RESUMO
Sitosterolemia is an autosomal recessive and very rare disease. Its main characteristic is that there is a greater absorption and a decrease in the excretion of sterols, which leads to them being deposited in tissues. It is given by mutations in the ABCG5 or ABCG8 genes found on chromosome 2p21. In this clinical note, we describe the first two patients with familial sitosterolemia described in Colombia, brothers, one of them with xanthomas in extremities as the only symptom, and the other, completely asymptomatic. Genetic studies were performed as a diagnostic test in both patients, where a pathogenic homozygous variant could be identified in the ABCG8 gene in the first case (symptomatic), and a heterozygous variant in the ABCG8 gene in the second case (asymptomatic); the first patient has responded to treatment with ezetimibe. In conclusion, xanthomas should be studied in depth in pediatric age as they may be the only visible sign of such complex and hereditary diseases as familial sitosterolemia, which can be controlled and prevent cardiovascular complications of the disease.
Assuntos
Membro 8 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Ezetimiba , Hipercolesterolemia , Enteropatias , Erros Inatos do Metabolismo Lipídico , Fitosteróis , Humanos , Erros Inatos do Metabolismo Lipídico/genética , Erros Inatos do Metabolismo Lipídico/diagnóstico , Masculino , Colômbia , Fitosteróis/efeitos adversos , Fitosteróis/genética , Enteropatias/genética , Enteropatias/diagnóstico , Membro 8 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Hipercolesterolemia/genética , Hipercolesterolemia/tratamento farmacológico , Hipercolesterolemia/diagnóstico , Ezetimiba/uso terapêutico , Xantomatose/genética , Xantomatose/patologia , Xantomatose/diagnóstico , Anticolesterolemiantes/uso terapêutico , Anticolesterolemiantes/administração & dosagem , Mutação , Membro 5 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Homozigoto , Criança , Heterozigoto , Lipoproteínas/genéticaRESUMO
PURPOSE OF REVIEW: The purpose of this review was to summarize important and updated information on sitosterolemia. Sitosterolemia is an inherited lipid disorder consisting of high levels of plasma plant sterols. This sterol storage condition is caused by biallelic loss-of-function genetic variants in either ABCG5 or ABCG8, leading to increased intestinal absorption and decreased hepatic excretion of plant sterols. Clinically, patients with sitosterolemia usually exhibit xanthomatosis, high levels of plasma cholesterol, and premature atherosclerotic disease, but presentation can be highly heterogeneous. Therefore, recognition of this condition requires a high level of suspicion, with confirmation upon genetic diagnosis or through measurement of plasma phytosterols. Treatment of sitosterolemia with both a plant sterol-restricted diet and the intestinal cholesterol absorption inhibitor ezetimibe can reduce efficiently the levels of plasma plant sterols, consisting in the first-line therapy for this disease. RECENT FINDINGS: Since hypercholesterolemia is often present in individuals with sitosterolemia, it is important to search for genetic variants in ABCG5 and ABCG8 in patients with clinical criteria for familial hypercholesterolemia (FH), but no variants in FH implicated genes. Indeed, recent studies have suggested that genetic variants in ABCG5/ABCG8 can mimic FH, and even when in heterozygosis, they may potentially exacerbate the phenotype of patients with severe dyslipidemia. Sitosterolemia is a genetic lipid disorder characterized by increased circulating levels of plant sterols and clinically manifested by xanthomatosis, hematologic disorders, and early atherosclerosis. Awareness about this condition, a rare, but commonly underdiagnosed and yet treatable cause of premature atherosclerotic disease, is imperative.
