|
1
|
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.
Collapse
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
| |
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
|
Sustar U, Groselj U, Trebusak Podkrajsek K, Mlinaric M, Kovac J, Thaler M, Drole Torkar A, Skarlovnik A, Battelino T, Hovnik T. Early Discovery of Children With Lysosomal Acid Lipase Deficiency With the Universal Familial Hypercholesterolemia Screening Program. Front Genet 2022; 13:936121. [PMID: 35903350 PMCID: PMC9314654 DOI: 10.3389/fgene.2022.936121] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Accepted: 05/31/2022] [Indexed: 01/28/2023] Open
Abstract
Lysosomal acid lipase deficiency (LAL-D) is an autosomal recessive lysosomal storage disorder, caused by homozygous or compound heterozygous pathogenic variants in the LIPA gene. Clinically, LAL-D is under- and misdiagnosed, due to similar clinical and laboratory findings with other cholesterol or liver misfunctions. As a part of the Slovenian universal familial hypercholesterolemia (FH) screening, LAL-D is screened as a secondary condition among other rare dyslipidemias manifesting with hypercholesterolemia. Out of 669 children included, three were positive for a homozygous disease-causing splicing variant NM_000235.4: c.894G > A (NP_000226.2:p. Gln298Gln) in the LIPA gene (NG_008194.1). The mean age by the diagnosis of LAL-D was 9.8 ± 0.9 years. Moreover, all three LAL-D-positive children had an important elevation of transaminases and decreased activity of the lysosomal acid lipase enzyme. Abdominal MRI in all children detected an enlarged liver but a normal-sized spleen. In conclusion, universal FH screening algorithms with the confirmatory genetic analysis in the pediatric population enable also rare dyslipidemia detection at an early age. An important clinical criterion for differentiation between FH and the LAL-D-positive children has elevated transaminase levels (AST and ALT). In all three LAL-D positive children, an improvement in cholesterol and transaminase levels and steatosis of the liver has been seen after early treatment initiation.
Collapse
Affiliation(s)
- Ursa Sustar
- Department of Endocrinology, Diabetes and Metabolic Diseases, University Children’s Hospital, University Medical Centre Ljubljana, Ljubljana, Slovenia
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Urh Groselj
- Department of Endocrinology, Diabetes and Metabolic Diseases, University Children’s Hospital, University Medical Centre Ljubljana, Ljubljana, Slovenia
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
- Department of Medicine, Division of Cardiovascular Medicine, Stanford University, Stanford, CA, United States
- *Correspondence: Urh Groselj, ; Tinka Hovnik,
| | - Katarina Trebusak Podkrajsek
- Clinical Institute of Special Laboratory Diagnostics, University Children’s Hospital, University Medical Centre Ljubljana, Ljubljana, Slovenia
- Faculty of Medicine, Institute of Biochemistry and Molecular Genetics, University of Ljubljana, Ljubljana, Slovenia
| | - Matej Mlinaric
- Department of Endocrinology, Diabetes and Metabolic Diseases, University Children’s Hospital, University Medical Centre Ljubljana, Ljubljana, Slovenia
| | - Jernej Kovac
- Clinical Institute of Special Laboratory Diagnostics, University Children’s Hospital, University Medical Centre Ljubljana, Ljubljana, Slovenia
| | - Martin Thaler
- Department of Radiology, University Children’s Hospital Ljubljana, Ljubljana, Slovenia
| | - Ana Drole Torkar
- Department of Endocrinology, Diabetes and Metabolic Diseases, University Children’s Hospital, University Medical Centre Ljubljana, Ljubljana, Slovenia
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Ajda Skarlovnik
- Department of Vascular Diseases, University Medical Centre Ljubljana, Ljubljana, Slovenia
| | - Tadej Battelino
- Department of Endocrinology, Diabetes and Metabolic Diseases, University Children’s Hospital, University Medical Centre Ljubljana, Ljubljana, Slovenia
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Tinka Hovnik
- Clinical Institute of Special Laboratory Diagnostics, University Children’s Hospital, University Medical Centre Ljubljana, Ljubljana, Slovenia
- Faculty of Medicine, Institute of Biochemistry and Molecular Genetics, University of Ljubljana, Ljubljana, Slovenia
- *Correspondence: Urh Groselj, ; Tinka Hovnik,
| |
Collapse
|
|
4
|
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
|
|
5
|
Diagnosis and management of secondary causes of steatohepatitis. J Hepatol 2021; 74:1455-1471. [PMID: 33577920 DOI: 10.1016/j.jhep.2021.01.045] [Citation(s) in RCA: 63] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Revised: 01/09/2021] [Accepted: 01/25/2021] [Indexed: 02/06/2023]
Abstract
The term non-alcoholic fatty liver disease (NAFLD) was originally coined to describe hepatic fat deposition as part of the metabolic syndrome. However, a variety of rare hereditary liver and metabolic diseases, intestinal diseases, endocrine disorders and drugs may underlie, mimic, or aggravate NAFLD. In contrast to primary NAFLD, therapeutic interventions are available for many secondary causes of NAFLD. Accordingly, secondary causes of fatty liver disease should be considered during the diagnostic workup of patients with fatty liver disease, and treatment of the underlying disease should be started to halt disease progression. Common genetic variants in several genes involved in lipid handling and metabolism modulate the risk of progression from steatosis to fibrosis, cirrhosis and hepatocellular carcinoma development in NAFLD, alcohol-related liver disease and viral hepatitis. Hence, we speculate that genotyping of common risk variants for liver disease progression may be equally useful to gauge the likelihood of developing advanced liver disease in patients with secondary fatty liver disease.
Collapse
|
|
6
|
Genes Potentially Associated with Familial Hypercholesterolemia. Biomolecules 2019; 9:biom9120807. [PMID: 31795497 PMCID: PMC6995538 DOI: 10.3390/biom9120807] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [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
|
|
7
|
Bychkov IO, Kamenets EA, Filatova AY, Skoblov MY, Mikhaylova SV, Strokova TV, Gundobina OS, Zakharova EY. The novel synonymous variant in LIPA gene affects splicing and causes lysosomal acid lipase deficiency. Mol Genet Metab 2019; 127:212-215. [PMID: 31230978 DOI: 10.1016/j.ymgme.2019.06.005] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2019] [Revised: 04/26/2019] [Accepted: 06/15/2019] [Indexed: 01/24/2023]
Abstract
Lysosomal acid lipase deficiency (LALD; MIM#278000) is a continuum of autosomal recessive diseases caused by defects in the gene LIPA and historically divided into two phenotypes: severe infantile-onset form called Wolman disease (WD) and childhood/adult-onset form known as cholesteryl ester storage disease (CESD). We report a novel synonymous homozygous variant c.600G > A in LIPA of a patient with LALD. Functional analysis of the patient cDNA and minigene assay revealed this variant as the cause of exonic cryptic splice site activation and 63 b.p. deletion in exon 6. To investigate the impact of this in-frame deletion on protein function, we performed 3D modeling of the human lysosomal acid lipase and showed the alteration of highly conservative region in close proximity to protein active site, which may completely eliminate the enzymatic activity. Using transcript specific real-time quantitative PCR method, we evaluated the relative ratio of the patient's wild type transcript isoform which is significantly reduced and correlates with severe childhood-onset variant of LALD.
