RESUMO
BACKGROUND: Cholesterol ester storage disorder (CESD; OMIM: 278,000) was formerly assumed to be an autosomal recessive allelic genetic condition connected to diminished lysosomal acid lipase (LAL) activity due to LIPA gene abnormalities. CESD is characterized by abnormal liver function and lipid metabolism, and in severe cases, liver failure can occur leading to death. In this study, one Chinese nonclassical CESD pedigree with dominant inheritance was phenotyped and analyzed for the corresponding gene alterations. METHODS: Seven males and eight females from nonclassical CESD pedigree were recruited. Clinical features and LAL activities were documented. Whole genome Next-generation sequencing (NGS) was used to screen candidate genes and mutations, Sanger sequencing confirmed predicted mutations, and qPCR detected LIPA mRNA expression. RESULTS: Eight individuals of the pedigree were speculatively thought to have CESD. LAL activity was discovered to be lowered in four living members of the pedigree, but undetectable in the other four deceased members who died of probable hepatic failure. Three of the four living relatives had abnormal lipid metabolism and all four had liver dysfunctions. By liver biopsy, the proband exhibited diffuse vesicular fatty changes in noticeably enlarged hepatocytes and Kupffer cell hyperplasia. Surprisingly, only a newly discovered heterozygous mutation, c.1133T>C (p. Ile378Thr) on LIPA, was found by gene sequencing in the proband. All living family members who carried the p.I378T variant displayed reduced LAL activity. CONCLUSIONS: Phenotypic analyses indicate that this may be an autosomal dominant nonclassical CESD pedigree with a LIPA gene mutation.
Assuntos
Doença do Armazenamento de Colesterol Éster , Heterozigoto , Linhagem , Esterol Esterase , Humanos , Masculino , Feminino , Doença do Armazenamento de Colesterol Éster/genética , Doença do Armazenamento de Colesterol Éster/diagnóstico , Esterol Esterase/genética , Adulto , Mutação , Genes Dominantes , Pessoa de Meia-Idade , Fenótipo , Adolescente , CriançaRESUMO
Lysosomal acid lipase (LAL) is a lysosomal enzyme essential for the degradation of cholesteryl esters through the endocytic pathway. Deficiency of the LAL enzyme encoded by the LIPA gene leads to LAL deficiency (LAL-D) (OMIM 278000), one of the lysosomal storage disorders involving 50-60 genes. Among the two disease subtypes, the severe disease subtype of LAL-D is known as Wolman disease, with typical manifestations involving hepatomegaly, splenomegaly, vomiting, diarrhea, and hematopoietic abnormalities, such as anemia. In contrast, the mild disease subtype of this disorder is known as cholesteryl ester storage disease, with hypercholesterolemia, hypertriglyceridemia, and high-density lipoprotein disappearance. The prevalence of LAL-D is rare, but several treatment options, including enzyme replacement therapy, are available. Accordingly, a number of screening methodologies have been developed for this disorder. This review summarizes the current discussion on LAL-D, covering genetics, screening, and the tertiary structure of human LAL enzyme and preclinical study for the future development of a novel therapy.
Assuntos
Doença do Armazenamento de Colesterol Éster , Doença de Wolman , Humanos , Doença de Wolman/diagnóstico , Doença de Wolman/genética , Doença de Wolman/metabolismo , Doença do Armazenamento de Colesterol Éster/diagnóstico , Doença do Armazenamento de Colesterol Éster/tratamento farmacológico , Doença do Armazenamento de Colesterol Éster/metabolismo , Esterol Esterase/metabolismo , Hepatomegalia/tratamento farmacológico , Doença de WolmanRESUMO
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.
Assuntos
Humanos , Lactente , Criança , Adolescente , Adulto , Doença do Armazenamento de Colesterol Éster/diagnóstico , Doença do Armazenamento de Colesterol Éster/genética , Doença do Armazenamento de Colesterol Éster/tratamento farmacológico , Doença de Wolman/diagnóstico , Doença de Wolman/genética , Esterol Esterase/genética , Esterol Esterase/uso terapêutico , HepatomegaliaRESUMO
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.
