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de las Heras J, Almohalla C, Blasco-Alonso J, Bourbon M, Couce ML, de Castro López MJ, García Jiménez MC, Gil Ortega D, González-Diéguez L, Meavilla S, Moreno-Álvarez A, Pastor-Rosado J, Sánchez-Pintos P, Serrano-Gonzalo I, López E, Valdivielso P, Yahyaoui R, Quintero J. Practical Recommendations for the Diagnosis and Management of Lysosomal Acid Lipase Deficiency with a Focus on Wolman Disease. Nutrients 2024; 16:4309. [PMID: 39770929 PMCID: PMC11678757 DOI: 10.3390/nu16244309] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Revised: 12/03/2024] [Accepted: 12/07/2024] [Indexed: 01/11/2025] Open
Abstract
Lysosomal acid lipase deficiency (LAL-D) is an ultra-rare lysosomal storage disease with two distinct phenotypes, an infantile-onset form (formerly Wolman disease) and a later-onset form (formerly cholesteryl ester storage disease). The objective of this narrative review is to examine the most important aspects of the diagnosis and treatment of LAL-D and to provide practical expert recommendations. The infantile-onset form occurs in the first weeks of life and is characterized by malnourishment and failure to thrive due to gastrointestinal impairment (vomiting, diarrhea, malabsorption), as well as systemic inflammation, hepatosplenomegaly, and adrenal calcifications. Mortality is close to 100% before one year of life in the absence of specific treatment. The later-onset form can be diagnosed in childhood or adulthood and is characterized by chronic liver injury and/or lipid profile alterations. When LAL-D is suspected, enzyme activity should be determined to confirm the diagnosis, with analysis from a dried blood spot sample being the quickest and most reliable method. In infantile-onset LAL-D, the initiation of enzyme replacement therapy (sebelipase α) and careful nutritional management with a low-lipid diet is very urgent, as prognosis is directly linked to the early initiation of specific treatment. In recent years, our knowledge of the management of LAL-D has increased considerably, with improvements regarding the initial enzyme replacement therapy dose and careful nutritional treatment with a low-lipid diet to decrease lipid deposition and systemic inflammation, leading to better outcomes. In this narrative review we offer a quick guide for the initial management of infantile-onset LAL-D.
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Affiliation(s)
- Javier de las Heras
- Division of Pediatric Metabolism, Cruces University Hospital, CIBER-ER, Metab-ERN, University of the Basque Country (UPV/EHU), Biobizkaia Health Research Institute, 48903 Bilbao, Spain
| | - Carolina Almohalla
- Unidad de Hepatología, Hospital Universitario Río Hortega, 47012 Valladolid, Spain
| | - Javier Blasco-Alonso
- Unidad de Diagnóstico y Tratamiento de Enfermedades Metabólicas Hereditarias, UGC Pediatría, Hospital Regional Universitario de Málaga, 29010 Málaga, Spain
| | - Mafalda Bourbon
- Grupo de Investigação Cardiovascular, Departamento de Promoção da Saúde e Prevenção de Doenças não Transmissíveis, Instituto Nacional de Saúde Doutor Ricardo Jorge, 1649-016 Lisboa, Portugal
- BioISI, Biosystems & Integrative Sciences Institute, Faculdade de Ciências, Universidade de Lisboa, 1649-004 Lisboa, Portugal
| | - Maria-Luz Couce
- Metabolic Unit, Department of Forensic Sciences, Pathology, Gynecology and Obstetrics, Pediatrics, Health Research Institute of Santiago de Compostela (IDIS), Hospital Clínico Universitario de Santiago de Compostela, CIBERER, MetabERN, 15706 Santiago de Compostela, Spain
| | - María José de Castro López
- Willink Biochemical Genetics Unit, St Mary’s Hospital, Manchester University Foundation Trust, University of Manchester, Manchester M13 9WL, UK