Collapse
Affiliation(s)
- I O Bychkov
- Federal State Budgetary Institution «Research Centre for Medical Genetics», Moscow, Russia.
| | - E A Kamenets
- Federal State Budgetary Institution «Research Centre for Medical Genetics», Moscow, Russia
| | - A Yu Filatova
- Federal State Budgetary Institution «Research Centre for Medical Genetics», Moscow, Russia
| | - M Yu Skoblov
- Federal State Budgetary Institution «Research Centre for Medical Genetics», Moscow, Russia
| | - S V Mikhaylova
- Federal State Budgetary Institution Children's Clinical Hospital of the Russian Federation Ministry of Health, Moscow, Russia
| | - T V Strokova
- Federal State Budgetary Institution «Federal Research Center for Nutrition and Biotechnology», Moscow, Russia; Federal State Budgetary Institution «Pirogov Russian National Research Medical University», Moscow, Russia
| | - O S Gundobina
- Federal State Autonomous Institution «National Medical Research Center for Children's Health» of the Russian Federation Ministry of Health, Moscow, Russia
| | - E Yu Zakharova
- Federal State Budgetary Institution «Research Centre for Medical Genetics», Moscow, Russia
| |
Collapse
|
|
8
|
Sánchez-Hernández RM, Tugores A, Nóvoa FJ, Brito-Casillas Y, Expósito-Montesdeoca AB, Garay P, Bea AM, Riaño M, Pocovi M, Civeira F, Wägner AM, Boronat M. The island of Gran Canaria: A genetic isolate for familial hypercholesterolemia. J Clin Lipidol 2019; 13:618-626. [PMID: 31153816 DOI: 10.1016/j.jacl.2019.04.099] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2018] [Revised: 04/24/2019] [Accepted: 04/30/2019] [Indexed: 11/16/2022]
Abstract
BACKGROUND Genetic diagnosis of familial hypercholesterolemia (FH) has not been universally performed in the Canary Islands (Spain). OBJECTIVES This study aimed to genetically characterize a cohort of patients with FH in the island of Gran Canaria. METHODS Study subjects were 70 unrelated index cases attending a tertiary hospital in Gran Canaria, with a clinical diagnosis of FH, according to the criteria of the Dutch Lipid Clinic Network. Given that 7 of the first 10 cases with positive genetic study were carriers of a single mutation in the LDLR gene [p.(Tyr400_Phe402del)], a specific polymerase chain reaction-based assay was developed for the detection of this variant as a first screening step on the remaining subjects. In those without this mutation, molecular diagnosis was completed using a next-generation sequencing panel including LDLR, APOB, PCSK9, LDLRAP1, APOE, STAP1, and LIPA genes and incorporating copy number variation detection in LDLR. RESULTS On the whole, 44 subjects (62%) had a positive genetic study, of whom 30 (68%) were heterozygous carriers of the p.(Tyr400_Phe402del) variant. Eleven subjects carried other mutations in LDLR, including the novel mutation NM_000527.4: c.877dupG; NP_000518.1: p.(Asp293Glyfs*8). An unclassified PCSK9 gene variant was found in one subject [(NM_174936.3:c.1496G>A; NP_777596.2: p.(Arg499His)]. Other single patients had mutations in APOB (heterozygous) and in LIPA (homozygous). All identified variants co-segregated with the disease phenotype. CONCLUSIONS These findings suggest a founder effect for the p.(Tyr400_Phe402del) LDLR mutation in Gran Canaria. A cost-effective local screening strategy for genetic diagnosis of FH could be implemented in this region.
Collapse
Affiliation(s)
- Rosa M Sánchez-Hernández
- Sección de Endocrinología y Nutrición, Complejo Hospitalario Universitario Insular Materno-Infantil de Gran Canaria, Las Palmas de Gran Canaria, Spain; Instituto Universitario de Investigaciones Biomédicas y Sanitarias (IUIBS), Universidad de Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain
| | - Antonio Tugores
- Instituto Universitario de Investigaciones Biomédicas y Sanitarias (IUIBS), Universidad de Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain; Unidad de Investigación, Complejo Hospitalario Universitario Insular Materno-Infantil de Gran Canaria, Las Palmas de Gran Canaria, Spain
| | - Francisco J Nóvoa
- Sección de Endocrinología y Nutrición, Complejo Hospitalario Universitario Insular Materno-Infantil de Gran Canaria, Las Palmas de Gran Canaria, Spain; Instituto Universitario de Investigaciones Biomédicas y Sanitarias (IUIBS), Universidad de Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain
| | - Yeray Brito-Casillas
- Instituto Universitario de Investigaciones Biomédicas y Sanitarias (IUIBS), Universidad de Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain
| | - Ana B Expósito-Montesdeoca
- Instituto Universitario de Investigaciones Biomédicas y Sanitarias (IUIBS), Universidad de Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain
| | - Paloma Garay
- Instituto Universitario de Investigaciones Biomédicas y Sanitarias (IUIBS), Universidad de Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain; Unidad de Investigación, Complejo Hospitalario Universitario Insular Materno-Infantil de Gran Canaria, Las Palmas de Gran Canaria, Spain
| | - Ana M Bea
- Hospital Universitario Miguel Servet, IIS Aragón, CIBERCV, Universidad de Zaragoza, Zaragoza, Spain
| | - Marta Riaño
- Servicio de Bioquímica, Complejo Hospitalario Universitario Insular Materno-Infantil de Gran Canaria, Las Palmas de Gran Canaria, Spain
| | - Miguel Pocovi
- Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Ciencias, Universidad de Zaragoza & IIS Aragón, Zaragoza, Spain
| | - Fernando Civeira
- Hospital Universitario Miguel Servet, IIS Aragón, CIBERCV, Universidad de Zaragoza, Zaragoza, Spain
| | - Ana M Wägner
- Sección de Endocrinología y Nutrición, Complejo Hospitalario Universitario Insular Materno-Infantil de Gran Canaria, Las Palmas de Gran Canaria, Spain; Instituto Universitario de Investigaciones Biomédicas y Sanitarias (IUIBS), Universidad de Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain.
| | - Mauro Boronat
- Sección de Endocrinología y Nutrición, Complejo Hospitalario Universitario Insular Materno-Infantil de Gran Canaria, Las Palmas de Gran Canaria, Spain; Instituto Universitario de Investigaciones Biomédicas y Sanitarias (IUIBS), Universidad de Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain.
| |
Collapse
|
|
9
|
Cappuccio G, Donti TR, Hubert L, Sun Q, Elsea SH. Opening a window on lysosomal acid lipase deficiency: Biochemical, molecular, and epidemiological insights. J Inherit Metab Dis 2019; 42:509-518. [PMID: 30684275 PMCID: PMC8564860 DOI: 10.1002/jimd.12057] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2018] [Accepted: 12/11/2018] [Indexed: 11/08/2022]
Abstract
Lysosomal acid lipase deficiency (LAL-D) is a multi-organ autosomal recessive disease caused by mutations in LIPA. We reviewed data from 681 samples (white blood cells [WBC] n = 625, fibroblasts = 30, liver = 4, amniocytes = 13, chorionic villus = 9) received for analysis of lysosomal acid lipase (LAL) activity over a 15-year period. LIPA sequencing was performed in 49 patients with reduced (n = 26) or deficient (n = 23) LAL activity. The Exome Aggregation Consortium and Genome Aggregation Database dataset were used for LAL-D prevalence calculations. LAL WBC activity was reduced in 67 patients (10.72%) and deficient in 37 (5.92%). The average of LAL activity ± margin of error (CI 95%) was 19.32 ± 0.86 pmol/min/mg for reduced activity patients and 5.90 ± 1.42 pmol/min/mg for deficient patients. The average age at diagnosis for LAL-D was 23.6 years with several patients older than age 30. The correlation between the age at diagnosis and LAL activity showed a significant moderate direct correlation (Pearson's r = 0.46, P < 0.005). Homozygous or compound heterozygous mutations were identified in 9 out of 23 patients with deficient results (detection rate 39.1%). The average LAL activity in molecularly confirmed patients was 4.02 ± 2.02 pmol/min/mg protein, while in molecularly negative patients was 13.886 ± 1.49 pmol/min/mg (P < 0.0001). Twenty-two different mutations were identified including two novel variants (c.309C>A and c.856G>C). A carrier frequency of approximately 1 in 350 was inferred. LAL activity in WBC is a validated tool for LAL-D diagnosis. Higher residual enzymatic activity might result in a milder phenotype leading to diagnosis delay. A cut-off below 12 pmol/min/mg protein might be useful to discriminate patients with LIPA mutations.