Assuntos
Doença do Armazenamento de Colesterol Éster , Doença de Wolman , Adolescente , Adulto , Criança , Doença do Armazenamento de Colesterol Éster/diagnóstico , Doença do Armazenamento de Colesterol Éster/tratamento farmacológico , Doença do Armazenamento de Colesterol Éster/genética , Hepatomegalia , Humanos , Lactente , Esterol Esterase/genética , Esterol Esterase/uso terapêutico , Doença de Wolman/diagnóstico , Doença de Wolman/genética , Doença de WolmanRESUMO
BACKGROUND: Lysosomal acid lipase deficiency (LALD, OMIM#278000) is a rare lysosomal disorder with an autosomal recessive inheritance. The main clinical manifestations are related to a progressive accumulation of cholesteryl esters, triglycerides or both within the lysosome in different organs such as the liver, spleen, and cardiovascular system. A wide range of clinical severity is associated with LALD including a severe very rare antenatal/neonatal/infantile phenotype named Wolman disease and a late-onset form named cholesteryl ester storage disease (CESD). METHODS: This study aimed to investigate a cohort of at-risk patients (4174) presenting with clinical or biological signs consistent with LALD using the assessment of LAL activity on dried blood spots. RESULTS: LAL activity was lower than 0.05 nmol/punch/L (cut-off: 0.12) in 19 patients including 13 CESD and 6 Wolman. Molecular study has been conducted in 17 patients and succeeded in identifying 34 mutated alleles. Fourteen unique variants have been characterized, 7 of which are novel. CONCLUSION: This study allowed to identify a series of patients and expanded the molecular spectrum knowledge of LALD. Besides, a new screening criteria grid based on the clinical/biological data from our study and the literature has been proposed in order to enhance the diagnosis rate in at risk populations.
Assuntos
Doença do Armazenamento de Colesterol Éster , Doença de Wolman , Doença do Armazenamento de Colesterol Éster/diagnóstico , Doença do Armazenamento de Colesterol Éster/genética , Ésteres do Colesterol , Feminino , Humanos , Recém-Nascido , Lipase , Gravidez , Esterol Esterase/genética , Doença de Wolman/diagnóstico , Doença de Wolman/genéticaRESUMO
BACKGROUND: Lysosomal acid lipase deficiency (LAL-D), also known as cholesteryl ester storage disease or Wolman disease, is a multi-systemic autosomal recessive genetic disorder caused by mutations in the lysosomal acid lipase gene (LIPA). CASE: A 14-year-old female patient was diagnosed as LAL-D with the findings of hepatomegaly, splenomegaly, elevated liver enzyme levels, and abnormal lipid profile. Her sister had similar laboratory and ultrasonographic findings. Both siblings had a homozygous c.894 G > A mutation in the LIPA gene, and their parents were heterozygous for this mutation. CONCLUSIONS: This case is one of the similar reports in the literature regarding clinical, biochemical, and genetic findings. It is well-known that LAL-D has overlapping clinical manifestations, and early diagnosis is quite challenging. Therefore, most patients die in the first year of life. After the determination of novel mutations in LAL-D patients, it is thought that LAL-D can present with heterogeneous signs and symptoms.
Assuntos
Doença do Armazenamento de Colesterol Éster , Dislipidemias , Doença de Wolman , Adolescente , Doença do Armazenamento de Colesterol Éster/diagnóstico , Doença do Armazenamento de Colesterol Éster/genética , Feminino , Hepatomegalia/genética , Humanos , Doença de Wolman/diagnóstico , Doença de Wolman/genética , Doença de WolmanRESUMO
Lysosomal acid lipase (LAL) deficiency, or cholesterol ester storage disease, is a disorder affecting the breakdown of cholesterol esters and triglycerides within lysosomes. Clinical findings include hepatomegaly, hepatic dysfunction, and dyslipidemia with a wide range of phenotypic variability and age of onset. The available clinical and molecular information of the patient presented herein was consistent with a diagnosis of LAL deficiency, but her LAL activity assay repeatedly showed normal or borderline low results. Her response to enzyme replacement therapy and demonstrable deficiency on a newer specific enzymatic assay ultimately confirmed her diagnosis of LAL deficiency.
