleles from healthy African-American, Asian, Caucasian, Hispanic, and Ashkenazi Jewish individuals from the greater New York metropolitan area and 6,578 LIPA alleles from African-American, Caucasian, and Hispanic subjects enrolled in the Dallas Heart Study. The combined c.894G>A allele frequencies from the two cohorts ranged from 0.0005 (Asian) to 0.0017 (Caucasian and Hispanic), which translated to carrier frequencies of 1 in 1,000 to ∼1 in 300, respectively. No African-American heterozygotes were detected. Additionally, by surveying the available literature, c.894G>A was estimated to account for 60% (95% confidence interval [CI]: 51%-69%) of reported mutations among multiethnic CESD patients. Using this estimate, the predicted prevalence of CESD in the Caucasian and Hispanic populations is ∼0.8 per 100,000 (∼1 in 130,000; 95% CI: ∼1 in 90,000 to 1 in 170,000). CONCLUSION These data indicate that CESD may be underdiagnosed in the general Caucasian and Hispanic populations, which is important since clinical trials of enzyme replacement therapy for LAL deficiency are currently being developed. Moreover, future studies on CESD prevalence in African and Asian populations may require full-gene LIPA sequencing to determine heterozygote frequencies, since c.894G>A is not common in these racial groups.
Collapse
Affiliation(s)
- Stuart A. Scott
- Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, NY 10029
| | - Benny Liu
- Department of Internal Medicine, University of California San Francisco, San Francisco, CA 94122,Alameda County Medical Center Highland Hospital, Oakland, CA 94602
| | - Irina Nazarenko
- Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, NY 10029
| | - Suparna Martis
- Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, NY 10029
| | - Julia Kozlitina
- McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX 75390
| | - Yao Yang
- Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, NY 10029
| | - Charina Ramirez
- Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390
| | - Yumi Kasai
- Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, NY 10029
| | - Tommy Hyatt
- Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390
| | - Inga Peter
- Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, NY 10029
| | - Robert J. Desnick
- Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, NY 10029
| |
Collapse
|
|
38
|
Muntoni S, Wiebusch H, Jansen-Rust M, Rust S, Schulte H, Berger K, Pisciotta L, Bertolini S, Funke H, Seedorf U, Assmann G. Heterozygosity for lysosomal acid lipase E8SJM mutation and serum lipid concentrations. Nutr Metab Cardiovasc Dis 2013; 23:732-736. [PMID: 22795295 DOI: 10.1016/j.numecd.2012.05.009] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2012] [Revised: 04/20/2012] [Accepted: 05/24/2012] [Indexed: 01/12/2023]
Abstract
BACKGROUND AND AIM The complete absence of the lysosomal acid lipase (LAL) enzyme function causes Wolman's Disease that is fatal within the first six months of life. Subtotal defects cause Cholesteryl ester storage disease (CESD), an autosomal recessive disorder leading to hepatic steatosis, fibrosis, micronodular cirrhosis, combined hyperlipidemia with low HDL-cholesterol, increased risk for atherosclerosis, premature death. Since the frequency of the Exon 8 splice junction mutation (c.894 G > A, E8SJM), the CESD leading mutation, is not rare in the general population (allele frequency 0.0025), we investigated the impact of this mutation on serum lipid profile in E8SJM carriers. METHODS AND RESULTS We collected E8SJM carriers both form genetic study-population analysis and from Outpatient Lipid Clinics and then we assessed their serum lipid profile. We found thirteen individuals heterozygote for E8SJM. Most of them were Germans, three Spanish and two Italian. We found a significant increase in total cholesterol levels in both sexes with E8SJM mutation, leading to a significant increase in LDL cholesterol in males. CONCLUSIONS Our results show that LAL E8SJM carriers have an alteration in lipid profile with a Polygenic Hypercholesterolemia phenotype, leading to an increase in cardiovascular risk profile.
Collapse
Affiliation(s)
- Sa Muntoni
- Department of Toxicology, Oncology and Molecular Pathology Unit, University of Cagliari, Italy.