Collapse
Affiliation(s)
- Gerarda Cappuccio
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas
- Department of Translational Medical Sciences, Section of Pediatrics, Federico II University, Naples, Italy
| | - Taraka R. Donti
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas
| | - Leroy Hubert
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas
| | - Qin Sun
- Department of Translational Medical Sciences, Section of Pediatrics, Federico II University, Naples, Italy
| | - Sarah H. Elsea
- Department of Translational Medical Sciences, Section of Pediatrics, Federico II University, Naples, Italy
| |
Collapse
|
|
10
|
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
|
|
11
|
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
|
|
12
|
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]
|
|
13
|
Korber M, Klein I, Daum G. Steryl ester synthesis, storage and hydrolysis: A contribution to sterol homeostasis. Biochim Biophys Acta Mol Cell Biol Lipids 2017; 1862:1534-1545. [DOI: 10.1016/j.bbalip.2017.09.002] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2017] [Revised: 08/25/2017] [Accepted: 09/05/2017] [Indexed: 02/01/2023]
|
|
14
|
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
|
|
15
|
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.
Collapse
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.
| |
Collapse
|
|
16
|
Maciejko JJ, Anne P, Raza S, Lyons HJ. Lysosomal acid lipase deficiency in all siblings of the same parents. J Clin Lipidol 2017; 11:567-574. [PMID: 28502515 DOI: 10.1016/j.jacl.2017.02.006] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2016] [Revised: 02/02/2017] [Accepted: 02/13/2017] [Indexed: 02/06/2023]
Abstract
We present 4 normal-weight sibling children with lysosomal acid lipase deficiency (LAL-D). LAL-D was considered in the differential diagnosis based on the absence of secondary causes and primary inherited traits for their marked hyperlipidemia, together with unexplained hepatic transaminase elevation. Residual lysosomal acid lipase activity confirmed the diagnosis. DNA sequencing of LIPA indicated that the siblings were compound heterozygotes (c.894G>A and c.428+1G>A). This case describes the unusual occurrence of all offspring from the same nonconsanguineous mother and father inheriting compound heterozygosity of a recessive trait and the identification of an apparently unique LIPA mutation (c.428+1G>A). It highlights the collaborative effort between a lipidologist and gastroenterologist in developing a differential diagnosis leading to the confirmatory diagnosis of this rare, life-threatening disease. With the availability of an effective enzyme replacement therapy (sebelipase alfa), LAL-D should be entertained in the differential diagnosis of children, adolescents, and young adults with idiopathic hyperlipidemia and unexplained hepatic transaminase elevation.
Collapse
Affiliation(s)
- James J Maciejko
- Division of Cardiology, Department of Internal Medicine, St. John Hospital and Medical Center, and Wayne State University School of Medicine, Department of Internal Medicine, Detroit, MI, USA.
| | - Premchand Anne
- Department of Pediatrics, St. John Providence Children's Hospital, and Wayne State University School of Medicine, Department of Pediatrics, Detroit, MI, USA
| | - Saleem Raza
- Department of Pediatrics, St. John Providence Children's Hospital, and Wayne State University School of Medicine, Department of Pediatrics, Detroit, MI, USA
| | - Hernando J Lyons
- Department of Pediatrics, St. John Providence Children's Hospital, and Wayne State University School of Medicine, Department of Pediatrics, Detroit, MI, USA
| |
Collapse
|
|
17
|
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: 33] [Impact Index Per Article: 4.1] [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
|
|
18
|
Ruiz-Andrés C, Sellés E, Arias A, Gort L. Lysosomal Acid Lipase Deficiency in 23 Spanish Patients: High Frequency of the Novel c.966+2T>G Mutation in Wolman Disease. JIMD Rep 2017; 37:7-12. [PMID: 28220406 DOI: 10.1007/8904_2017_6] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2016] [Revised: 01/11/2017] [Accepted: 01/16/2017] [Indexed: 12/24/2022] Open
Abstract
Lysosomal acid lipase (LAL) is a lysosomal key enzyme involved in the intracellular hydrolysis of cholesteryl esters and triglycerides. Patients with very low residual LAL activity present with the infantile severe form Wolman disease (WD), while patients with some residual activity develop the less severe disorder known as Cholesteryl ester storage disorder (CESD). We present the clinical, biochemical, and molecular findings of 23 Spanish patients (22 families) with LAL deficiency. We identified eight different mutations, four of them not previously reported. The novel c.966+2T>G mutation accounted for 75% of the Wolman disease alleles, and the frequent CESD associated c.894G>A mutation accounted for 55% of the CESD alleles in our cohort. Haplotype analysis showed that both mutations co-segregated with a unique haplotype suggesting a common ancestor. Our study contributes to the LAL deficiency acknowledgement with novel mutations and with high frequencies of some unknown mutations for WD.
Collapse
Affiliation(s)
- Carla Ruiz-Andrés
- Errors Congènits del Metabolisme-IBC, Serv. Bioquímica i Genètica Molecular, CDB, Hospital Clínic, C/Mejía Lequerica, s/n, Edifici Helios III, Barcelona, 08028, Spain
| | - Elena Sellés
- Errors Congènits del Metabolisme-IBC, Serv. Bioquímica i Genètica Molecular, CDB, Hospital Clínic, C/Mejía Lequerica, s/n, Edifici Helios III, Barcelona, 08028, Spain
| | - Angela Arias
- Errors Congènits del Metabolisme-IBC, Serv. Bioquímica i Genètica Molecular, CDB, Hospital Clínic, C/Mejía Lequerica, s/n, Edifici Helios III, Barcelona, 08028, Spain.,CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras and IDIBAPS, Barcelona, Spain
| | - Laura Gort
- Errors Congènits del Metabolisme-IBC, Serv. Bioquímica i Genètica Molecular, CDB, Hospital Clínic, C/Mejía Lequerica, s/n, Edifici Helios III, Barcelona, 08028, Spain. .,CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras and IDIBAPS, Barcelona, Spain.
| | | |
Collapse
|
|
19
|
Racimo F, Marnetto D, Huerta-Sánchez E. Signatures of Archaic Adaptive Introgression in Present-Day Human Populations. Mol Biol Evol 2017; 34:296-317. [PMID: 27756828 PMCID: PMC5400396 DOI: 10.1093/molbev/msw216] [Citation(s) in RCA: 79] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
Comparisons of DNA from archaic and modern humans show that these groups interbred, and in some cases received an evolutionary advantage from doing so. This process-adaptive introgression-may lead to a faster rate of adaptation than is predicted from models with mutation and selection alone. Within the last couple of years, a series of studies have identified regions of the genome that are likely examples of adaptive introgression. In many cases, once a region was ascertained as being introgressed, commonly used statistics based on both haplotype as well as allele frequency information were employed to test for positive selection. Introgression by itself, however, changes both the haplotype structure and the distribution of allele frequencies, thus confounding traditional tests for detecting positive selection. Therefore, patterns generated by introgression alone may lead to false inferences of positive selection. Here we explore models involving both introgression and positive selection to investigate the behavior of various statistics under adaptive introgression. In particular, we find that the number and allelic frequencies of sites that are uniquely shared between archaic humans and specific present-day populations are particularly useful for detecting adaptive introgression. We then examine the 1000 Genomes dataset to characterize the landscape of uniquely shared archaic alleles in human populations. Finally, we identify regions that were likely subject to adaptive introgression and discuss some of the most promising candidate genes located in these regions.
