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1.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(11): 1067-1072, 2019 Nov 10.
Artigo em Chinês | MEDLINE | ID: mdl-31703127

RESUMO

OBJECTIVE: To determine the incidence and mutational types of fatty acid oxidation disorders (FAOD) in central-northern region of Guangxi. METHODS: A total of 62 953 neonates were screened for FAOD during December 2012 and December 2017. Acyl-carnitine profiling of neonatal blood sample was performed by tandem mass spectrometry using dry blood spots on a filter paper. The diagnosis of FAOD was confirmed by organic acid profiling of urea and genetic testing. RESULTS: Eighteen cases of FAOD were diagnosed among the 62 953 neonates. Among these, primary carnitine deficiency (PCD) was the most common type (n=13), which was followed by short-chain acyl-CoA dehydrogenase deficiency (SCADD) (n=2), medium-chain acyl-CoA dehydrogenase deficiency (MCADD) (n=1), multiple acyl-CoA dehydrogenase deficiency (MADD) (n=1), and carnitine palmitoyltransferase II deficiency (CPT II D) (n=1). Genetic testing has revealed two previously unreported variants, i.e., c.337G to A (p.Gly113Arg) of ACADS gene and c.737G TO T (p.Gly246Val) of ETFA gene. CONCLUSION: PCD is the most common FAOD in central-northern Guangxi. Tandem mass spectrometry combined with genetic testing may facilitate early diagnosis of FAOD.


Assuntos
Erros Inatos do Metabolismo Lipídico/diagnóstico , Erros Inatos do Metabolismo Lipídico/genética , Acil-CoA Desidrogenase/deficiência , Acil-CoA Desidrogenase/genética , Carnitina/sangue , Carnitina O-Palmitoiltransferase/deficiência , China , Flavoproteínas Transferidoras de Elétrons/genética , Humanos , Recém-Nascido , Erros Inatos do Metabolismo/diagnóstico , Deficiência Múltipla de Acil Coenzima A Desidrogenase/diagnóstico , Triagem Neonatal , Espectrometria de Massas em Tandem
2.
J Pediatr Ophthalmol Strabismus ; 56: e60-e64, 2019 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-31622479

RESUMO

Retinopathy of prematurity (ROP) is a biphasic disease in which the first phase is characterized by high oxygen tension leading to vaso-obliteration in the retina. Pearson syndrome is a rare multisystem mitochondrial disease with a defect in cellular respiration. The authors describe a patient with Pearson syndrome and delayed onset of ROP at a postconceptual age of 42 weeks. The proposed mechanistic theory was the increased oxygen use associated with the metabolic impairments in Pearson syndrome counterbalancing the effects of supplemental oxygen during the vaso-obliterative stage of ROP. [J Pediatr Ophthalmol Strabismus. 2019;56:e60-e64.].


Assuntos
Acil-CoA Desidrogenase de Cadeia Longa/deficiência , Recém-Nascido de Baixo Peso , Erros Inatos do Metabolismo Lipídico/diagnóstico , Doenças Mitocondriais/diagnóstico , Doenças Musculares/diagnóstico , Oxigênio/metabolismo , Retinopatia da Prematuridade/diagnóstico , Acil-CoA Desidrogenase de Cadeia Longa/metabolismo , Progressão da Doença , Feminino , Angiofluoresceinografia/métodos , Seguimentos , Fundo de Olho , Idade Gestacional , Humanos , Recém-Nascido , Erros Inatos do Metabolismo Lipídico/metabolismo , Doenças Mitocondriais/metabolismo , Doenças Musculares/metabolismo , Retinopatia da Prematuridade/metabolismo , Fatores de Tempo
3.
Pediatrics ; 144(1)2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31227563

RESUMO

A 2-day old term male infant was found to be hypotonic and minimally reactive during routine nursing care in the newborn nursery. At 40 hours of life, he was hypoglycemic and had intermittent desaturations to 70%. His mother had an unremarkable pregnancy and spontaneous vaginal delivery. The mother's prenatal serology results were negative for infectious risk factors. Apgar scores were 9 at 1 and 5 minutes of life. On day 1 of life, he fed, stooled, and voided well. Our expert panel discusses the differential diagnosis of hypotonia in a neonate, offers diagnostic and management recommendations, and discusses the final diagnosis.