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
39
|
Abstract
PURPOSE OF REVIEW Mutations in lysosomal acid lipase A (LIPA) result in two phenotypes depending on the extent of lysosomal acid lipase (LAL) deficiency: the severe, early-onset Wolman disease or the less severe cholesteryl ester storage disease (CESD). In CESD, the severity of the symptoms, hepatomegaly and hypercholesterolaemia, can be highly variable, presenting in childhood or adulthood. Therefore, it is likely that many patients are undiagnosed or misdiagnosed. Nevertheless, LAL deficiency has been recognized for more than 25 years, but adequate therapeutic strategies are limited. RECENT FINDINGS CESD has an estimated prevalence of one in 90,000 to 170,000 individuals in the general population, confirming the likelihood that this disease is currently underdiagnosed. A number of studies have shown that in LIPA deficient patients the hypercholesterolaemic phenotype can be attenuated using statin therapy, and favourable effects on reduction of lipid accumulation in lysosomes have been reported. Targeting lysosomal exocytosis with LAL replacement therapy was shown to be successful in animal models and recently a phase I/II study demonstrated its safety and its potential metabolic efficacy on transaminase levels. SUMMARY The hypercholesterolaemic phenotype in CESD can be difficult to distinguish from other known hypercholesterolaemic disorders. In the majority of CESD cases with hypercholesterolaemia favourable responses on statin treatment are observed, but the effect on reduction of lipid accumulation in lysosomes needs to be further evaluated. Combining statins with LAL replacement therapy may provide a promising approach for optimal treatment of LIPA deficiencies in the future.
Collapse
Affiliation(s)
- Sigrid W Fouchier
- Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands.
| | | |
Collapse
|
|
40
|
Dugail I. Lysosome/lipid droplet interplay in metabolic diseases. Biochimie 2013; 96:102-5. [PMID: 23880642 DOI: 10.1016/j.biochi.2013.07.008] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2013] [Accepted: 07/08/2013] [Indexed: 01/22/2023]
Abstract
Lysosomes and lipid droplets are generally considered as intracellular compartments with divergent roles in cell metabolism, lipid droplets serving as lipid reservoirs in anabolic pathways, whereas lysosomes are specialized in the catabolism of intracellular components. During the last few years, new insights in the biology of lysosomes has challenged this view by providing evidence for the importance of lysosome recycling as a sparing mechanism to maintain cellular fitness. On the other hand the understanding of lipid droplets has evolved from an inert intracellular deposit toward the status of an intracellular organelle with dynamic roles in cellular homeostasis beyond storage. These unrelated aspects have also recently converged in the finding of unexpected lipid droplet/lysosome communication through autophagy, and the discovery of lysosome-mediated lipid droplet degradation called lipopagy. Furthermore, adipocytes which are professional cells for lipid droplet formation were also shown to be active in peptide antigen presentation a pathway requiring lysosomal activity. The potential importance of lipid droplet/lysosome interplay is discussed in the context of metabolic diseases and the setting of chronic inflammation.
Collapse
Affiliation(s)
- Isabelle Dugail
- Centre de Recherche des Cordeliers, INSERM, U872, Paris F-75006, France; Université Pierre et Marie Curie - Paris6, UMR S872, Paris F-75006, France.