| | - Mª Concepción García Jiménez
- NeuroMetabolic Unit, Pediatría, Hospital Universitario Miguel Servet, Aragon Health Research Institute (IIS Aragón), 50009 Zaragoza, Spain
| | - David Gil Ortega
- Unidad de Gastroenterología, Hepatología y Nutrición Pediátrica, Hospital Universitario Virgen de la Arrixaca, 30120 Murcia, Spain
| | - Luisa González-Diéguez
- Liver Unit, Division of Gastroenterology and Hepatology, Hospital Universitario Central de Asturias, 33011 Oviedo, Spain
| | - Silvia Meavilla
- Metabolic Unit, Gastroenterology, Hepatology and Nutrition Department, Sant Joan de Déu Hospital, 08950 Barcelona, Spain
| | - Ana Moreno-Álvarez
- Pediatric Gastroenterology, Hepatology and Nutrition Unit, Department of Pediatrics, A Coruña University Hospital, 15006 A Coruña, Spain
| | - José Pastor-Rosado
- Lipid Unit, Department of Pediatrics, Hospital General Universitario de Elche, Universidad Miguel Hernandez de Elche, 03202 Elche, Spain
| | - Paula Sánchez-Pintos
- Metabolic Unit, Department of Forensic Sciences, Pathology, Gynecology and Obstetrics, Pediatrics, Health Research Institute of Santiago de Compostela (IDIS), Hospital Clínico Universitario de Santiago de Compostela, CIBERER, MetabERN, 15706 Santiago de Compostela, Spain
| | - Irene Serrano-Gonzalo
- Fundación Española Para el Estudio y Terapéutica de la Enfermedad de Gaucher y Otras Lisosomales (FEETEG), 50009 Zaragoza, Spain
- GIIS-012 Group, Aragon Health Research Institute (IIS Aragón), 50009 Zaragoza, Spain
| | - Eduardo López
- Spanish LAL-D Patient Organization, 08918 Badalona, Spain
| | - Pedro Valdivielso
- Unidad de Lípidos, Hospital Universitario Virgen de la Victoria, Instituto de Investigación Biomédica de Málaga (IBIMA), Universidad de Málaga, 29010 Málaga, Spain
| | - Raquel Yahyaoui
- Clinical Laboratory, Laboratory of Inherited Metabolic Disorders, Hospital Regional Universitario de Málaga, Instituto de Investigación Biomédica de Málaga IBIMA-Plataforma BIONAND, 29590 Málaga, Spain
| | - Jesús Quintero
- Pediatric Hepatology and Liver Transplant Unit, Department of Pediatrics, ERN Rare Liver ERN TransplantChild, Vall d’Hebron Barcelona Hospital Campus, Universitat Autònoma de Barcelona, 08193 Barcelona, Spain
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Strebinger G, Müller E, Feldman A, Aigner E. Lysosomal acid lipase deficiency - early diagnosis is the key. Hepat Med 2019; 11:79-88. [PMID: 31213932 PMCID: PMC6536894 DOI: 10.2147/hmer.s201630] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2019] [Accepted: 02/22/2019] [Indexed: 01/21/2023] Open
Abstract
Lysosomal acid lipase deficiency (LAL-D) is an ultra-rare lysosomal storage disease that may present from infancy to late adulthood depending on residual enzyme activity. While the severe form manifests as a rapidly progressive disease with near universal mortality within the first 6 months of life, milder forms frequently go undiagnosed for prolonged periods and typically present with progressive fatty liver disease, enlarged spleen, atherogenic dyslipidemia and premature atherosclerosis. The adult variant of LAL-D is typically diagnosed late or even overlooked due to the unspecific nature of the presenting symptoms, which are similar to common changes observed in the context of the metabolic syndrome. This review is aimed at delineating clinically useful scenarios in which pediatric or adult medicine clinicians should be aware of LAL-D as a differential diagnosis for selected patients. This is particularly relevant as a potentially life-saving enzyme replacement therapy has become available and the diagnosis can easily be ruled out or confirmed using a dried blood spot test.