Collapse
Affiliation(s)
- Fernando Racimo
- Department of Integrative Biology, University of California Berkeley, Berkeley, CA
| | - Davide Marnetto
- Department of Molecular Biotechnology and Health Sciences, University of Torino, Turin, Italy
| | | |
Collapse
|
|
20
|
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
|
|
21
|
Miller WL. Disorders in the initial steps of steroid hormone synthesis. J Steroid Biochem Mol Biol 2017; 165:18-37. [PMID: 26960203 DOI: 10.1016/j.jsbmb.2016.03.009] [Citation(s) in RCA: 133] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2015] [Revised: 03/01/2016] [Accepted: 03/03/2016] [Indexed: 12/29/2022]
Abstract
Steroidogenesis begins with cellular internalization of low-density lipoprotein particles and subsequent intracellular processing of cholesterol. Disorders in these steps include Adrenoleukodystrophy, Wolman Disease and its milder variant Cholesterol Ester Storage Disease, and Niemann-Pick Type C Disease, all of which may present with adrenal insufficiency. The means by which cholesterol is directed to steroidogenic mitochondria remains incompletely understood. Once cholesterol reaches the outer mitochondrial membrane, its delivery to the inner mitochondrial membrane is regulated by the steroidogenic acute regulatory protein (StAR). Severe StAR mutations cause classic congenital lipoid adrenal hyperplasia, characterized by lipid accumulation in the adrenal, adrenal insufficiency, and disordered sexual development in 46,XY individuals. The lipoid CAH phenotype, including spontaneous puberty in 46,XX females, is explained by a two-hit model. StAR mutations that retain partial function cause a milder, non-classic disease characterized by glucocorticoid deficiency, with lesser disorders of mineralocorticoid and sex steroid synthesis. Once inside the mitochondria, cholesterol is converted to pregnenolone by the cholesterol side-chain cleavage enzyme, P450scc, encoded by the CYP11A1 gene. Rare patients with mutations of P450scc are clinically and hormonally indistinguishable from those with lipoid CAH, and may also present as milder non-classic disease. Patients with P450scc defects do not have the massive adrenal hyperplasia that characterizes lipoid CAH, but adrenal imaging may occasionally fail to distinguish these, necessitating DNA sequencing.
Collapse
Affiliation(s)
- Walter L Miller
- Center for Reproductive Sciences, University of California, San Francisco, CA 94143-0556, United States.
| |
Collapse
|
|
22
|
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
|
|
23
|
Vega AI, Medrano C, Navarrete R, Desviat LR, Merinero B, Rodríguez-Pombo P, Vitoria I, Ugarte M, Pérez-Cerdá C, Pérez B. Molecular diagnosis of glycogen storage disease and disorders with overlapping clinical symptoms by massive parallel sequencing. Genet Med 2016; 18:1037-43. [PMID: 26913919 DOI: 10.1038/gim.2015.217] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2015] [Accepted: 12/17/2015] [Indexed: 12/30/2022] Open
Abstract
PURPOSE Glycogen storage disease (GSD) is an umbrella term for a group of genetic disorders that involve the abnormal metabolism of glycogen; to date, 23 types of GSD have been identified. The nonspecific clinical presentation of GSD and the lack of specific biomarkers mean that Sanger sequencing is now widely relied on for making a diagnosis. However, this gene-by-gene sequencing technique is both laborious and costly, which is a consequence of the number of genes to be sequenced and the large size of some genes. METHODS This work reports the use of massive parallel sequencing to diagnose patients at our laboratory in Spain using either a customized gene panel (targeted exome sequencing) or the Illumina Clinical-Exome TruSight One Gene Panel (clinical exome sequencing (CES)). Sequence variants were matched against biochemical and clinical hallmarks. RESULTS Pathogenic mutations were detected in 23 patients. Twenty-two mutations were recognized (mostly loss-of-function mutations), including 11 that were novel in GSD-associated genes. In addition, CES detected five patients with mutations in ALDOB, LIPA, NKX2-5, CPT2, or ANO5. Although these genes are not involved in GSD, they are associated with overlapping phenotypic characteristics such as hepatic, muscular, and cardiac dysfunction. CONCLUSIONS These results show that next-generation sequencing, in combination with the detection of biochemical and clinical hallmarks, provides an accurate, high-throughput means of making genetic diagnoses of GSD and related diseases.Genet Med 18 10, 1037-1043.
Collapse
Affiliation(s)
- Ana I Vega
- Centro de Diagnóstico de Enfermedades Moleculares, Centro de Biología Molecular-SO UAM-CSIC, Universidad Autónoma de Madrid, Campus de Cantoblanco, Madrid, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.,Instituto de Investigación La Paz (IdiPAZ), Madrid, Spain
| | - Celia Medrano
- Centro de Diagnóstico de Enfermedades Moleculares, Centro de Biología Molecular-SO UAM-CSIC, Universidad Autónoma de Madrid, Campus de Cantoblanco, Madrid, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.,Instituto de Investigación La Paz (IdiPAZ), Madrid, Spain
| | - Rosa Navarrete
- Centro de Diagnóstico de Enfermedades Moleculares, Centro de Biología Molecular-SO UAM-CSIC, Universidad Autónoma de Madrid, Campus de Cantoblanco, Madrid, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.,Instituto de Investigación La Paz (IdiPAZ), Madrid, Spain
| | - Lourdes R Desviat
- Centro de Diagnóstico de Enfermedades Moleculares, Centro de Biología Molecular-SO UAM-CSIC, Universidad Autónoma de Madrid, Campus de Cantoblanco, Madrid, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.,Instituto de Investigación La Paz (IdiPAZ), Madrid, Spain
| | - Begoña Merinero
- Centro de Diagnóstico de Enfermedades Moleculares, Centro de Biología Molecular-SO UAM-CSIC, Universidad Autónoma de Madrid, Campus de Cantoblanco, Madrid, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.,Instituto de Investigación La Paz (IdiPAZ), Madrid, Spain
| | - Pilar Rodríguez-Pombo
- Centro de Diagnóstico de Enfermedades Moleculares, Centro de Biología Molecular-SO UAM-CSIC, Universidad Autónoma de Madrid, Campus de Cantoblanco, Madrid, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.,Instituto de Investigación La Paz (IdiPAZ), Madrid, Spain
| | - Isidro Vitoria
- Unidad de Nutrición y Metabolopatías, Hospital La Fe, Valencia, Spain
| | - Magdalena Ugarte
- Centro de Diagnóstico de Enfermedades Moleculares, Centro de Biología Molecular-SO UAM-CSIC, Universidad Autónoma de Madrid, Campus de Cantoblanco, Madrid, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.,Instituto de Investigación La Paz (IdiPAZ), Madrid, Spain
| | - Celia Pérez-Cerdá
- Centro de Diagnóstico de Enfermedades Moleculares, Centro de Biología Molecular-SO UAM-CSIC, Universidad Autónoma de Madrid, Campus de Cantoblanco, Madrid, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.,Instituto de Investigación La Paz (IdiPAZ), Madrid, Spain
| | - Belen Pérez
- Centro de Diagnóstico de Enfermedades Moleculares, Centro de Biología Molecular-SO UAM-CSIC, Universidad Autónoma de Madrid, Campus de Cantoblanco, Madrid, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.,Instituto de Investigación La Paz (IdiPAZ), Madrid, Spain
| |
Collapse
|
|
24
|
Pullinger CR, Stock EO, Movsesyan I, Malloy MJ, Frost PH, Tripuraneni R, Quinn AG, Ishida BY, Schaefer EJ, Asztalos BF, Kane JP. Identification and metabolic profiling of patients with lysosomal acid lipase deficiency. J Clin Lipidol 2015; 9:716-26.e1. [PMID: 26350820 DOI: 10.1016/j.jacl.2015.07.008] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2015] [Revised: 06/29/2015] [Accepted: 07/18/2015] [Indexed: 11/21/2022]
Abstract
BACKGROUND Lysosomal acid lipase (LAL), encoded by the LIPA gene, catalyzes the intracellular hydrolysis of cholesteryl esters and triglycerides in hepatocytes and macrophages. LIPA defects cause accumulation of these lipids in lysosomes. LAL deficiency (LAL D) presents and progresses as a continuum with dyslipidemia, hepatomegaly, and liver fibrosis. OBJECTIVE To improve the understanding of the genetic basis of LAL D, an underappreciated cause of dyslipidemia and cirrhosis, we studied DNA samples from patients with various phenotypes of dyslipidemia. METHODS Participants (N = 1357) were identified by lipid profiles and screened for the common disease causing LIPA exon 8 skipping splice-site mutation (c.894G>A; p.Ser275_Gln298del; rs116928232). RESULTS Six patients were heterozygous for this variant. Complete LIPA sequencing revealed a patient, subsequently confirmed to have LAL D, with a heterozygous frameshift mutation involving deletion of exon 4 (p.Gly77Valfs*17 c.230-106_c.428+541del). A family study revealed a sister with the same genotype and phenotype. Genetic, clinical, and lipoprotein profiles of these sisters plus 6 additional family members are reported. Profiles of 2 other LAL D patients monitored for 2 decades are presented. Cholesterol homeostasis was studied to investigate rates of cholesterol synthesis and absorption in 4 LAL D patients. High-density lipoprotein (HDL) subspecies were also analyzed. CONCLUSIONS We used this LIPA sequencing strategy (detection of the relatively common exon 8 variant followed by complete gene sequencing to identify additional mutations) as a means to further elucidate the genetic basis of LAL D among individuals with a suggestive clinical phenotype.