| |
Collapse
|
|
41
|
Bernstein DL, Hülkova H, Bialer MG, Desnick RJ. Cholesteryl ester storage disease: review of the findings in 135 reported patients with an underdiagnosed disease. J Hepatol 2013; 58:1230-43. [PMID: 23485521 DOI: 10.1016/j.jhep.2013.02.014] [Citation(s) in RCA: 250] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2012] [Revised: 02/12/2013] [Accepted: 02/18/2013] [Indexed: 12/11/2022]
Abstract
Cholesteryl ester storage disease (CESD) is caused by deficient lysosomal acid lipase (LAL) activity, predominantly resulting in cholesteryl ester (CE) accumulation, particularly in the liver, spleen, and macrophages throughout the body. The disease is characterized by microvesicular steatosis leading to liver failure, accelerated atherosclerosis and premature demise. Although CESD is rare, it is likely that many patients are unrecognized or misdiagnosed. Here, the findings in 135 CESD patients described in the literature are reviewed. Diagnoses were based on liver biopsies, LAL deficiency and/or LAL gene (LIPA) mutations. Hepatomegaly was present in 99.3% of patients; 74% also had splenomegaly. When reported, most patients had elevated serum total cholesterol, LDL-cholesterol, triglycerides, and transaminases (AST, ALT, or both), while HDL-cholesterol was decreased. All 112 liver biopsied patients had the characteristic pathology, which is progressive, and includes microvesicular steatosis, which leads to fibrosis, micronodular cirrhosis, and ultimately to liver failure. Pathognomonic birefringent CE crystals or their remnant clefts were observed in hepatic cells. Extrahepatic manifestations included portal hypertension, esophageal varices, and accelerated atherosclerosis. Liver failure in 17 reported patients resulted in liver transplantation and/or death. Genotyping identified 31 LIPA mutations in 55 patients; 61% of mutations were the common exon 8 splice-junction mutation (E8SJM(-1G>A)), for which 18 patients were homozygous. Genotype/phenotype correlations were limited; however, E8SJM(-1G>A) homozygotes typically had early-onset, slowly progressive disease. Supportive treatment included cholestyramine, statins, and, ultimately, liver transplantation. Recombinant LAL replacement was shown to be effective in animal models, and recently, a phase I/II clinical trial demonstrated its safety and indicated its potential metabolic efficacy.
Collapse
Affiliation(s)
- Donna L Bernstein
- Division of Medical Genetics, North Shore-Long Island Jewish Health System, 1554 Northern Boulevard, Suite 204, Manhasset, NY 11030, United States
| | | | | | | |
Collapse
|
|
42
|
Zhang B, Porto AF. Cholesteryl ester storage disease: protean presentations of lysosomal acid lipase deficiency. J Pediatr Gastroenterol Nutr 2013; 56:682-5. [PMID: 23403440 DOI: 10.1097/mpg.0b013e31828b36ac] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE LIPA gene mutations result in deficiency of lysosomal acid lipase and present phenotypically as Wolman disease or cholesteryl ester storage disease (CESD) depending on the level of deficiency. Patients with CESD may often be misdiagnosed because symptoms may be nonspecific. Symptoms may present in infancy if there is complete loss of lysosomal acid lipase or in early childhood or adulthood when there is partial loss. The purpose of the present study is to review the literature for pediatric cases of CESD to better understand the phenotype of CESD. METHODS A PubMed search of all English-language publications from 1966 through June 2012 for pediatric CESD case reports using the following key words CESD, fatty liver, and NAFLD was performed. All of the cases were reviewed and information regarding age, sex, presenting symptoms, and pertinent laboratory tests were recorded. RESULTS Seventy-one cases were culled from 39 published case reports. Nearly two-thirds of these patients presented with their first symptoms when they were younger than 5 years. Hepatomegaly and splenomegaly were common features. Serum transaminases and lipids were often elevated. Gastrointestinal symptoms were noted in approximately one-third of cases. Two-thirds of patients had liver fibrosis. CONCLUSIONS CESD has an estimated incidence as high as 1 in 40,000, which means that it is presently underdiagnosed. Education about common symptoms of CESD as well as a higher level of suspicion for screening for CESD will lead to earlier diagnosis. New treatments for CESD including possible enzyme replacement therapy make early diagnosis especially important.
