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: Kearns-Sayre Syndrome (KSS) and Pearson Marrow-Pancreas Syndrome (PMPS) are among the classic phenotypes caused by mitochondrial DNA (mtDNA) deletions. KSS is a rare mitochondrial disease defined by a classic triad of progressive external ophthalmoplegia, atypical pigmentary retinopathy, and onset before 20 years. PMPS presents in the first year of life with bone marrow failure and exocrine pancreatic dysfunction, and can evolve into KSS later in life. Even though an mtDNA deletion is the most frequent mutation in KSS and PMPS, cases of duplications and molecular rearrangements have also been described. In Colombia, few case reports of KSS and PMPS have been published in indexed journals or have been registered in scientific events. METHODS: We discuss clinical and genetic aspects of two case reports of pediatric female patients, with initial clinical diagnosis of PMPS who later evolved into KSS, with confirmatory molecular studies of an mtDNA deletion and an mtDNA duplication. RESULTS: A large-scale mtDNA deletion, NC_012920.1:m.8286_14416del, was confirmed by Southern Blot in patient 1. An mtDNA duplication of 7.9 kb was confirmed by MLPA in patient 2. CONCLUSIONS: Our findings are compatible with the phenotypic and genetic presentation of PMPS and KSS. We present the first molecularly confirmed case reports of Colombian patients, diagnosed initially with PMPS, who later evolved to KSS.
Assuntos
Síndrome Congênita de Insuficiência da Medula Óssea/genética , DNA Mitocondrial/genética , Síndrome de Kearns-Sayre/genética , Erros Inatos do Metabolismo Lipídico/genética , Doenças Mitocondriais/genética , Doenças Musculares/genética , Criança , Síndrome Congênita de Insuficiência da Medula Óssea/patologia , Diagnóstico Diferencial , Feminino , Duplicação Gênica , Humanos , Síndrome de Kearns-Sayre/patologia , Erros Inatos do Metabolismo Lipídico/patologia , Doenças Mitocondriais/patologia , Doenças Musculares/patologia , Fenótipo , Deleção de SequênciaRESUMO
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
Sitosterolemia is a disease characterized by an intestinal hyperabsorption of plant sterols and cholesterol. Affected individuals have mutations in both alleles of either ABCG5 or ABCG8 genes, leading to a total loss of one of the proteins and subsequent functional deficiency. We here report a Mexican family with clinical and biochemical features of sitosterolemia carrying 2 new mutations of the ABCG5 gene. Concentrations of sitosterol, campesterol, and cholesterol were found to be higher for the index case (a 10-year-old girl) than for her also affected sibling (64.1 vs 19 mg/dL, 32 vs 12.1 mg/dL, and cholesterol 295 vs 235 mg/dL, respectively). Both individuals showed 2 new ABCG5 gene mutations identified by sequencing, which is concordant with their biochemical diagnosis of sitosterolemia. The first mutation was a c.144 -1G>A transition that disrupts the intron 1 splicing acceptor site. The second mutation is the deletion c.1523 delC, which occurred in exon 11, causing an amino acid change at codon 510 (p.His510Thr) and a stop codon at codon 511 (p.Leu511X). The father is heterozygote for the mutation c.144 -1G>A, whereas the mother is heterozygote for the mutation c.1523 delC. In conclusion, we here report the first case of a Mexican family with sitosterolemia carrying two new ABCG5 gene mutations.
Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Hipercolesterolemia/genética , Enteropatias/genética , Erros Inatos do Metabolismo Lipídico/genética , Lipoproteínas/genética , Mutação , Linhagem , Fitosteróis/efeitos adversos , Membro 5 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Adolescente , Sequência de Bases , Criança , Feminino , Humanos , Masculino , México , Pessoa de Meia-Idade , Dados de Sequência Molecular , Fitosteróis/genética , Adulto JovemRESUMO
PURPOSE OF REVIEW: The purpose of this review is to describe advances in the diagnosis, cause, metabolism, risk factors for atherosclerosis, and treatment of familial hypercholesterolemia. RECENT FINDINGS: Heterozygous familial hypercholesterolemia is almost four-fold more frequent than previously thought and is associated with 10-fold to 13-fold risk of cardiovascular disease comparing with normolipidemics. LDL receptor (LDLR) dysfunction and LDL-cholesterol (LDL-C) accumulation disturb the metabolism of other lipoprotein classes, such as chylomicrons and remnants and HDL. Next-generation sequencing can improve familial hypercholesterolemia molecular diagnosis due to its better performance and lower costs than usual techniques. Despite this, roughly 40% of familial hypercholesterolemia patients do not present mutations on the LDLR, apolipoprotein B, or proprotein convertase subtilisin/kexin type 9 genes. Many individuals with familial hypercholesterolemia phenotype have polygenic instead of monogenic cause of their elevated LDL-C concentrations. Individuals with familial hypercholesterolemia show elevated burden of subclinical atherosclerosis. The intensity of atherosclerosis burden is associated with the severity of LDLR mutation rather than maternal or paternal heritability. Newer-approved and on-development medications that reduce LDL-C hold promise for preventing cardiovascular disease in familial hypercholesterolemia. SUMMARY: Familial hypercholesterolemia is frequent and currently underdiagnosed and undertreated, but effective cascade screening programs and early and intensive LDL-C lowering can change this picture and the natural history of the disease.