Assuntos
Acil-CoA Desidrogenase de Cadeia Longa/deficiência , Letargia/etiologia , Erros Inatos do Metabolismo Lipídico/diagnóstico , Doenças Mitocondriais/diagnóstico , Hipotonia Muscular/etiologia , Doenças Musculares/diagnóstico , /terapia , Diagnóstico Diferencial , Humanos , Hipotermia/etiologia , Recém-Nascido , Erros Inatos do Metabolismo Lipídico/terapia , Masculino , Doenças Mitocondriais/terapia , Doenças Musculares/terapia
5.
Clin Chim Acta ; 495: 476-480, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31108048

RESUMO

Carnitine-acylcarnitine translocase deficiency (CACTD) is a rare autosomal recessive disorder of mitochondrial fatty acid oxidation that occurs due to mutations in the SLC25A20 gene. Severe CACTD results in neonatal or infantile sudden death. Herein, we reported six patients with CACTD diagnosed based on biochemical and molecular findings from 5 unrelated families in Guangdong from 2016 to 2017. Among them, five patients presented with hypotonia, nonketotic hypoglycemia, and arrhythmia 2 days after birth, while the other patient presented with respiratory distress, hypotonia, and arrhythmia. Five of the patients died in the neonatal period. Blood acylcarnitine concentrations determination from dried blood spots (DBS) were measured by tandem mass spectrometry (MS/MS). The SLC25A20 and CPT2 gene sequences were analyzed by direct Sanger sequencing. SLC25A20 gene analysis revealed a c.199-10T>G (IVS2-10T>G) homozygous variants in four unrelated patients and a novel mutation c.199-10T>G/c.719-8_c.719-1dupCCCACAG compound heterozygous variants in twins. This report describes the clinical characteristics, biochemical findings and molecular analysis of SLC25A20 gene of patients with CACTD in Guangdong. And our results show that the c.199-10T>G is likely the most common variant of CACTD in Guangdong population as it accounts for 83% (10/12) of the observed mutant alleles. Individuals with the c.199-10T>G genotype had a severe CACTD phenotype.


Assuntos
Carnitina Aciltransferases/deficiência , Erros Inatos do Metabolismo Lipídico/diagnóstico , Erros Inatos do Metabolismo Lipídico/genética , Proteínas de Transporte de Ânions/genética , Carnitina Aciltransferases/genética , China , Feminino , Genótipo , Humanos , Recém-Nascido , Masculino , Proteínas Mitocondriais/genética , Triagem Neonatal , Linhagem , Análise de Sequência de DNA
6.
Pediatr Int ; 61(6): 551-557, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31033143

RESUMO

BACKGROUND: Medium-chain acyl-coenzyme A dehydrogenase deficiency (MCADD) is a rare autosomal recessive disorder that affects the degradation of medium-chain fatty acids. Few cases of MCADD have been documented to date in mainland China. METHODS: Medium-chain acyl-coenzyme A dehydrogenase deficiency was diagnosed in six patients (three girls and three boys) from six unrelated Chinese families at ages ranging from 10 days to 3 years old. The diagnosis was confirmed by the identification of a primary biomarker of serum octanoyl-carnitine (C8) and genetic pathogenic mutations. RESULTS: Only two patients were admitted because of vomiting, diarrhea, myasthenia, and coma; the other four patients were diagnosed via the newborn screening process. Six mutations were found in acyl-CoA dehydrogenase medium chain (ACADM). One mutation (c.727C>T) was novel and the others (c.158G>A, c.387+1delG, c.449_452del, c.1045C>T, and c.1085G>A) have been previously reported. CONCLUSIONS: Six Chinese cases of MCADD were identified. One novel mutation was found. c.449_452del and c.1085G>A were common mutations in this study.


Assuntos
Acil-CoA Desidrogenase/deficiência , Acil-CoA Desidrogenase/genética , Erros Inatos do Metabolismo Lipídico/diagnóstico , Acil-CoA Desidrogenase/sangue , Biomarcadores/sangue , Carnitina/análogos & derivados , Carnitina/sangue , Pré-Escolar , China , Feminino , Marcadores Genéticos , Humanos , Lactente , Recém-Nascido , Erros Inatos do Metabolismo Lipídico/sangue , Erros Inatos do Metabolismo Lipídico/genética , Masculino , Mutação , Triagem Neonatal
7.
Mol Genet Metab ; 127(1): 64-73, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31031081