Collapse
Affiliation(s)
- Bingnan Zhang
- Yale University School of Medicine, New Haven, CT 06510, USA
| | | |
Collapse
|
|
43
|
Fasano T, Pisciotta L, Bocchi L, Guardamagna O, Assandro P, Rabacchi C, Zanoni P, Filocamo M, Bertolini S, Calandra S. Lysosomal lipase deficiency: molecular characterization of eleven patients with Wolman or cholesteryl ester storage disease. Mol Genet Metab 2012; 105:450-6. [PMID: 22227072 DOI: 10.1016/j.ymgme.2011.12.008] [Citation(s) in RCA: 62] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2011] [Revised: 12/09/2011] [Accepted: 12/09/2011] [Indexed: 12/23/2022]
Abstract
Wolman Disease (WD) and cholesteryl ester storage disease (CESD) represent two distinct phenotypes of the same recessive disorder caused by the complete or partial deficiency of lysosomal acidic lipase (LAL), respectively. LAL, encoded by the LIPA gene, hydrolyzes cholesteryl esters derived from cell internalization of plasma lipoproteins. WD is a rapidly progressive and lethal disease characterized by intestinal malabsorption, hepatic and adrenal failure. CESD is characterized by hepatic fibrosis, hyperlipidemia and accelerated atherosclerosis. Aim of the study was the identification of LIPA mutations in three WD and eight CESD patients. The WD patients, all deceased before the first year of age, were homozygous for two novel mutations (c.299+1G>A and c.419G>A) or a mutation (c.796G>T) previously reported as compound heterozygosity in a CESD patient. The two mutations (c.419G>A and c.796G>T) resulting in truncated proteins (p.W140* and p.G266*) and the splicing mutation (c.229+1G>A) were associated with undetectable levels of LIPA mRNA in fibroblasts. All eight CESD patients carried the common mutation c.894G>A known to result not only in a major non-functional transcript with the skipping of exon 8 (p.S275_Q298del), but also in a minor normally spliced transcript producing 5-10% residual LAL activity. The c.894G>A mutation was found in homozygosity in four patients and, as compound heterozygosity, in association with a known (p.H295Y and p.G342R) or a novel (p.W140*) mutation in four other CESD patients. Segregation analysis performed in all patients harboring c.895G>A showed its occurrence on the same haplotype suggesting a common founder ancestor. The other WD and CESD mutations were associated with different haplotypes.
Collapse
Affiliation(s)
- Tommaso Fasano
- Department of Biomedical Sciences, University of Modena and Reggio Emilia, Via Campi 287, Modena, Italy
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
44
|
Saito S, Ohno K, Suzuki T, Sakuraba H. Structural bases of Wolman disease and cholesteryl ester storage disease. Mol Genet Metab 2012; 105:244-8. [PMID: 22138108 DOI: 10.1016/j.ymgme.2011.11.004] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2011] [Revised: 11/05/2011] [Accepted: 11/05/2011] [Indexed: 01/27/2023]
Abstract
To elucidate the bases of Wolman disease (WD) and cholesteryl ester storage disease (CESD) from the viewpoint of enzyme structure, we constructed a structural model of human lysosomal acid lipase (LAL) using molecular modeling software Modeller. The results revealed that the residues responsible for WD/CESD tend to be less solvent-accessible than others. Then, we examined the structural changes in the LAL protein caused by the WD/CESD mutations, using molecular modeling software TINKER. The results indicated that conformational changes of the functionally important residues and/or large conformational changes tend to cause the severe clinical phenotype (WD), whereas small conformational changes tend to cause the mild clinical phenotype (CESD), although there have been several exceptions. Further structural analysis is required to clarify the relationship between the three-dimensional structural changes and clinical phenotypes.
Collapse
Affiliation(s)
- Seiji Saito
- Department of Medical Management and Informatics, Hokkaido Information University, Ebetsu, Hokkaido, Japan
| | | | | | | |
Collapse
|
|
45
|
Lee TM, Welsh M, Benhamed S, Chung WK. Intragenic deletion as a novel type of mutation in Wolman disease. Mol Genet Metab 2011; 104:703-5. [PMID: 21963785 PMCID: PMC3781170 DOI: 10.1016/j.ymgme.2011.09.006] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2011] [Accepted: 09/07/2011] [Indexed: 11/29/2022]
Abstract
Two clinically distinct disorders, Wolman disease (WD) and cholesteryl ester storage disease (CESD), are allelic autosomal recessive disorders caused by different mutations in lysosomal acid lipase (LIPA) which encodes for an essential enzyme involved in the hydrolysis of intracellular cholesteryl esters and triglycerides. We describe a case of lysosomal acid lipase deficiency in an infant with WD and report on a novel mutation type, intragenic deletion.