Assuntos
Hipercolesterolemia , Erros Inatos do Metabolismo Lipídico , Apolipoproteínas B/sangue , Apolipoproteínas B/genética , Aterosclerose/sangue , Aterosclerose/tratamento farmacológico , Aterosclerose/genética , LDL-Colesterol/sangue , LDL-Colesterol/genética , Humanos , Hipercolesterolemia/sangue , Hipercolesterolemia/tratamento farmacológico , Hipercolesterolemia/genética , Erros Inatos do Metabolismo Lipídico/sangue , Erros Inatos do Metabolismo Lipídico/tratamento farmacológico , Erros Inatos do Metabolismo Lipídico/genética , Mutação , Receptores de LDL/genética , Receptores de LDL/metabolismo , Fatores de RiscoRESUMO
TITLE: Enfermedades mitocondriales.
Assuntos
Erros Inatos do Metabolismo dos Carboidratos/genética , Erros Inatos do Metabolismo Lipídico/genética , Doenças Musculares/genética , HumanosRESUMO
Mutation in ABHD5 causes Dorfman-Chanarin syndrome (DCS), a multisystem triglyceride storage disorder. Ultrastructural study of leukocytes confirmed DCS in a child homozygous for a novel ABHD5 mutation, with ichthyosis, developmental delay, and steatohepatitis with cirrhosis, manifest only as elevated aminotranferase levels. We recommend early assessment for liver disease in DCS.
Assuntos
Fígado Gorduroso/etiologia , Hepatite/etiologia , Erros Inatos do Metabolismo Lipídico/complicações , Cirrose Hepática/etiologia , Triglicerídeos/metabolismo , 1-Acilglicerol-3-Fosfato O-Aciltransferase , Criança , Esterases/genética , Fígado Gorduroso/diagnóstico , Fígado Gorduroso/terapia , Feminino , Hepatite/diagnóstico , Hepatite/terapia , Humanos , Lipase/genética , Erros Inatos do Metabolismo Lipídico/genética , Erros Inatos do Metabolismo Lipídico/terapia , Cirrose Hepática/patologia , Cirrose Hepática/terapia , SíndromeRESUMO
OBJECTIVES: To evaluate the feasibility of molecular prenatal diagnosis in families with mitochondrial trifunctional protein (TFP) mutations and prospectively study the effects of fetal genotype on pregnancy outcome. TFP catalyzes the last 3 steps in mitochondrial long-chain fatty acid oxidation. STUDY DESIGN: We performed molecular prenatal diagnosis in 9 pregnancies, 8 in 6 families with isolated long-chain 3-hydroxyacyl-coenzyme A dehydrogenase (LCHAD) deficiency and one in a family with complete TFP deficiency. Analyses were performed on chorionic villous samples in 7 pregnancies and on amniocytes in 2. RESULTS: Molecular prenatal diagnosis successfully identified the fetal genotype in all 9 pregnancies. Two fetuses were affected, and both pregnancies were terminated by family decision. Two other fetuses had normal genotype and 5 others were heterozygotes. These 7 pregnancies were uncomplicated, and all the offspring are alive and apparently healthy. Genotypes of the aborted fetuses and neonates were confirmed by molecular analysis and enzymatic assays. CONCLUSIONS: Molecular prenatal diagnosis is possible and valid in guiding management of pregnancies in families with known TFP defects. Women heterozygous for TFP alpha-subunit mutations who carry fetuses with wild-type or heterozygous genotypes have uncomplicated pregnancies.