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Affiliation(s)
- Georg Strebinger
- First Department of Medicine, Paracelsus Medical University, Salzburg, Austria
| | - Elena Müller
- First Department of Medicine, Paracelsus Medical University, Salzburg, Austria
| | - Alexandra Feldman
- First Department of Medicine, Paracelsus Medical University, Salzburg, Austria
| | - Elmar Aigner
- First Department of Medicine, Paracelsus Medical University, Salzburg, Austria
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Erwin AL. The role of sebelipase alfa in the treatment of lysosomal acid lipase deficiency. Therap Adv Gastroenterol 2017; 10:553-562. [PMID: 28804516 PMCID: PMC5484437 DOI: 10.1177/1756283x17705775] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2017] [Accepted: 03/28/2017] [Indexed: 02/04/2023] Open
Abstract
Lysosomal acid lipase deficiency (LALD) is a lysosomal storage disorder (LSD) characterized either by infantile onset with fulminant clinical course and very poor prognosis or childhood/adult-onset disease with an attenuated phenotype. The disorder is often misdiagnosed or remains undiagnosed in children and adults due to a rather unspecific clinical presentation with dyslipidemia and steatohepatitis. Until recently, no good treatment options were available for LALD. Despite supportive and symptomatic therapies, death occurred before 1 year of age in patients with infantile-onset disease and patients with childhood/adult-onset LALD suffered from significant complications, such as liver cirrhosis, requiring liver transplantation and early-onset cardiovascular disease. With the recent approval of sebelipase alfa for clinical use in infantile- as well as childhood/adult-onset LALD, a new treatment era for this disorder has begun. Sebelipase alfa is a recombinant human lysosomal acid lipase (LAL), which is administered via the intravenous route. Clinical trials have shown significant improvement of disease parameters such as liver transaminases, hepatomegaly, and dyslipidemia in childhood/adult-onset LALD patients. Treatment of infants with the severe infantile-onset form of the disease has led to improved survival beyond the age of 1 year, and also showed improvement of hepatic and gastrointestinal symptoms, as well as growth. Overall, sebelipase alfa has a favorable safety profile and promises to be a good long-term treatment option for patients with LALD, with significant reduction of disease burden and increased life expectancy.
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Affiliation(s)
- Angelika L. Erwin
- Center for Personalized Genomic Healthcare, Genomic Medicine Institute, Cleveland Clinic, 9500 Euclid Ave, NE-50, Cleveland, OH 44195, USA
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Nistal M, Paniagua R, González-Peramato P, Reyes-Múgica M. Perspectives in Pediatric Pathology, Chapter 21. Testicular Pathology in Heritable Metabolic Disease. Pediatr Dev Pathol 2017; 19:371-382. [PMID: 25361068 DOI: 10.2350/14-06-1519-pb.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Inborn errors of metabolism have wide and profound effects in many or all organs, and especially so in those with endocrine functions. The testes are greatly affected by systemic metabolic disorders, leading to specific histological findings that generally reveal the nature of the underlying disorder. Here we describe the main testicular changes seen in the setting of metabolic disease.
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Affiliation(s)
- Manuel Nistal
- 1 Department of Pathology, Hospital La Paz, Universidad Autónoma de Madrid, Calle Arzobispo Morcillo No. 2, Madrid 28029, Spain
| | - Ricardo Paniagua
- 2 Department of Cell Biology, Universidad de Alcala, Madrid, Spain
| | - Pilar González-Peramato
- 1 Department of Pathology, Hospital La Paz, Universidad Autónoma de Madrid, Calle Arzobispo Morcillo No. 2, Madrid 28029, Spain
| | - Miguel Reyes-Múgica
- 3 Department of Pathology, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, One Children's Hospital Drive, 4401 Penn Avenue, Pittsburgh, PA 15224, USA
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Abstract
Lysosomal acid lipase deficiency (LAL-D) is a rare, life-threatening, autosomal recessive, lysosomal storage disease caused by mutations in the LIPA gene, which encodes for lysosomal acid lipase (LAL). This enzyme is necessary for the hydrolysis of cholesteryl ester and triglyceride in lysosomes. Deficient LAL activity causes accumulation of these lipids in lysosomes and a marked decrease in the cytoplasmic free cholesterol concentration, leading to dysfunctional cholesterol homeostasis. The accumulation of neutral lipid occurs predominantly in liver, spleen, and macrophages throughout the body, and the aberrant cholesterol homeostasis causes a marked dyslipidemia. LAL-D is characterized by accelerated atherosclerotic cardiovascular disease (ASCVD) and hepatic microvesicular or mixed steatosis, leading to inflammation, fibrosis, cirrhosis and liver failure. LAL-D presents as a clinical continuum with two phenotypes: the infantile-onset phenotype, formally referred to as Wolman disease, and the later-onset phenotype, formerly referred to as cholesteryl ester storage disease. Infants with LAL-D present within the first few weeks of life with vomiting, diarrhea, hepatosplenomegaly, failure to thrive and rapid progression to liver failure and death by 6-12 months of age. Children and young adults with LAL-D generally present with marked dyslipidemia, hepatic enzyme elevation, hepatomegaly and mixed steatosis by liver biopsy. The average age of the initial signs and symptoms of the later-onset phenotype is about 5 years old. The typical dyslipidemia is a significantly elevated low-density lipoprotein cholesterol (LDL-C) concentration and a low high-density lipoprotein cholesterol (HDL-C) concentration, placing these individuals at heightened risk for premature ASCVD. Diagnosis of the later-onset phenotype of LAL-D requires a heightened awareness of the disease because the dyslipidemia and hepatic transaminase elevation combination are common and overlap with other metabolic disorders. LAL-D should be considered in the differential diagnosis of healthy weight children and young adults with unexplained hepatic transaminase elevation accompanied by an elevated LDL-C level (>160 mg/dL) and low HDL-C level (<35 mg/dL) that is not caused by monogenic and polygenic lipid disorders or secondary factors. Treatment of LAL-D with sebelipase alfa (LAL replacement enzyme) should be considered as the standard of treatment in all individuals diagnosed with LAL-D. Other ASCVD risk factors that may be present (hypertension, tobacco use, diabetes mellitus, etc.) should be managed appropriately, consistent with secondary prevention goals.