Collapse
Affiliation(s)
- Teresa M. Lee
- Department of Pediatrics, Columbia University Medical Center, 1150 St. Nicholas Avenue, Russ Berrie Medical Science Pavilion, New York, New York 10032, USA
| | - Mariko Welsh
- Institute of Human Nutrition, College of Physicians and Surgeons, Columbia University, 630 West 168 Street, Presbyterian Hospital 15 Floor East, Suite 1512, New York, New York 10032, USA
| | - Sonia Benhamed
- GeneDx, 207 Perry Parkway, Gaithersburg, Maryland, 20877, USA
| | - Wendy K. Chung
- Department of Pediatrics, Columbia University Medical Center, 1150 St. Nicholas Avenue, Russ Berrie Medical Science Pavilion, New York, New York 10032, USA
- Corresponding author at: Department of Pediatrics, Columbia University Medical Center, 1150 St. Nicholas Avenue, Russ Berrie Medical Science Pavilion, New York, New York 10032, USA, Phone: +1 212 851 5315, Fax: +1 212 851 5306,
| |
Collapse
|
|
46
|
Bowden KL, Bilbey NJ, Bilawchuk LM, Boadu E, Sidhu R, Ory DS, Du H, Chan T, Francis GA. Lysosomal acid lipase deficiency impairs regulation of ABCA1 gene and formation of high density lipoproteins in cholesteryl ester storage disease. J Biol Chem 2011; 286:30624-30635. [PMID: 21757691 PMCID: PMC3162423 DOI: 10.1074/jbc.m111.274381] [Citation(s) in RCA: 67] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2011] [Indexed: 11/06/2022] Open
Abstract
ATP-binding cassette transporter A1 (ABCA1) mediates the rate-limiting step in high density lipoprotein (HDL) particle formation, and its expression is regulated primarily by oxysterol-dependent activation of liver X receptors. We previously reported that ABCA1 expression and HDL formation are impaired in the lysosomal cholesterol storage disorder Niemann-Pick disease type C1 and that plasma HDL-C is low in the majority of Niemann-Pick disease type C patients. Here, we show that ABCA1 regulation and activity are also impaired in cholesteryl ester storage disease (CESD), caused by mutations in the LIPA gene that result in less than 5% of normal lysosomal acid lipase (LAL) activity. Fibroblasts from patients with CESD showed impaired up-regulation of ABCA1 in response to low density lipoprotein (LDL) loading, reduced phospholipid and cholesterol efflux to apolipoprotein A-I, and reduced α-HDL particle formation. Treatment of normal fibroblasts with chloroquine to inhibit LAL activity reduced ABCA1 expression and activity, similar to that of CESD cells. Liver X receptor agonist treatment of CESD cells corrected ABCA1 expression but failed to correct LDL cholesteryl ester hydrolysis and cholesterol efflux to apoA-I. LDL-induced production of 27-hydroxycholesterol was reduced in CESD compared with normal fibroblasts. Treatment with conditioned medium containing LAL from normal fibroblasts or with recombinant human LAL rescued ABCA1 expression, apoA-I-mediated cholesterol efflux, HDL particle formation, and production of 27-hydroxycholesterol by CESD cells. These results provide further evidence that the rate of release of cholesterol from late endosomes/lysosomes is a critical regulator of ABCA1 expression and activity, and an explanation for the hypoalphalipoproteinemia seen in CESD patients.