Collapse
Affiliation(s)
- Clive R Pullinger
- Cardiovascular Research Institute, University of California, San Francisco, CA, USA; Department of Physiological Nursing, University of California, San Francisco, CA, USA.
| | - Eveline Oestreicher Stock
- Cardiovascular Research Institute, University of California, San Francisco, CA, USA; Department of Medicine, University of California, San Francisco, CA, USA
| | - Irina Movsesyan
- Cardiovascular Research Institute, University of California, San Francisco, CA, USA
| | - Mary J Malloy
- Cardiovascular Research Institute, University of California, San Francisco, CA, USA; Department of Medicine, University of California, San Francisco, CA, USA
| | - Philip H Frost
- Cardiovascular Research Institute, University of California, San Francisco, CA, USA; Department of Medicine, University of California, San Francisco, CA, USA
| | | | | | | | | | | | - John P Kane
- Cardiovascular Research Institute, University of California, San Francisco, CA, USA; Department of Medicine, University of California, San Francisco, CA, USA; Department of Biochemistry and Biophysics
| |
Collapse
|
|
25
|
Novel mutation in a patient with cholesterol ester storage disease. Case Rep Genet 2015; 2015:347342. [PMID: 25722898 PMCID: PMC4334435 DOI: 10.1155/2015/347342] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2014] [Accepted: 01/27/2015] [Indexed: 11/23/2022] Open
Abstract
Cholesterol ester storage disease (CESD) is a chronic liver disease that typically presents with hepatomegaly. It is characterized by hypercholesterolemia, hypertriglyceridemia, high-density lipoprotein deficiency, and abnormal lipid deposition within multiple organs. It is an autosomal recessive disease that is due to a deficiency in lysosomal acid lipase (LAL) activity, which is coded by the lysosomal acid lipase gene (LIPA). We describe the case of a 5-year-old south Asian female incidentally found to have hepatomegaly, and subsequent workup confirmed the diagnosis of CESD. DNA sequencing confirmed the presence of a novel hepatic mutation. It is a four-nucleotide deletion c.57_60delTGAG in exon 2 of the LIPA gene. This mutation is predicted to result in a premature translation stop downstream of the deletion (p.E20fs) and, therefore, is felt to be a disease-causing mutation.
Collapse
|
|
26
|
Scorza M, Elce A, Zarrilli F, Liguori R, Amato F, Castaldo G. Genetic diseases that predispose to early liver cirrhosis. Int J Hepatol 2014; 2014:713754. [PMID: 25132997 PMCID: PMC4123515 DOI: 10.1155/2014/713754] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2014] [Accepted: 06/30/2014] [Indexed: 12/11/2022] Open
Abstract
Inherited liver diseases are a group of metabolic and genetic defects that typically cause early chronic liver involvement. Most are due to a defect of an enzyme/transport protein that alters a metabolic pathway and exerts a pathogenic role mainly in the liver. The prevalence is variable, but most are rare pathologies. We review the pathophysiology of such diseases and the diagnostic contribution of laboratory tests, focusing on the role of molecular genetics. In fact, thanks to recent advances in genetics, molecular analysis permits early and specific diagnosis for most disorders and helps to reduce the invasive approach of liver biopsy.
Collapse
Affiliation(s)
- Manuela Scorza
- CEINGE—Biotecnologie Avanzate Scarl, Via Gaetano Salvatore 486, 80145 Napoli, Italy
- Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli Federico II, Via Sergio Pansini 5, 80131 Napoli, Italy
| | - Ausilia Elce
- CEINGE—Biotecnologie Avanzate Scarl, Via Gaetano Salvatore 486, 80145 Napoli, Italy
- Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli Federico II, Via Sergio Pansini 5, 80131 Napoli, Italy
- Università Telematica Pegaso, Piazza Trieste e Trento 48, 80132 Napoli, Italy
| | - Federica Zarrilli
- CEINGE—Biotecnologie Avanzate Scarl, Via Gaetano Salvatore 486, 80145 Napoli, Italy
- Dipartimento di Bioscienze e Territorio, Università del Molise, Contrada Fonte Lappone, Pesche, 86090 Isernia, Italy
| | - Renato Liguori
- CEINGE—Biotecnologie Avanzate Scarl, Via Gaetano Salvatore 486, 80145 Napoli, Italy
- Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli Federico II, Via Sergio Pansini 5, 80131 Napoli, Italy
| | - Felice Amato
- CEINGE—Biotecnologie Avanzate Scarl, Via Gaetano Salvatore 486, 80145 Napoli, Italy
- Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli Federico II, Via Sergio Pansini 5, 80131 Napoli, Italy
| | - Giuseppe Castaldo
- CEINGE—Biotecnologie Avanzate Scarl, Via Gaetano Salvatore 486, 80145 Napoli, Italy
- Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli Federico II, Via Sergio Pansini 5, 80131 Napoli, Italy
| |
Collapse
|
|
27
|
Kojima S, Watanabe N, Takashimizu S, Kagawa T, Shiraishi K, Koizumi J, Hirabayashi KI, Ohkubo T, Kamiguchi H, Tsuda M, Mine T. Senescent case of cholesterol ester storage disease that progressed to liver cirrhosis with a novel mutation (N250H) of lysosomal acid lipase gene. Hepatol Res 2013; 43:1361-1367. [PMID: 23675960 DOI: 10.1111/hepr.12087] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2012] [Revised: 01/16/2013] [Accepted: 01/31/2013] [Indexed: 12/24/2022]
Abstract
The patient, a 69-year-old man, had a chief complaint of hepatomegaly. The liver was palpated four fingerbreadths below the costal margin, and the spleen was three fingerbreadths below the costal margin. There were no other abnormal findings. Laparoscopy showed that the liver resembled an orange-yellow crayon in appearance and was nodular. The pathological findings of the liver biopsy tissue were consistent with liver cirrhosis. Inside the fibrous septum was an apparent aggregation of enlarged macrophages that phagocytosed lipid components, as well as enlarged Kupffer cells that phagocytosed lipid droplets. Electron microscopy showed the lipid droplets to have a moth-eaten appearance. Using monocytes extracted from the peripheral blood, acid lipase activity was measured by fluorescence spectrometry using 4-methylumbelliferone palmitate as a substrate. This patient's human lysosomal acid lipase activity was 0.020 nM/min per 10(6) cells, corresponding to 5.9% of that in healthy subjects (0.332 ± 0.066 nM/min per 10(6) cells). Cholesterol ester storage disease was therefore diagnosed. The acid lipase A base sequence obtained from leukocytes by direct sequencing was compared with a library. This patient had a point mutation of N250H/N250H in exon 7, a novel gene abnormality that has not previously been reported.
Collapse
Affiliation(s)
- Seiichiro Kojima
- Department of Gastroenterology, Tokai University Hachioji Hospital, Tokyo
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
28
|
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: 36] [Impact Index Per Article: 3.0] [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.