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Affiliation(s)
- James J Maciejko
- Division of Cardiology, St. John Hospital and Medical Center, 22101 Moross Road, Detroit, MI, 48236, USA.
- Department of Internal Medicine, Wayne State University School of Medicine, 540 East Canfield, Detroit, MI, 48201, USA.
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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.
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Affiliation(s)
- Kim Su
- Division of Gastroenterology/Hepatology
| | | | - Reena Sharma
- The Mark Holland Metabolic Unit, Salford Royal Hospital NHS Foundation Trust, Salford, UK
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Reynolds T. Cholesteryl ester storage disease: a rare and possibly treatable cause of premature vascular disease and cirrhosis. J Clin Pathol 2013; 66:918-23. [PMID: 23999269 DOI: 10.1136/jclinpath-2012-201302] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Cholesteryl ester storage disease (CESD) is an autosomal recessive lysosomal storage disorder caused by a variety of mutations of the LIPA gene. These cause reduced activity of lysosomal acid lipase, which results in accumulation of cholesteryl esters in lysosomes. If enzyme activity is very low/absent, presentation is in infancy with failure to thrive, malabsorption, hepatosplenomegaly and rapid early death (Wolman disease). With higher but still low enzyme activity, presentation is later in life with hepatic fibrosis, dyslipidaemia and early atherosclerosis.Identification of this rare disorder is difficult as it is essential to assay leucocyte acid phosphatase activity. An assay using specific inhibitors has now been developed that facilitates measurement in dried blood spots. Treatment of CESD has until now been limited to management of the dyslipidaemia, but this does not influence the liver effects. A new enzyme replacement therapy (Sebelipase) has now been developed that could change treatment options for the future.
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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.
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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
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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.
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Affiliation(s)
- Sigrid W Fouchier
- Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands.
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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.
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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
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Chatrath H, Keilin S, Attar BM. Cholesterol ester storage disease (CESD) diagnosed in an asymptomatic adult. Dig Dis Sci 2009; 54:168-73. [PMID: 18478331 DOI: 10.1007/s10620-008-0310-2] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2008] [Accepted: 04/23/2008] [Indexed: 12/20/2022]
Affiliation(s)
- Hemant Chatrath
- Department of Medicine, John H. Stroger Jr. Hospital of Cook County, Rush University, 1901 W Harrison St, Chicago, IL 60612, USA.
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Muntoni S, Wiebusch H, Jansen-Rust M, Rust S, Seedorf U, Schulte H, Berger K, Funke H, Assmann G. Prevalence of cholesteryl ester storage disease. Arterioscler Thromb Vasc Biol 2007; 27:1866-8. [PMID: 17634524 DOI: 10.1161/atvbaha.107.146639] [Citation(s) in RCA: 88] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Tadiboyina VT, Liu DM, Miskie BA, Wang J, Hegele RA. Treatment of dyslipidemia with lovastatin and ezetimibe in an adolescent with cholesterol ester storage disease. Lipids Health Dis 2005; 4:26. [PMID: 16255772 PMCID: PMC1291391 DOI: 10.1186/1476-511x-4-26] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2005] [Accepted: 10/28/2005] [Indexed: 11/13/2022] Open
Abstract
Background Cholesterol ester storage disease (CESD) is an autosomal recessive illness that results from mutations in the LIPA gene encoding lysosomal acid lipase. CESD patients present in childhood with hepatomegaly and dyslipidemia characterized by elevated total and low-density lipoprotein cholesterol (LDL-C), with elevated triglycerides and depressed high-density lipoprotein cholesterol (HDL-C). Usual treatment includes a low fat diet and a statin drug. Results In an 18-year old with CESD, we documented compound heterozygosity for two LIPA mutations: a novel frameshift nonsense mutation and a deletion of exon 8. The patient had been treated with escalating doses of lovastatin for ~80 months, with ~15% decline in mean LDL-C. The addition of ezetimibe 10 mg to lovastatin 40 mg resulted in an additional ~16% decline in mean LDL-C. Conclusion These preliminary anecdotal findings in a CESD patient with novel LIPA mutations support the longer term safety of statins in an adolescent patient and provide new data about the potential efficacy and tolerability of ezetimibe in this patient group.