Collapse
Affiliation(s)
- Kristin L Bowden
- Department of Medicine, Institute for Heart and Lung Health, St. Paul's Hospital, Vancouver, British Columbia V6Z 1Y6, Canada
| | - Nicolas J Bilbey
- Department of Medicine, Institute for Heart and Lung Health, St. Paul's Hospital, Vancouver, British Columbia V6Z 1Y6, Canada
| | - Leanne M Bilawchuk
- Department of Medicine, Institute for Heart and Lung Health, St. Paul's Hospital, Vancouver, British Columbia V6Z 1Y6, Canada
| | - Emmanuel Boadu
- Department of Medicine, Institute for Heart and Lung Health, St. Paul's Hospital, Vancouver, British Columbia V6Z 1Y6, Canada
| | - Rohini Sidhu
- Diabetic Cardiovascular Disease Center, Washington University School of Medicine, St. Louis, Missouri 63110
| | - Daniel S Ory
- Diabetic Cardiovascular Disease Center, Washington University School of Medicine, St. Louis, Missouri 63110
| | - Hong Du
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio 45229
| | - Teddy Chan
- Department of Medicine, Institute for Heart and Lung Health, St. Paul's Hospital, Vancouver, British Columbia V6Z 1Y6, Canada
| | - Gordon A Francis
- Department of Medicine, Institute for Heart and Lung Health, St. Paul's Hospital, Vancouver, British Columbia V6Z 1Y6, Canada.
| |
Collapse
|
|
47
|
Valles-Ayoub Y, Esfandiarifard S, No D, Sinai P, Khokher Z, Kohan M, Kahen T, Darvish D. Wolman disease (LIPA p.G87V) genotype frequency in people of Iranian-Jewish ancestry. Genet Test Mol Biomarkers 2011; 15:395-8. [PMID: 21291321 DOI: 10.1089/gtmb.2010.0203] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
Wolman disease (WD) is a rare inherited condition caused by lysosomal acid lipase (LAL) deficiency first described in Iranian-Jewish (IJ) children. Newborns with WD are healthy and active, but soon the infant develops symptoms of severe malnutrition in the first few months of life, and often dies before the age of 1 year. Harmful amounts of lipids accumulate in the spleen, liver, bone marrow, intestine, adrenal glands, and lymph nodes. Although worldwide incidence is estimated at 1/350,000 newborns, WD occurs at higher than expected frequency in the IJ community of the Los Angeles area. As a validation study, we analyzed 162 DNA specimens of IJ origin by automated sequencing. For LIPA p.G87V (ggc>gtc, alternative numbering p.G66V), a heterozygous frequency of 5/162 (3.086%) was discovered. Thus, we estimate that as high as 1 in 4200 newborns of IJ couples may be at risk. Additional studies are required to confirm and further validate the higher frequencies seen in our sample pool, and to determine if people of IJ and even possibly Middle Eastern descent are at a higher risk for WD.
Collapse
|
|
48
|
Abstract
Cholesterol is an important lipid of mammalian cells. Its unique physicochemical properties modulate membrane behavior and it serves as the precursor for steroid hormones, oxysterols and vitamin D. Cholesterol is effluxed from the late endosomes/lysosomes via the concerted action of at least two distinct proteins: Niemann-Pick C (NPC)1 and NPC2. Mutations in these two proteins manifest as NPC disease - a very rare, usually fatal, autosomal, recessive, neurovisceral, lysosomal storage disorder. In this review, we discuss the possible mechanisms of action for NPC1 and NPC2 in mediating cholesterol efflux, as well as the different therapeutic approaches being pursued for the treatment of this lipid storage disorder.