Assuntos
Aterosclerose , Hipercolesterolemia , Hiperlipoproteinemia Tipo II , Enteropatias , Erros Inatos do Metabolismo Lipídico , Fitosteróis , Xantomatose , Humanos , Hipercolesterolemia/tratamento farmacológico , Fitosteróis/efeitos adversos , Fitosteróis/genética , Erros Inatos do Metabolismo Lipídico/diagnóstico , Erros Inatos do Metabolismo Lipídico/genética , Erros Inatos do Metabolismo Lipídico/terapia , Enteropatias/diagnóstico , Enteropatias/genética , Enteropatias/tratamento farmacológico , Hiperlipoproteinemia Tipo II/complicações , Colesterol , Xantomatose/etiologia , Aterosclerose/genética , Aterosclerose/complicaçõesRESUMO
Mitochondrial fatty acid ß-oxidation disorders (FAODs) are a group of about 20 diseases which are caused by specific mutations in genes that codify proteins or enzymes involved in the fatty acid transport and mitochondrial ß-oxidation. As a consequence of these inherited metabolic defects, fatty acids can not be used as an appropriate energetic source during special conditions, such as prolonged fasting, exercise or other catabolic states. Therefore, patients usually present hepatopathy, cardiomyopathy, severe skeletal myopathy and neuropathy, besides biochemical features like hypoketotic hypoglycemia, metabolic acidosis, hypotony and hyperammonemia. This set of symptoms seems to be related not only with the energy deficiency, but also with toxic effects provoked by fatty acids and carnitine derivatives accumulated in the tissues of the patients. The understanding of the mechanisms by which these metabolites provoke tissue injury in FAODs is crucial for the developmental of novel therapeutic strategies that promote increased life expectancy, as well as improved life quality for patients. In this sense, the objective of this review is to present evidence from the scientific literature on the role of oxidative damage and mitochondrial dysfunction in the pathogenesis of the most prevalent FAODs: medium-chain acyl-CoA dehydrogenase (MCAD), long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) and very long-chain acyl-CoA dehydrogenase (VLCAD) deficiencies. It is expected that the findings presented in this review, obtained from both animal model and patients studies, may contribute to a better comprehension of the pathophysiology of these diseases.
Assuntos
Acidose , Erros Inatos do Metabolismo Lipídico , Doenças Musculares , Acidose/metabolismo , Animais , Ácidos Graxos , Humanos , Erros Inatos do Metabolismo Lipídico/diagnóstico , Erros Inatos do Metabolismo Lipídico/genética , Erros Inatos do Metabolismo Lipídico/metabolismo , Mitocôndrias/metabolismo , Doenças Musculares/metabolismo , Oxirredução , Estresse OxidativoRESUMO
BACKGROUND: Inborn errors of metabolism (IEM) are diseases which can lead to accumulation of toxic metabolites in the organism. AIM OF THE STUDY: To investigate, by selective screening, mitochondrial fatty acid oxidation defects (FAOD) and organic acidemias in Brazilian individuals with clinical suspicion of IEM. METHODS: A total of 7,268 individuals, from different regions of Brazil, had whole blood samples impregnated on filter paper which were submitted to the acylcarnitines analysis by liquid chromatography/tandem mass spectrometry (LC/MS/MS) at the Medical Genetics Service of Hospital de Clínicas de Porto Alegre, Brazil, during July 2008-July 2016. RESULTS: Our results showed that 68 patients (0.93%) were diagnosed with FAOD (19 cases) and organic acidemias (49 cases). The most prevalent FAOD was multiple acyl CoA dehydrogenase deficiency (MADD), whereas glutaric type I and 3-OH-3-methylglutaric acidemias were the most frequent disorders of organic acid metabolism. Neurologic symptoms and metabolic acidosis were the most common clinical and laboratory features, whereas the average age of the patients at diagnosis was 2.3 years. CONCLUSIONS: Results demonstrated a high incidence of glutaric acidemia type I and 3-OH-3- methylglutaric acidemia in Brazil and an unexpectedly low incidence of FAOD, particularly medium-chain acyl-CoA dehydrogenase deficiency (MCADD).
Assuntos
Acil-CoA Desidrogenase/deficiência , Erros Inatos do Metabolismo dos Aminoácidos/diagnóstico , Encefalopatias Metabólicas/diagnóstico , Carnitina/análogos & derivados , Ácidos Graxos/metabolismo , Glutaril-CoA Desidrogenase/deficiência , Erros Inatos do Metabolismo Lipídico/diagnóstico , Acil-CoA Desidrogenase/sangue , Erros Inatos do Metabolismo dos Aminoácidos/sangue , Encefalopatias Metabólicas/sangue , Brasil , Carnitina/análise , Pré-Escolar , Cromatografia Líquida , Feminino , Glutaratos/metabolismo , Glutaril-CoA Desidrogenase/sangue , Humanos , Recém-Nascido , Erros Inatos do Metabolismo Lipídico/sangue , Masculino , Programas de Rastreamento , Oxirredução , Prevalência , Espectrometria de Massas em Tandem , Adulto JovemRESUMO
Sitosterolemia is an autosomal recessive metabolic disease caused by mutations in ABCG5 or ABCG8 genes which encode for the (ATP)-binding cassette (ABC) transporters that are responsible for the trafficking of xenosterols. Liver involvement is not a recognized manifestation of this disease, and cirrhosis has been reported only once in the medical literature. We describe a fatal case of a 21-year old South Asian male who presented with decompensated cirrhosis, and biochemical abnormalities consistent with sitosterolemia. Genetic testing showed a homozygous pathogenic mutation in ABCG5, confirming the diagnosis. Sitosterolemia is a rare, but likely under-recognized condition, and a high degree of suspicion is imperative to make the diagnosis. We propose that sitosterolemia should be included in the differential diagnosis for patients with cryptogenic cirrhosis, especially as there are effective oral therapies to treat this condition. Newly diagnosed sitosterolemia patients should undergo a thorough hepatology evaluation and follow-up to evaluate for the presence, development, and progression of any hepatic involvement.