Assuntos
Doença do Armazenamento de Colesterol Éster , Esterol Esterase , Doença de Wolman , Doença do Armazenamento de Colesterol Éster/diagnóstico , Doença do Armazenamento de Colesterol Éster/tratamento farmacológico , Doença do Armazenamento de Colesterol Éster/genética , Feminino , Humanos , Esterol Esterase/genética , Esterol Esterase/uso terapêutico , Doença de Wolman/diagnóstico , Doença de Wolman/tratamento farmacológico , Doença de Wolman/genética , Doença de WolmanRESUMO
BACKGROUND AND AIMS: Cholesteryl ester storage disease (CESD) due to LIPA gene mutations is characterized by hepatic steatosis, hypercholesterolemia and hypoalphalipoproteinemia, exposing affected patients to an increased cardiovascular risk. Further insights into the impact of LIPA gene mutations on lipid/lipoprotein metabolism are limited. Aim of the study was to investigate the effect of carrying one or two mutant LIPA alleles on lipoprotein composition and function. METHODS: Lipoproteins were isolated from 6 adult CESD patients, 5 relatives carrying one mutant LIPA allele (carriers) and 12 sex/age matched controls. Lipid profile, lipoprotein mass composition and the fatty acid distribution of cholesteryl esters (CEs) were assessed. HDL function was evaluated as the ability to promote nitric oxide release by endothelial cells. RESULTS: Despite the lipid-lowering therapy, total cholesterol, LDL-cholesterol and triglycerides were increased in CESD patients compared to controls, while HDL-cholesterol was reduced. Carriers also displayed elevated total and LDL-cholesterol. Very low and intermediate density lipoproteins from CESD patients and carriers were enriched in CEs compared to the control ones, with a concomitant reduction of triglycerides. Fatty acid composition of CEs in serum and lipoproteins showed a depletion of linoleate content in CESD patients, due to the reduced LCAT activity. In CESD HDL, fatty acid distribution of CEs was shifted towards saturated ones, if compared to control HDL. The changes in HDL composition did not affect HDL ability to promote nitric oxide release by endothelial cells. CONCLUSIONS: LIPA gene mutations significantly affected plasma levels and lipid composition of lipoproteins, likely contributing to the increased cardiovascular risk of affected patients.
Assuntos
Acetil-CoA C-Acetiltransferase/metabolismo , Doença do Armazenamento de Colesterol Éster/sangue , Doença do Armazenamento de Colesterol Éster/genética , Ésteres do Colesterol/sangue , Lipoproteínas/sangue , Mutação , Esterol Esterase/genética , Adolescente , Adulto , Idoso , Biomarcadores/sangue , Estudos de Casos e Controles , Células Cultivadas , Doença do Armazenamento de Colesterol Éster/diagnóstico , Doença do Armazenamento de Colesterol Éster/enzimologia , HDL-Colesterol , LDL-Colesterol/sangue , Feminino , Predisposição Genética para Doença , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Óxido Nítrico/metabolismo , Fenótipo , Fosfatidilcolina-Esterol O-Aciltransferase/metabolismo , Triglicerídeos/sangue , Adulto JovemAssuntos
Neoplasias dos Ductos Biliares/etiologia , Carcinoma Hepatocelular/etiologia , Colangiocarcinoma/etiologia , Doença do Armazenamento de Colesterol Éster/complicações , Cirrose Hepática/etiologia , Neoplasias Hepáticas/etiologia , Neoplasias dos Ductos Biliares/patologia , Carcinoma Hepatocelular/patologia , Colangiocarcinoma/patologia , Doença do Armazenamento de Colesterol Éster/diagnóstico , Humanos , Fígado/diagnóstico por imagem , Fígado/patologia , Cirrose Hepática/patologia , Neoplasias Hepáticas/patologia , Masculino , Adulto JovemRESUMO
BACKGROUND AND AIMS: Lysosomal acid lipase deficiency (LAL-D) is a lysosomal storage disorder. In severe cases, it can cause life-threatening organ failure due to lipid substrates accumulation. However, mild phenotypes of this disorder are increasingly recognized. The aim of this study is to determine the number of missed LAL-D patients in a large pediatric hospital population. METHODS: In a retrospective data mining study, the medical files of children, who visited the outpatient clinic at a university hospital between 2000 and 2016, with high plasma low density lipoprotein cholesterol (LDL-C) levels, were evaluated. Previously developed LAL-D screening criteria, with lipid and alanine aminotransferase (ALT) values adjusted for children, were used to analyze which children are suspect for LAL-D. For suspicion of LAL-D, at least 3 out of 5 screening criteria had to be met. Subsequently data on presentation and follow-up were collected to determine if the clinical picture was compatible with LAL-D. RESULTS: We identified 2037 children with high LDL-C levels. Of those, 36 children complied with ≥3 screening criteria. Thirty-one of those had an underlying disorder other than LAL-D that explained the abnormalities and, in the 5 remaining children, ALT and lipid levels normalized spontaneously, thus excluding LAL-D. CONCLUSIONS: This study shows that retrospective data mining is unlikely to yield a significant number of LAL-D cases in children. The screening algorithm adjusted for children seems useful and accurate in the selection of children for further testing, suggesting it can be applied prospectively, although further validation is warranted.