Collapse
Affiliation(s)
- Anton I Rosenbaum
- Department of Biochemistry, Weill Cornell Medical College, New York, New York 10065, USA
| | | |
Collapse
|
|
49
|
Decarlis S, Agostoni C, Ferrante F, Scarlino S, Riva E, Giovannini M. Combined hyperlipidaemia as a presenting sign of cholesteryl ester storage disease. J Inherit Metab Dis 2009; 32 Suppl 1:S11-3. [PMID: 19214773 DOI: 10.1007/s10545-008-1027-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2008] [Revised: 12/05/2008] [Accepted: 12/16/2008] [Indexed: 01/19/2023]
Abstract
Lysosomal acid lipase (LAL) deficiency results in Wolman disease and cholesteryl ester storage disease (CESD), a more benign form. CESD is a recessive disorder characterized by hypercholesterolaemia, hypertriglyceridaemia, low blood HDL and variable phenotype, while hepatomegaly is usually evident during childhood or adolescence. An 11-year-old girl was referred to our department for combined hyperlipidaemia (total cholesterol 323, triglycerides 259 mg/dl). All family members had normal lipid profile and liver function tests. At 8 years she was admitted for acute Epstein-Barr virus infection, with hepatosplenomegaly and elevation of liver enzymes. Liver-spleen enlargement resolved, but serum alanine aminotransferase and aspartate aminotransferase were persistently twice the upper limits, with other liver function tests within the normal range. Ultrasonography showed normal liver and spleen size and minimal hepatic steatosis. Infectious, autoimmune and metabolic causes of elevated liver enzymes were ruled out, including glycogen storage disease. Dysbetalipoproteinaemia was also ruled out (ApoE phenotype: E3E3). In the following 2 years the girl was symptom-free, BMI was at the 50th-75th centile for age and lipid profile was unchanged despite a low-fat diet. At 13 years of age, low acid lipase activity was demonstrated in leukocytes (10 nmol/h/ per mg protein, normal 140-380) and cultured skin fibroblasts (181 nmol/h per mg protein, normal 1100-2400), leading to diagnosis of CESD. CESD usually progresses to hepatic fibrosis, with high risk of premature atherosclerosis. CESD prevalence may be underestimated in the general population. The diagnosis may be considered in all subjects with atypical combined hyperlipidaemia (usually dominant in transmission or related to metabolic syndrome) and atypical 'fatty liver disease', in the absence of overweight.
Collapse
Affiliation(s)
- S Decarlis
- Department of Pediatrics, San Paolo Hospital, University of Milan Via Antonio di Rudinì, Milan, Italy.
| | | | | | | | | | | |
Collapse
|
|
50
|
Pisciotta L, Fresa R, Bellocchio A, Pino E, Guido V, Cantafora A, Di Rocco M, Calandra S, Bertolini S. Cholesteryl Ester Storage Disease (CESD) due to novel mutations in the LIPA gene. Mol Genet Metab 2009; 97:143-8. [PMID: 19307143 DOI: 10.1016/j.ymgme.2009.02.007] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2009] [Revised: 02/17/2009] [Accepted: 02/17/2009] [Indexed: 02/07/2023]
Abstract
Cholesteryl Ester Storage Disease (CESD) is a rare recessive disorder due to mutations in LIPA gene encoding the lysosomal acidic lipase (LAL). CESD patients have liver disease associated with mixed hyperlipidemia and low plasma levels of high-density lipoproteins (HDL). The aim of this study was the molecular characterization of three patients with CESD. LAL activity was measured in blood leukocytes. In two patients (twin sisters) the clinical diagnosis of CESD was made at 9 years of age, following the fortuitous discovery of elevated serum liver enzymes in apparently healthy children. They had mixed hyperlipidemia, hepatosplenomegaly, reduced LAL activity (approximately 5% of control) and heteroalleic mutations in LIPA gene coding sequence: (i) the common c.894 G>A mutation and (ii) a novel nonsense mutation c.652 C>T (p.R218X). The other patient was an 80 year-old female who for several years had been treated with simvastatin because of severe hyperlipidemia associated with low plasma HDL. In this patient the sequence of major candidate genes for monogenic hypercholesterolemia and hypoalphalipoproteinemia was negative. She was found to be a compound heterozygote for two LIPA gene mutations resulting in 5% LAL activity: (i) c.894 G>A and (ii) a novel complex insertion/deletion leading to a premature termination codon at position 82. These findings suggest that, in view of the variable severity of its phenotypic expression, CESD may sometimes be difficult to diagnose, but it should be considered in patients with severe type IIb hyperlipidemia associated with low HDL, mildly elevated serum liver enzymes and hepatomegaly.
Collapse
Affiliation(s)
- Livia Pisciotta
- Department of Internal Medicine, University of Genoa, Viale Benedetto XV 6, I-16132 Genoa, Italy
| | | | | | | | | | | | | | | | | |
Collapse
|