Assuntos
Hipercolesterolemia/complicações , Enteropatias/complicações , Erros Inatos do Metabolismo Lipídico/complicações , Cirrose Hepática/etiologia , Fitosteróis/efeitos adversos , Membro 5 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Anemia Hemolítica/etiologia , Anticolesterolemiantes/uso terapêutico , Biópsia , Angiografia Coronária , Doença da Artéria Coronariana/etiologia , Análise Mutacional de DNA , Dieta com Restrição de Gorduras , Ezetimiba/uso terapêutico , Evolução Fatal , Predisposição Genética para Doença , Hereditariedade , Homozigoto , Humanos , Hipercolesterolemia/diagnóstico , Hipercolesterolemia/genética , Hipercolesterolemia/terapia , Enteropatias/diagnóstico , Enteropatias/genética , Enteropatias/terapia , Erros Inatos do Metabolismo Lipídico/diagnóstico , Erros Inatos do Metabolismo Lipídico/genética , Erros Inatos do Metabolismo Lipídico/terapia , Lipoproteínas/genética , Cirrose Hepática/diagnóstico , Masculino , Microscopia Eletrônica , Mutação , Linhagem , Fenótipo , Fitosteróis/genética , Fatores de Risco , Resultado do Tratamento , Xantomatose/etiologia , Adulto JovemRESUMO
OBJECTIVES: To test whether follow-up testing for very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency uncovers a diagnosis in patients with elevations of C14:1 and C14:2 plasma acylcarnitines after a controlled fasting study performed for clinically suspected hypoglycemia and to compare the acylcarnitine profiles from fasted patients without VLCAD deficiency vs patients with known VLCAD deficiency to determine whether metabolite testing distinguishes these groups. STUDY DESIGN: We performed a retrospective chart review and identified 17 patients with elevated C14:1 and C14:2 plasma acylcarnitine levels after a controlled fast and with testing for VLCAD deficiency (ACADVL sequencing or fibroblast fatty acid oxidation studies). The follow-up testing in all patients was inconsistent with a diagnosis of VLCAD deficiency. We compared the plasma acylcarnitine profiles from these fasted patients vs patients with VLCAD deficiency. RESULTS: C14:1/C12:1 was significantly lower (P < .001) in fasted patients vs patients with VLCAD deficiency. Metabolomics analysis performed in 2 fasted patients and 1 patient with VLCAD deficiency demonstrated evidence for up-regulated lipolysis and ß-oxidation in the fasted state. CONCLUSIONS: Elevations of plasma C14:1 and C14:2 acylcarnitines appear to be a physiologic result of lipolysis that occurs with fasting. Both metabolomics analysis and/or C14:1/C12:1 may distinguish C14:1 elevations from physiologic fasting-induced lipolysis vs VLCAD deficiency.