Assuntos
Doença do Armazenamento de Colesterol Éster/diagnóstico , LDL-Colesterol/sangue , Mineração de Dados , Doença de Wolman/diagnóstico , Adolescente , Alanina Transaminase/metabolismo , Algoritmos , Cardiologia/normas , Criança , Pré-Escolar , Doença do Armazenamento de Colesterol Éster/metabolismo , Feminino , Humanos , Lactente , Recém-Nascido , Fígado/metabolismo , Masculino , Programas de Rastreamento/métodos , Pacientes Ambulatoriais , Fenótipo , Estudos Retrospectivos , Esterol Esterase/genética , Doença de Wolman/metabolismo , Doença de WolmanRESUMO
BACKGROUND: Lysosomal acid lipase deficiency (LAL-D) is a rare autosomal recessive lysosomal lipid storage disorder that results in an early-onset, severe, and lethal phenotype, known as Wolman disease, or a late-onset, attenuated phenotype, cholesteryl ester storage disease (CESD). The aim of our study was to describe the clinical presentation of CESD, focusing on the first noted abnormalities in patients. A diagnostic algorithm of CESD was also proposed. METHODS: This is an observational, 1-center study of 19 Polish patients with late-onset LAL-D. RESULTS: The mean age at which the first symptoms were reported was 4 years and 6 months. A mild hepatomegaly was the most common initial abnormality observed in all (100%) patients. Seven (37%) patients were noted to have mildly to moderately elevated serum transaminases. At the time of first hospitalization all (100%) patients presented with hepatomegaly, 15 (79%) patients presented with elevated serum transaminases and all (100%) patients had dyslipidemia. The mean age at the time of CESD diagnosis was 7 years and 2 months. Diagnoses were based on a deficient LAL activity in leukocytes (in all patients) and the LIPA gene mutations (in 47% of them). All the patients were carriers for the mutation c.894G>A in the LIPA gene. There was approximately a 3-year delay from initial symptoms to final diagnosis. CONCLUSIONS: Hepatomegaly constitutes the most common presenting clinical sign of CESD. Hepatomegaly and dyslipidemia defined as elevated serum total and LDL cholesterol, elevated triglycerides and normal to low HDL cholesterol, comprises the most characteristic findings at CESD diagnosis.
Assuntos
Algoritmos , Doença do Armazenamento de Colesterol Éster/diagnóstico , Dislipidemias/diagnóstico , Hepatomegalia/diagnóstico , Esterol Esterase/análise , Criança , Pré-Escolar , Doença do Armazenamento de Colesterol Éster/genética , Dislipidemias/sangue , Dislipidemias/genética , Feminino , Hepatomegalia/sangue , Hepatomegalia/genética , Humanos , Masculino , Mutação , Polônia , Esterol Esterase/genética , Transaminases/sangueRESUMO
Lysosomal acid lipase deficiency is a rare, autosomal recessive condition caused by mutations in the gene encoding lysosomal acid lipase (LIPA) that result in reduced or absent activity of this essential enzyme. The severity of the resulting disease depends on the nature of the underlying mutation and magnitude of its effect on enzymatic function. Wolman's disease is a severe disorder that presents during infancy, resulting in failure to thrive, hepatomegaly, and hepatic failure, and an average life expectancy of less than 4 months. Cholesteryl ester storage disorder arises later in life and is less severe, although the two diseases share many common features, including dyslipidaemia and transaminitis. The prevalence of these diseases has been estimated at one in 40â000 to 300â000, but many cases are undiagnosed and unreported, and awareness among clinicians is low. Lysosomal acid lipase deficiency-which can be diagnosed using dry blood spot testing-is often misdiagnosed as non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), hereditary dyslipidaemia, or cryptogenic cirrhosis. There are no formal guidelines for treatment of these patients, and treatment options are limited. In this Review we appraise the existing literature on Wolman's disease and cholesteryl ester storage disease, and discuss available treatments, including enzyme replacement therapy, oral lipid-lowering therapy, stem-cell transplantation, and liver transplantation.