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Affiliation(s)
- Venu T Tadiboyina
- Department of Medicine, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, N6A 5C1, Canada
- Vascular Biology Group and Blackburn Cardiovascular Genetics, Laboratory, Robarts Research Institute, London, ON, N6A 5K8, Canada
| | - Dora M Liu
- Department of Medicine, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, N6A 5C1, Canada
| | - Brooke A Miskie
- Vascular Biology Group and Blackburn Cardiovascular Genetics, Laboratory, Robarts Research Institute, London, ON, N6A 5K8, Canada
| | - Jian Wang
- Vascular Biology Group and Blackburn Cardiovascular Genetics, Laboratory, Robarts Research Institute, London, ON, N6A 5K8, Canada
| | - Robert A Hegele
- Department of Medicine, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, N6A 5C1, Canada
- Vascular Biology Group and Blackburn Cardiovascular Genetics, Laboratory, Robarts Research Institute, London, ON, N6A 5K8, Canada
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Drebber U, Andersen M, Kasper HU, Lohse P, Stolte M, Dienes HP. Severe chronic diarrhea and weight loss in cholesteryl ester storage disease: A case report. World J Gastroenterol 2005; 11:2364-6. [PMID: 15818756 PMCID: PMC4305829 DOI: 10.3748/wjg.v11.i15.2364] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: An inherited deficiency of human lysosomal acid lipase (LAL) results in the rare conditions of Wolman disease and cholesteryl ester storage disease (CESD). We want to present the rare case of CESD in an adult.
METHODS: We report about an adult female patient with severe chronic diarrhea and weight loss as a consequence of CESD. Clinical examination revealed signs of malabsorption and slightly elevated liver enzymes.
RESULTS: Histopathologic changes in the liver tissue and DNA sequence analysis confirmed the diagnosis of CESD due to homozygosity for the most common CESD mutation, a G934A splice site defect encoded by exon 8 of the lysosomal acid lipase (LIPA) gene.
CONCLUSION: It is the first case in the literature with diarrhea as a putative symptom of CESD in adult patients.
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Affiliation(s)
- Uta Drebber
- Institute of Pathology, University of Cologne, Joseph-Stelzmann-Strasse 9, D-59031 Cologne, Germany.
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Du H, Heur M, Witte DP, Ameis D, Grabowski GA. Lysosomal acid lipase deficiency: correction of lipid storage by adenovirus-mediated gene transfer in mice. Hum Gene Ther 2002; 13:1361-72. [PMID: 12162818 DOI: 10.1089/104303402760128586] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Lysosomal acid lipase (LAL) is the essential enzyme for hydrolysis of triglycerides (TGs) and cholesteryl esters (CEs) in lysosomes. Its deficiency produces two human phenotypes: Wolman disease (WD) and cholesteryl ester storage disease (CESD). The LAL null (lal(-/-)) mouse mimicks aspects of human WD and CESD. The potential for gene therapy of LAL deficiency was tested with first-generation adenoviral vectors containing human LAL cDNA (Ad-hLAL) by intravenous injection into lal(-/-) mice. Compared with phosphate-buffered saline-injected controls, the mice receiving Ad-hLAL had increased hepatic LAL activity, decreased hepatomegaly, and normalization of histopathology. hLAL protein and mRNA were detected by immunohistochemical staining and in situ hybridization in hepatic parenchymal and sinusoid lining cells, splenic sinusoidal cells, lung macrophages, and adrenal cortical cells. Mice showed TG reductions in liver, spleen, and small intestine of 68, 54, and 50%, respectively, and cholesterol reductions of 55, 52, and 34%, respectively, at 20 days postinjection. These studies provide the basis for the use of gene therapy, in the form of gene transfer via intravenously administered adenovirus, to correct deficiency states, such as WD and CESD, and histopathology of a variety of tissues.
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Affiliation(s)
- Hong Du
- Division of Human Genetics, Cincinnati Children's Hospital Research Foundation, Cincinnati, OH 45229, USA.
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