Assuntos
Acil-CoA Desidrogenase de Cadeia Longa/deficiência , Carnitina/análogos & derivados , Jejum/sangue , Erros Inatos do Metabolismo Lipídico/sangue , Erros Inatos do Metabolismo Lipídico/diagnóstico , Doenças Mitocondriais/sangue , Doenças Mitocondriais/diagnóstico , Doenças Musculares/sangue , Doenças Musculares/diagnóstico , Acil-CoA Desidrogenase de Cadeia Longa/sangue , Adolescente , Carnitina/sangue , Criança , Pré-Escolar , Síndrome Congênita de Insuficiência da Medula Óssea , Feminino , Humanos , Lactente , Masculino , Estudos RetrospectivosRESUMO
INTRODUCTION: Acylcarnitine measurement in blood is a useful test for the diagnosis of inherited errors of mitochondrial fatty acid beta-oxidation. However, there are few data in the literature on the reference ranges of the various acylcarnitines and on whether these reference ranges are age- or sex-dependent. OBJECTIVES: To draw attention to inherited errors of mitochondrial fatty acid beta-oxidation and to establish reference acylcarnitine values in children. PATIENTS AND METHODS: A total of 309 blood samples from healthy children divided into four age groups (group A: <1 month; group B: 1-12 months; group C: 1-7 years; group D: 7-18 years) were obtained and analyzed using tandem mass spectrometry. RESULTS AND CONCLUSION: Reference acylcarnitine values in children are provided. No significant differences were found in relation to age or sex. Our results differ from those reported in the literature reviewed. Importantly, hydroxyacylcarnitines and glutaryl carnitine are absent when normal samples are processed. We review the literature on the main clinical and laboratory findings in mitochondrial fatty acid beta-oxidation deficiencies.
Assuntos
Carnitina/análogos & derivados , Ácidos Graxos/metabolismo , Erros Inatos do Metabolismo Lipídico/sangue , Erros Inatos do Metabolismo Lipídico/diagnóstico , Doenças Mitocondriais/diagnóstico , Adolescente , Carnitina/sangue , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Doenças Mitocondriais/sangue , Oxirredução , Valores de ReferênciaRESUMO
OBJECTIVE: To assess the cost-effectiveness of neonatal screening on medium chain acyl-CoA dehydrogenase (MCAD) deficiency in a homogeneous population. STUDY DESIGN: For the scenario without neonatal screening, medical chart review and interviews were performed with physicians and families of 116 Dutch patients born between 1985 and July 2003 with clinically ascertained MCAD deficiency. For the scenario with neonatal screening, 66,205 unaffected and 11 affected newborns identified by prospective neonatal screening for MCAD deficiency in the northern part of the Netherlands were evaluated. The incremental cost-effectiveness ratio (ICER) used life years (LYs) as the outcome measure by combining both scenarios in a decision model with second-order Monte Carlo simulation. RESULTS: For the scenarios with and without neonatal screening for MCAD deficiency, costs were $6.10 and $4.22 per newborn, respectively. The main cost categories were institutionalization (64%), admissions (17%), special education (8%), laboratory testing (4%), and (para)medical contact (4%). The resulting ICER was $1653 per LY gained. Sensitivity analysis generated an ICER between $14,839 and $4345 per LY gained. CONCLUSIONS: Screening for MCAD deficiency in a well-defined population generates an ICER well within accepted boundaries for cost-effective interventions, even after sensitivity analysis.
Assuntos
Acil-CoA Desidrogenase/deficiência , Efeitos Psicossociais da Doença , Custos de Cuidados de Saúde , Erros Inatos do Metabolismo Lipídico/economia , Triagem Neonatal/economia , Estudos de Casos e Controles , Análise Custo-Benefício , Feminino , Humanos , Incidência , Recém-Nascido , Erros Inatos do Metabolismo Lipídico/diagnóstico , Erros Inatos do Metabolismo Lipídico/epidemiologia , Masculino , Triagem Neonatal/normas , Países Baixos , Valores de Referência , Estudos Retrospectivos , Medição de RiscoRESUMO
OBJECTIVE: To describe and analyze the use and costs of hospital services for children diagnosed with medium-chain acyl-CoA dehydrogenase (MCAD) deficiency either with newborn screening or clinical diagnosis in Australia between 1994 and 2002. MCAD deficiency is a potentially lethal disorder of fatty-acid oxidation. STUDY DESIGN: We conducted a retrospective audit of medical records supplemented by a parental survey. RESULTS: A total of 59 children with MCAD deficiency were identified, 24 by using newborn screening. In the first 4 years of life, screening children cost an average of A$1676 (US$1297) per year for inpatient, emergency department, and outpatient visits, compared with A$1796 (US$1390) for children in whom a clinical diagnosis was made. Forty-two percent of the children who underwent screening were admitted to the hospital, compared with 71% of children who did not undergo screening. Children who did not undergo screening used significantly more inpatient services and cost significantly more in emergency services. There were also some significant differences in use on a year-by-year basis. CONCLUSIONS: Children who do not undergo screening may be more likely to be admitted to the hospital and to incur higher emergency department costs than children who underwent screening, and children seem more likely to attend hospital outpatient clinics. Screening does not result in higher costs from a hospital perspective.