Assuntos
Doença do Armazenamento de Colesterol Éster/diagnóstico , Doença de Wolman/diagnóstico , Doença do Armazenamento de Colesterol Éster/epidemiologia , Doença do Armazenamento de Colesterol Éster/etiologia , Doença do Armazenamento de Colesterol Éster/terapia , Diagnóstico Diferencial , Humanos , Prevalência , Doença de Wolman/epidemiologia , Doença de Wolman/etiologia , Doença de Wolman/terapia , Doença de WolmanRESUMO
BACKGROUND: A considerable number of lysosomal storage diseases (LSD), which can occur at any age in life, should be included in the differential diagnosis of histiocytic diseases. OBJECTIVE: To what extent can pathologists contribute to the diagnostics of LSD? MATERIAL AND METHODS: In material collected from LSD, morphological storage phenomena in some disease forms, particularly in histiocytic cells from bone marrow smears and some tissues are highlighted, presented and described. Due to the multitude and heterogeneity of LSDs this list is by no means exhaustive. RESULTS: In Gaucher disease, the forms of Niemann-Pick disease, cholesteryl ester storage disease (CESD), GM1 gangliosidosis and other LSDs, the histiocytic storage cells seen, for example, in bone marrow smears can be finely and ultrastructurally differentiated. Thereby, not only the presence of an LSD in general but also some individual types of LSD can be identified, even though preliminarily. To confirm the diagnosis the genetic and sometimes biochemical analysis of blood samples or fibroblast cultures from patients is usually required. CONCLUSION: The pathologist may be the first to suspect LSD and this applies to LSDs that show storage histiocytes or one of a number of other LSDs in which only minor or absent storage is seen in histiocytes but marked storage phenomena are found in other cell systems. Some of the numerous, extremely heterogeneous LSDs may, however, be overlooked as detailed knowledge of the generally rare LSDs is the domain of LSD specialists. Clinicians, pathologists, geneticists and biochemists should cooperate in solving the diagnostic problems.
Assuntos
Doenças por Armazenamento dos Lisossomos/patologia , Medula Óssea/patologia , Doença do Armazenamento de Colesterol Éster/diagnóstico , Doença do Armazenamento de Colesterol Éster/patologia , Comportamento Cooperativo , Diagnóstico Diferencial , Gangliosidose GM1/diagnóstico , Gangliosidose GM1/patologia , Doença de Gaucher/diagnóstico , Doença de Gaucher/patologia , Histiócitos/patologia , Comunicação Interdisciplinar , Lipidoses/diagnóstico , Lipidoses/patologia , Doenças por Armazenamento dos Lisossomos/diagnóstico , Doenças de Niemann-Pick/diagnóstico , Doenças de Niemann-Pick/patologiaRESUMO
Cholesterol ester storage disease is an exceptionally rare dyslipidemia with less than 150 cases reported in the medical literature. The diagnosis of Cholesterol Ester Storage Disease is often missed by virtue of the fact that the symptoms mimic both inborn metabolic defects and hepatic steatosis. Patients with Cholesterol Ester Storage Disease usually present with atypical complaints including abdominal pain from altered gut motility. Blood analysis typically reveals abnormal liver function tests with coincident dyslipidemia. We present a case of a young woman with Cholesterol Ester Storage Disease who was followed over two decades. We discuss issues common to her initial protracted diagnosis with management options over time.