Collapse
|
|
29
|
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
|
|
30
|
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
|
|
31
|
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
|
|
32
|
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
|
|
33
|
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
|
|
34
|
Zhang LN, Liu PP, Zhou J, Huang RS, Yuan F, Fei LJ, Huang Y, Xu L, Hao LM, Qiu XJ, Le Y, Yang X, Xu W, Huang X, Ye M, Lian J, Duan S. Positive correlation between variants of lipid metabolism‑related genes and coronary heart disease. Mol Med Rep 2013; 8:260-6. [PMID: 23653095 PMCID: PMC3724684 DOI: 10.3892/mmr.2013.1454] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2012] [Accepted: 04/23/2013] [Indexed: 02/02/2023] Open
Abstract
Four gene variants related to lipid metabolism (including the rs562338 and rs503662 variants of the APOB gene, the rs7767084 variant of the LPA gene and the rs2246942 variant of the LIPA gene) have been shown to be associated with coronary heart disease (CHD). The aim of the present study was to assess their association with CHD in the Han Chinese population and to assess the contribution of these gene variants to CHD. Using the standardized coronary angiography method, we enrolled 290 CHD patients and 193 non-CHD patients as non-CHD controls from Lihuili Hospital (Ningbo, China). In addition, we recruited 330 unrelated healthy volunteers as healthy controls from the Xi Men Community (Ningbo, China). Our results demonstrated that the rs503662 and rs562338 variants of the APOB gene were extremely rare in the Han Chinese population (minor allele frequency <1%). Genotype rs2246942-GG of the LIPA gene was associated with an increased risk of CHD [CHD cases versus healthy controls: P=0.04; odds ratio (OR)=1.63; 95% confidence interval (CI)=1.02–2.60). Genotype rs7767084-CC of the LPA gene was identified as a protective factor against CHD in females (CHD cases versus non-CHD controls: P=0.04, OR=0.21; CHD cases versus healthy controls: P=0.02, OR=0.21). The results of our meta-analysis indicated that rs7767084 was not associated with a high risk of CHD (P=0.83; combined OR=0.93; 95% CI=0.47–1.85). In the present study, two single nucleotide polymorphisms (SNPs) of genes involved in lipid metabolism (rs2246942 and rs7767084) were identified to be significantly associated with CHD in the Han Chinese population. Specifically, rs2246942-GG of the LIPA gene was a risk factor for CHD, while rs7767084-CC of the LPA gene was a protective factor against CHD in females. However, our meta-analysis indicated that rs7767084 is not associated with a higher risk of CHD.
Collapse
Affiliation(s)
- Li-Na Zhang
- School of Medicine, Ningbo University, Ningbo, Zhejiang 315211, PR China.
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
35
|
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
|
|
36
|
Walker RH, Schulz VP, Tikhonova IR, Mahajan MC, Mane S, Arroyo Muniz M, Gallagher PG. Genetic diagnosis of neuroacanthocytosis disorders using exome sequencing. Mov Disord 2011; 27:539-43. [PMID: 22038564 DOI: 10.1002/mds.24020] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2011] [Revised: 09/24/2011] [Accepted: 10/03/2011] [Indexed: 02/03/2023] Open
Abstract
Neuroacanthocytoses are neurodegenerative disorders marked by phenotypic and genetic heterogeneity. There are several associated genetic loci, and many defects, including gene deletions and insertions, and missense, nonsense, and splicing mutations, have been found spread over hundreds of kilobases of genomic DNA. In some cases, specific diagnosis is unclear, particularly in the early stages of disease or when there is an atypical presentation. Determination of the precise genetic defect allows assignment of the diagnosis and permits carrier detection and genetic counseling. The objective of this report was to utilize exome sequencing for genetic diagnosis in the neuroacanthocytosis syndromes. Genomic DNA from 2 patients with clinical features of chorea-acanthocytosis was subjected to targeted exon capture. Captured DNA was subjected to ultrahigh throughput next-generation sequencing. Sequencing data were assembled, filtered against known human variant genetic databases, and results were analyzed. Both patients were compound heterozygotes for mutations in the VPS13A gene, the gene associated with chorea-acanthocytosis. Patient 1 had a 4-bp deletion that removes the 5' donor splice site of exon 58 and a nucleotide substitution that disrupts the 5' donor splice site of exon 70. Patient 2 had a dinucleotide deletion in exon 16 and a dinucleotide insertion in exon 33. No mutations were identified in the XK, PANK2, or JPH3 gene loci. Exome sequencing is a valuable diagnostic tool in the neuroacanthocytosis syndromes. These studies may provide a better understanding of the function of the associated proteins and provide insight into the pathogenesis of these disorders.
Collapse
Affiliation(s)
- Ruth H Walker
- Department of Neurology, James J Peters Veterans Affairs Medical Center, Bronx, New York 10468, USA.
| | | | | | | | | | | | | |
Collapse
|
|
37
|
Miller WL, Bose HS. Early steps in steroidogenesis: intracellular cholesterol trafficking. J Lipid Res 2011; 52:2111-2135. [PMID: 21976778 DOI: 10.1194/jlr.r016675] [Citation(s) in RCA: 387] [Impact Index Per Article: 27.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Steroid hormones are made from cholesterol, primarily derived from lipoproteins that enter cells via receptor-mediated endocytosis. In endo-lysosomes, cholesterol is released from cholesterol esters by lysosomal acid lipase (LAL; disordered in Wolman disease) and exported via Niemann-Pick type C (NPC) proteins (disordered in NPC disease). These diseases are characterized by accumulated cholesterol and cholesterol esters in most cell types. Mechanisms for trans-cytoplasmic cholesterol transport, membrane insertion, and retrieval from membranes are less clear. Cholesterol esters and "free" cholesterol are enzymatically interconverted in lipid droplets. Cholesterol transport to the cholesterol-poor outer mitochondrial membrane (OMM) appears to involve cholesterol transport proteins. Cytochrome P450scc (CYP11A1) then initiates steroidogenesis by converting cholesterol to pregnenolone on the inner mitochondrial membrane (IMM). Acute steroidogenic responses are regulated by cholesterol delivery from OMM to IMM, triggered by the steroidogenic acute regulatory protein (StAR). Chronic steroidogenic capacity is determined by CYP11A1 gene transcription. StAR mutations cause congenital lipoid adrenal hyperplasia, with absent steroidogenesis, potentially lethal salt loss, and 46,XY sex reversal. StAR mutations initially destroy most, but not all steroidogenesis; low levels of StAR-independent steroidogenesis are lost later due to cellular damage, explaining the clinical findings. Rare P450scc mutations cause a similar syndrome. This review addresses these early steps in steroid biosynthesis.
Collapse
Affiliation(s)
- Walter L Miller
- Department of Pediatrics, School of Medicine, University of California, San Francisco, CA 94143; UCSF Benioff Children's Hospital, San Francisco, CA 94143.