Assuntos
Dor Abdominal/complicações , Dor Abdominal/diagnóstico , Doença do Armazenamento de Colesterol Éster/complicações , Doença do Armazenamento de Colesterol Éster/diagnóstico , Dislipidemias/complicações , Dislipidemias/diagnóstico , Dor Abdominal/tratamento farmacológico , Adulto , Doença do Armazenamento de Colesterol Éster/tratamento farmacológico , Diagnóstico Diferencial , Dislipidemias/tratamento farmacológico , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêuticoRESUMO
Lysosomal acid lipase deficiency is an autosomal recessive disorder with two distinct clinical phenotypes. Wolman disease is rapidly progressive with onset in early infancy. Complete enzyme deficiency results in massive accumulation of cholesterol esters and triglycerides in intestines, liver, spleen and other monocyte-macrophage system cells causing malabsorption, hepatosplenomegaly, liver failure and death in early infancy. Cholesterol ester storage disease may be diagnosed in childhood or later in life. It is characterized by chronic course and variable progression. Main features are variously expressed hepatopathy, including cirrhosis and liver failure, hypercholesterolemia and premature atherosclerosis. Characteristic is pathohistological finding of microvesicular steatosis and fibrosis and patognomonic are typical cholesterol ester crystals. Diagnosis is confirmed by enzyme assay and/or gene analysis. Until recently treatment was symptomatic. Ongoing clinical trials of enzyme replacement therapy have shown very promising results. We are presenting an infant with Wolman disease and two children with cholesterol ester storage disease with the aim to raise awareness about this disease and to start optimal care early.
Assuntos
Doença do Armazenamento de Colesterol Éster/tratamento farmacológico , Terapia de Reposição de Enzimas , Doença de Wolman/tratamento farmacológico , Criança , Doença do Armazenamento de Colesterol Éster/complicações , Doença do Armazenamento de Colesterol Éster/diagnóstico , Humanos , Lactente , Doença de Wolman/complicações , Doença de Wolman/diagnóstico , Doença de WolmanRESUMO
Familial hypercholesterolemia (FH) is a genetic disorder characterized by elevated low-density lipoprotein (LDL) cholesterol and premature cardiovascular disease, with a prevalence of approximately 1 in 200-500 for heterozygotes in North America and Europe. Monogenic FH is largely attributed to mutations in the LDLR, APOB, and PCSK9 genes. Differential diagnosis is critical to distinguish FH from conditions with phenotypically similar presentations to ensure appropriate therapeutic management and genetic counseling. Accurate diagnosis requires careful phenotyping based on clinical and biochemical presentation, validated by genetic testing. Recent investigations to discover additional genetic loci associated with extreme hypercholesterolemia using known FH families and population studies have met with limited success. Here, we provide a brief overview of the genetic determinants, differential diagnosis, genetic testing, and counseling of FH genetics.
Assuntos
Hiperlipoproteinemia Tipo II/genética , Apolipoproteína B-100/genética , Doença do Armazenamento de Colesterol Éster/diagnóstico , Diagnóstico Diferencial , Aconselhamento Genético , Predisposição Genética para Doença , Testes Genéticos , Humanos , Hipercolesterolemia/diagnóstico , Hiperlipoproteinemia Tipo II/diagnóstico , Enteropatias/diagnóstico , Erros Inatos do Metabolismo Lipídico/diagnóstico , Fitosteróis/efeitos adversos , Pró-Proteína Convertase 9 , Pró-Proteína Convertases/genética , Receptores de LDL/genética , Serina Endopeptidases/genética , Xantomatose Cerebrotendinosa/diagnósticoRESUMO
Lysosomal acid lipase (LAL) is responsible for the hydrolysis of cholesterol esters and triglycerides. LAL is coded by the LIPA gene on chromosome 10q23.31. Its deficiency leads to two autosomal recessive disorders, Wolman disease (WD) and Cholesteryl Ester Storage Disease (CESD). WD has an estimated incidence of 1 in 500,000 live births and is the result of a complete loss of LAL and presents in infancy with vomiting, diarrhea, poor weight gain and hepatomegaly subsequently leading to death. CESD is the result of partial loss of LAL and its presentation is more variable. Patients may be asymptomatic or present with nonspecific gastrointestinal symptoms, hepatomegaly, elevated transaminases and dystipidemia which may be confused with the diagnosis of Non-alcoholic Fatty Liver Disease. CESD is currently underdiagnosed and has an estimated prevalence as high as I in 40,000 individuals. Radiologic findings in WD is calcification of the adrenal glands. Hepatomegaly is noted on CT scan in both WD and CESD. MRI may demonstrate accumulation of cholesterol esters and may be useful to study effects of potential medical therapies. The diagnosis of WD and CESD is based on LIPA gene sequencing and the measurement of LAL levels in peripheral blood leukocytes. Treatment of LAL deficiency is currently limited to control of cholesterol levels and to prevent premature atherosclerosis. Use of enzyme replacement therapy with recombinant human LAL in short-term studies has shown to be safe and effective.