| | - Himangshu S Bose
- Department of Biochemistry, Mercer University School of Medicine, Savannah, GA 31404; and; Memorial University Medical Center, Savannah, GA 31404
| |
Collapse
|
|
38
|
Wild PS, Zeller T, Schillert A, Szymczak S, Sinning CR, Deiseroth A, Schnabel RB, Lubos E, Keller T, Eleftheriadis MS, Bickel C, Rupprecht HJ, Wilde S, Rossmann H, Diemert P, Cupples LA, Perret C, Erdmann J, Stark K, Kleber ME, Epstein SE, Voight BF, Kuulasmaa K, Li M, Schäfer AS, Klopp N, Braund PS, Sager HB, Demissie S, Proust C, König IR, Wichmann HE, Reinhard W, Hoffmann MM, Virtamo J, Burnett MS, Siscovick D, Wiklund PG, Qu L, El Mokthari NE, Thompson JR, Peters A, Smith AV, Yon E, Baumert J, Hengstenberg C, März W, Amouyel P, Devaney J, Schwartz SM, Saarela O, Mehta NN, Rubin D, Silander K, Hall AS, Ferrieres J, Harris TB, Melander O, Kee F, Hakonarson H, Schrezenmeir J, Gudnason V, Elosua R, Arveiler D, Evans A, Rader DJ, Illig T, Schreiber S, Bis JC, Altshuler D, Kavousi M, Witteman JCM, Uitterlinden AG, Hofman A, Folsom AR, Barbalic M, Boerwinkle E, Kathiresan S, Reilly MP, O'Donnell CJ, Samani NJ, Schunkert H, Cambien F, Lackner KJ, Tiret L, Salomaa V, Munzel T, Ziegler A, Blankenberg S. A genome-wide association study identifies LIPA as a susceptibility gene for coronary artery disease. ACTA ACUST UNITED AC 2011; 4:403-12. [PMID: 21606135 DOI: 10.1161/circgenetics.110.958728] [Citation(s) in RCA: 111] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
BACKGROUND eQTL analyses are important to improve the understanding of genetic association results. We performed a genome-wide association and global gene expression study to identify functionally relevant variants affecting the risk of coronary artery disease (CAD). METHODS AND RESULTS In a genome-wide association analysis of 2078 CAD cases and 2953 control subjects, we identified 950 single-nucleotide polymorphisms (SNPs) that were associated with CAD at P<10(-3). Subsequent in silico and wet-laboratory replication stages and a final meta-analysis of 21 428 CAD cases and 38 361 control subjects revealed a novel association signal at chromosome 10q23.31 within the LIPA (lysosomal acid lipase A) gene (P=3.7×10(-8); odds ratio, 1.1; 95% confidence interval, 1.07 to 1.14). The association of this locus with global gene expression was assessed by genome-wide expression analyses in the monocyte transcriptome of 1494 individuals. The results showed a strong association of this locus with expression of the LIPA transcript (P=1.3×10(-96)). An assessment of LIPA SNPs and transcript with cardiovascular phenotypes revealed an association of LIPA transcript levels with impaired endothelial function (P=4.4×10(-3)). CONCLUSIONS The use of data on genetic variants and the addition of data on global monocytic gene expression led to the identification of the novel functional CAD susceptibility locus LIPA, located on chromosome 10q23.31. The respective eSNPs associated with CAD strongly affect LIPA gene expression level, which was related to endothelial dysfunction, a precursor of CAD.
Collapse
Affiliation(s)
- Philipp S Wild
- Department of Medicine II, University Medical Center Mainz, Germany
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
39
|
Hooper AJ, Adams LA, Burnett JR. Genetic determinants of hepatic steatosis in man. J Lipid Res 2011; 52:593-617. [PMID: 21245030 DOI: 10.1194/jlr.r008896] [Citation(s) in RCA: 98] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Hepatic steatosis is one of the most common liver disorders in the general population. The main cause of hepatic steatosis is nonalcoholic fatty liver disease (NAFLD), representing the hepatic component of the metabolic syndrome, which is characterized by type 2 diabetes, obesity, and dyslipidemia. Insulin resistance and excess adiposity are considered to play key roles in the pathogenesis of NAFLD. Although the risk factors for NAFLD are well established, the genetic basis of hepatic steatosis is largely unknown. Here we review recent progress on genomic variants and their association with hepatic steatosis and discuss the potential impact of these genetic studies on clinical practice. Identifying the genetic determinants of hepatic steatosis will lead to a better understanding of the pathogenesis and progression of NAFLD.
Collapse
Affiliation(s)
- Amanda J Hooper
- Department of Core Clinical Pathology and Biochemistry, Royal Perth Hospital, Perth, Australia
| | | | | |
Collapse
|
|
40
|
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
|
|
41
|
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.
| | | | | |
Collapse
|
|
42
|
Hooper AJ, Tran HA, Formby MR, Burnett JR. A novel missense LIPA gene mutation, N98S, in a patient with cholesteryl ester storage disease. Clin Chim Acta 2008; 398:152-4. [PMID: 18775687 DOI: 10.1016/j.cca.2008.08.007] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2008] [Revised: 08/06/2008] [Accepted: 08/06/2008] [Indexed: 12/13/2022]
Abstract
Lysosomal acid lipase plays an important role in maintaining cellular cholesterol homeostasis. Complete absence of lysosomal acid lipase activity results in Wolman disease and usually death in infancy, whereas partial deficiency of lysosomal acid lipase results in cholesteryl ester storage disease (CESD). We describe a 26 year-old female with CESD who presented with recurrent right upper quadrant abdominal pain. Abnormal liver function tests and a subsequent liver biopsy revealed features consistent with CESD. Sequencing of the LIPA gene revealed that she was a compound heterozygote for the previously reported exon 8 splice junction mutation and a novel missense mutation (N98S) in exon 4. The splice junction mutation allows some (approximately 3%) normal splicing to occur, and therefore gives rise to residual lysosomal acid lipase activity. Asn98 in lysosomal acid lipase is highly conserved among species and mutation of this residue could influence catalytic activity or accessibility to the active site. In summary, we describe a CESD patient compound heterozygous for the LIPA exon 8 splice junction mutation and a novel missense mutation, N98S.
Collapse
Affiliation(s)
- Amanda J Hooper
- Department of Core Clinical Pathology & Biochemistry, PathWest Laboratory Medicine WA, Royal Perth Hospital, Perth, Australia
| | | | | | | |
Collapse
|
|
43
|
Allen TC. Pulmonary Langerhans cell histiocytosis and other pulmonary histiocytic diseases: a review. Arch Pathol Lab Med 2008; 132:1171-81. [PMID: 18605769 DOI: 10.5858/2008-132-1171-plchao] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/14/2008] [Indexed: 11/06/2022]
Abstract
CONTEXT Pulmonary Langerhans cell histiocytosis is the most common and best known pulmonary histiocytic lesion; however, the realm of pulmonary histiocytic lesions also includes an assortment of uncommon diseases that may exhibit pulmonary involvement. OBJECTIVE To review pulmonary Langerhans cell histiocytosis and other pulmonary histiocytoses to better ensure correct diagnosis and optimal assessment of prognosis and treatment. DATA SOURCES Literature review and primary material from the author's institution. CONCLUSIONS This review discusses the most common pulmonary histiocytosis, pulmonary Langerhans cell histiocytosis, and also reviews the uncommon pulmonary histiocytic lesions, which are distinct from pulmonary Langerhans cell histiocytosis.
Collapse
Affiliation(s)
- Timothy Craig Allen
- Department of Pathology, The University of Texas Health Science Center at Tyler, Tyler, TX 75708, USA.
| |
Collapse
|
|
44
|
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]
|
|
45
|
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.
Collapse
Affiliation(s)
- Uta Drebber
- Institute of Pathology, University of Cologne, Joseph-Stelzmann-Strasse 9, D-59031 Cologne, Germany.
| | | | | | | | | | | |
Collapse
|
|
46
|
Steet RA, Hullin R, Kudo M, Martinelli M, Bosshard NU, Schaffner T, Kornfeld S, Steinmann B. A splicing mutation in the alpha/beta GlcNAc-1-phosphotransferase gene results in an adult onset form of mucolipidosis III associated with sensory neuropathy and cardiomyopathy. Am J Med Genet A 2005; 132A:369-75. [PMID: 15633164 DOI: 10.1002/ajmg.a.30498] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
A 47-year-old female who presented with a dilated cardiomyopathy and mild neuropathy was found to have pseudoHurler polydystrophy (mucolipidosis III). The serum lysosomal enzymes were strikingly elevated and GlcNAc-1-phosphotransferase activity in the patient's fibroblasts was 3% of normal. Sequence analysis of the patient's genomic DNA revealed a homozygous mutation of the last nucleotide of the 135-bp exon 7 of the phosphotransferase gene encoding the alpha/beta subunits, resulting in aberrant splicing and skipping of this exon. Remarkably, none of the skeletal and connective tissue anomalies characteristic of the disease were present. This case is the first example of mucolipidosis III presenting in an adult patient and further broadens the clinical spectrum of the disease.
Collapse
Affiliation(s)
- Richard A Steet
- Department of Internal Medicine, Washington University School of Medicine, Saint Louis, Missouri, USA
| | | | | | | | | | | | | | | |
Collapse
|
|
47
|
Ochi M, Osawa H, Onuma H, Murakami A, Nishimiya T, Shimada F, Kato K, Shimizu I, Shishino K, Murase M, Fujii Y, Ohashi J, Makino H. The absence of evidence for major effects of the frequent SNP +299G>A in the resistin gene on susceptibility to insulin resistance syndrome associated with Japanese type 2 diabetes. Diabetes Res Clin Pract 2003; 61:191-8. [PMID: 12965109 DOI: 10.1016/s0168-8227(03)00119-0] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
Resistin, specifically secreted from adipocytes, antagonizes insulin and represents a promising candidate gene for type 2 diabetes. We reported that a frequent single nucleotide polymorphism (SNP) +299G>A in this gene is not associated with type 2 diabetes. To determine whether this SNP affects insulin resistance syndrome associated with type 2 diabetes, we examined its effects on susceptibility to obesity, hyperlipidemia and hypertension in type 2 diabetic subjects and on susceptibility to type 2 diabetes by interaction with other frequent genes involved in lipid metabolism, namely, beta3-adrenergic receptor (b3AR) Trp64Arg, phosphodiesterase 3B (PDE3B) c.1389G>A or lysosomal acid lipase (LAL) Thr-6Pro. The 99 type 2 diabetic and 99 control subjects were typed by PCR direct sequencing or PCR-RFLP. No differences in frequencies of obesity, hyperlipidemia and hypertension were found between the type 2 diabetic subjects with G/G and those with G/A or A/A genotypes of the resistin SNP. When the combination of the resistin SNP with each of b3AR, PDE3B and LAL SNPs was assessed, no association with type 2 diabetes was evident. Therefore, the frequent SNP +299G>A in the resistin gene is unlikely to have major effects on susceptibility to insulin resistance syndrome associated with type 2 diabetes in Japanese subjects.
Collapse
Affiliation(s)
- Masaaki Ochi
- Department of Laboratory Medicine, Ehime University School of Medicine, Shigenobu, 791-0295 Ehime, Japan
| | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
48
|
Abstract
Splice site nucleotide substitutions can be analyzed by comparing the individual information contents (Ri, bits) of the normal and variant splice junction sequences [Rogan and Schneider, 1995]. In the present study, we related splicing abnormalities to changes in Ri values of 111 previously reported splice site substitutions in 41 different genes. Mutant donor and acceptor sites have significantly less information than their normal counterparts. With one possible exception, primary mutant sites with <2.4 bits were not spliced. Sites with Ri values > or = 2.4 bits but less than the corresponding natural site usually decreased, but did not abolish splicing. Substitutions that produced small changes in Ri probably do not impair splicing and are often polymorphisms. The Ri values of activated cryptic sites were generally comparable to or greater than those of the corresponding natural splice sites. Information analysis revealed preexisting cryptic splice junctions that are used instead of the mutated natural site. Other cryptic sites were created or strengthened by sequence changes that simultaneously altered the natural site. Comparison between normal and mutant splice site Ri values distinguishes substitutions that impair splicing from those which do not, distinguishes null alleles from those that are partially functional, and detects activated cryptic splice sites.
Collapse
Affiliation(s)
- P K Rogan
- Department of Human Genetics, Allegheny University of the Health Sciences, Pittsburgh, PA 15212, USA.
| | | | | |
Collapse
|
|
49
|
Ries S, Büchler C, Schindler G, Aslanidis C, Ameis D, Gasche C, Jung N, Schambach A, Fehringer P, Vanier MT, Belli DC, Greten H, Schmitz G. Different missense mutations in histidine-108 of lysosomal acid lipase cause cholesteryl ester storage disease in unrelated compound heterozygous and hemizygous individuals. Hum Mutat 2000; 12:44-51. [PMID: 9633819 DOI: 10.1002/(sici)1098-1004(1998)12:1<44::aid-humu7>3.0.co;2-o] [Citation(s) in RCA: 23] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Cholesteryl ester storage disease (CESD) and Wolman disease (WD) are both autosomal recessive disorders associated with reduced activity of lysosomal acid lipase (LAL), that leads to the tissue accumulation of cholesteryl esters in endosomes and lysosomes. WD is caused by genetic defects of LAL that leave no residual enzymatic activity, while in CESD patients a residual LAL activity can be identified. We have analyzed the LAL cDNA in three CESD patients from two nonrelated families and identified the mutations responsible for the disease. The associated genetic defects characterized revealed compound heterozygosity for a splice defect leading to skipping of exon 8, due to a G-->A transition at position -1 of the exon 8 splice donor site, and a point mutation leading to a Hisl08Pro change (CAT-->CCT) in two patients (siblings) with mild CESD phenotype. A further CESD patient was hemizygous for a His108-->Arg missense mutation (CAT-->CGT) in combination with a partial deletion of the LAL gene and was affected more severely. Expression of the LAL enzymes with the His108-->Pro and His108-->Arg mutation in insect cells revealed residual enzymatic activities of 4.6% versus 2.7%, respectively, compared with controls. Therefore, His108 seems to play a crucial role in folding or catalytic activity of the lysosomal acid lipase. This is the first description of two different, naturally occurring mutations involving the same amino acid residue in the lysosomal acid lipase in unrelated CESD patients. Moreover, our results demonstrate that the variable manifestation of CESD can be explained by mutation-dependent, variable inactivation of the LAL enzyme.
Collapse
Affiliation(s)
- S Ries
- Institute for Clinical Chemistry and Laboratory Medicine, University of Regensburg, Germany
| | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
50
|
Elleder M, Chlumská A, Hyánek J, Poupĕtová H, Ledvinová J, Maas S, Lohse P. Subclinical course of cholesteryl ester storage disease in an adult with hypercholesterolemia, accelerated atherosclerosis, and liver cancer. J Hepatol 2000; 32:528-34. [PMID: 10735626 DOI: 10.1016/s0168-8278(00)80407-9] [Citation(s) in RCA: 54] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Few cases of asymptomatic cholesteryl ester storage disease (CESD) due to low enzymatic activity of human lysosomal acid lipase/cholesteryl ester hydrolase (hLAL) have been reported thus far in adults Here, we describe a 51-year-old man with a long clinical history of mixed hyperlipoproteinemia and severe premature atherosclerosis, but with no signs of hepatomegaly, liver dysfunction, or splenomegaly. The disease was discovered by chance in a biopsy performed because of suspected liver cancer (proven to be a cholangiocarcinoma). Residual hLAL activity in peripheral leukocytes was determined to be 6% of control values. DNA sequence and restriction fragment length polymorphism analysis demonstrated that the patient was a compound heterozygote for the prevalent CESD exon 8 splice site mutation (G934A) and the deletion of a C (nucleotide 673, 674, or 675) in exon 6 of the hLAL gene, resulting in premature termination of protein translation at residue 195. The patient died of liver failure as a consequence of extensive tumor infiltration at age 52. Lipid analysis revealed moderate cholesteryl ester storage in the liver and in the suprarenal cortex, and massive accumulation in the testicular histiocytes and Leydig cells, resulting in a pronounced secondary atrophy of the seminiferous tubules. Our case study demonstrates that hepatomegaly is an inconstant feature, even in CESD patients compound heterozygous for a Wolman mutation which results in complete loss of hLAL enzymic activity. It also highlights the need to be aware of this condition as it may be underdiagnosed.
Collapse
Affiliation(s)
- M Elleder
- Institute of Inherited Metabolic Disorders, Charles University Prague, 1st Faculty of Medicine and General Faculty Hospital, Praha, Czech Republic.
| | | | | | | | | | | | | |
Collapse
|