Assuntos
Doença do Armazenamento de Colesterol Éster/diagnóstico , Doença do Armazenamento de Colesterol Éster/tratamento farmacológico , Doença de Wolman/diagnóstico , Doença de Wolman/tratamento farmacológico , Anticolesterolemiantes/uso terapêutico , Transplante de Medula Óssea , Terapia de Reposição de Enzimas , Humanos , Esterol Esterase/genética , Resultado do TratamentoRESUMO
Lysosomal acid lipase (LAL) deficiency produces two well defined inborn disorders, Wolman disease (WD) and cholesteryl ester storage disease (CESD). WD is a severe, early-onset condition involving massive storage of triglycerides and cholesteryl esters in the liver, with death usually occurring before one year of life. CESD is a more attenuated, later-onset disease that leads to a progressive and variable liver dysfunction. Diagnosis of LAL deficiency is mainly based on the enzyme assay of LAL activity in fibroblasts. Recently, a selective acid lipase inhibitor was used for the determination of enzyme activity in dried-blood filter paper (DBFP) samples. To extend and to validate these studies, we tested LAL activity with selective inhibition on DBFP samples, leukocytes and fibroblasts. Our results showed a clear discrimination between patients with LAL deficiency and healthy controls when using DBFP, leukocytes or fibroblasts (p<0.001). Deficiency of LAL was also demonstrated in individuals referred to our laboratory with suspected clinical diagnosis of WD, CESD, and Niemann-Pick type B. We conclude that the assay of LAL using selective inhibitor is a reliable and useful method for the identification of LAL deficiency, not only in DBFP samples but also in leukocytes and fibroblasts. This is important as enzyme replacement therapy for LAL deficiency is currently being developed, making the correct diagnosis a critical issue.
Assuntos
Carbamatos/farmacologia , Doença do Armazenamento de Colesterol Éster/diagnóstico , Lipase/antagonistas & inibidores , Tiadiazóis/farmacologia , Doença de Wolman/diagnóstico , Células Cultivadas , Teste em Amostras de Sangue Seco , Fibroblastos/enzimologia , Humanos , Leucócitos/enzimologia , Fígado/enzimologia , Doenças de Niemann-Pick/diagnóstico , Esterol Esterase/antagonistas & inibidores , Doença de WolmanRESUMO
Fluorometric measurements of 4-methylumbelliferone (4-MU) are generally used to screen lysosomal storage diseases (LSDs) using dried blood spots (DBSs). However, in DBS, it is difficult to measure lysosomal acid lipase (LAL) activity due to the influence of other lipases in whole blood. Recently, Hamilton used a fluorometric enzyme assay with 4-MU derivatives to measure the LAL activity in DBS. This method requires mercury chloride as stopping reagent, and the fluorescence intensity of 4-MU was measured at an acidic pH. We report a revised method to measure the LAL activity without using toxic mercury chloride and to measure the fluorescence intensity of 4-MU at a basic pH. For this measurement, we established a more practical method that does not require mercury chloride. The LAL activity in DBS was measured in 51 normal controls, seven obligate carriers and seven patients with CESD. The average LAL activities ± SD in the DBS from the normal, obligate carriers and CESD patients were 0.68 ± 0.2 (range: 0.3-1.08), 0.21 ± 0.1 (range: 0.11-0.41) and 0.02 ± 0.02 (range: 0-0.06) nmol/punch/h, respectively. There was a significant difference between the normal and the CESD. Our method does not require toxic mercury chloride and is an appropriate revised enzyme assay using DBS for screening patients with CESD.