RESUMO

BACKGROUND: Very-Long-Chain Acyl-CoA Dehydrogenase (VLCAD) deficiency is a disorder of fatty acid oxidation included in the recommended uniform newborn screening (NBS) panel in the USA. It can have variable clinical severity and there is limited information on the natural history of this condition, clinical presentation according to genotype and effectiveness of newborn screening. METHODS: Retrospective data (growth parameters, morbidity, biochemical and genetic testing results) were collected from patients with VLCAD deficiency, to evaluate biochemical and clinical outcomes. Descriptive statistics was used for qualitative variables, while linear regression analysis was used to correlate continuous variables. RESULTS: VLCAD deficiency (screened by measuring elevated levels of C14:1-carnitine in blood spots) was more frequent in Utah than the national average (1:27,617 versus 1:63,481) in the first ten years of screening. Twenty-six patients had a confirmed diagnosis of VLCAD deficiency using DNA testing or functional studies. The c.848T>C (p.V283A) variant in the ACADVL gene was the most frequent in our population. Novel variants (c.623-21A>G (IVS7-21A>G); c.1052C>T (p.T351I); c.1183-7A>G (IVS11-7A>G); c.1281G>C (p.W427C); c.1923G>C (p.L641F); c.1924G>A (p.V642M)) were identified in this study, with their pathogenicity remaining unclear in most cases. C14:1-carnitine levels decreased with age and significantly correlated with CK levels as index of muscle involvement. There were no cases of HELLP syndrome nor liver disease during pregnancies in the mothers of VLCAD patients. None of our patients developed cardiac involvement after birth and all patients had normal growth parameters while on treatment. Clinical manifestations were related to concomitant infections and altered biochemical parameters. DISCUSSION: VLCAD deficiency can be identified by neonatal screening. Most patients compliant with therapy normalized biochemical parameters and had no major clinical manifestations. Complications were completely prevented with a relatively low number of pre-emptive ER visits or hospital admissions. It remains unclear whether neonatal screening is now identifying less severely affected patient or if complications will arise as subjects become older. Observation beyond puberty is necessary to fully understand the impact of VLCAD deficiency on morbidity in patients with VLCAD deficiency.


Assuntos
Acil-CoA Desidrogenase de Cadeia Longa/deficiência , Variação Genética , Erros Inatos do Metabolismo Lipídico/diagnóstico , Erros Inatos do Metabolismo Lipídico/genética , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/genética , Doenças Musculares/diagnóstico , Doenças Musculares/genética , Triagem Neonatal , Acil-CoA Desidrogenase de Cadeia Longa/genética , Adolescente , Carnitina/sangue , Criança , Pré-Escolar , Feminino , Genótipo , Humanos , Lactente , Recém-Nascido , Erros Inatos do Metabolismo Lipídico/terapia , Masculino , Doenças Mitocondriais/terapia , Morbidade , Doenças Musculares/terapia , Estudos Retrospectivos , Resultado do Tratamento , Utah , Adulto Jovem
9.
Orphanet J Rare Dis ; 14(1): 70, 2019 03 22.
Artigo em Inglês | MEDLINE | ID: mdl-30902101

RESUMO

BACKGROUND: We describe early health services utilization for children diagnosed with medium-chain acyl-CoA dehydrogenase (MCAD) deficiency through newborn screening in Ontario, Canada, relative to a screen negative comparison cohort. METHODS: Eligible children were identified via newborn screening between April 1, 2006 and March 31, 2010. Age-stratified rates of physician encounters, emergency department (ED) visits and inpatient hospitalizations to March 31, 2012 were compared using incidence rate ratios (IRR) and incidence rate differences (IRD). We used negative binomial regression to adjust IRRs for sex, gestational age, birth weight, socioeconomic status and rural/urban residence. RESULTS: Throughout the first few years of life, children with MCAD deficiency (n = 40) experienced statistically significantly higher rates of physician encounters, ED visits, and hospital stays compared with the screen negative cohort. The highest rates of ED visits and hospitalizations in the MCAD deficiency cohort occurred from 6 months to 2 years of age (ED use: 2.1-2.5 visits per child per year; hospitalization: 0.5-0.6 visits per child per year), after which rates gradually declined. CONCLUSIONS: This study confirms that young children with MCAD deficiency use health services more frequently than the general population throughout the first few years of life. Rates of service use in this population gradually diminish after 24 months of age.


Assuntos
Acil-CoA Desidrogenase/deficiência , Mau Uso de Serviços de Saúde/estatística & dados numéricos , Erros Inatos do Metabolismo Lipídico/epidemiologia , Erros Inatos do Metabolismo Lipídico/terapia , Peso ao Nascer , Pré-Escolar , Estudos de Coortes , Serviço Hospitalar de Emergência/estatística & dados numéricos , Feminino , Idade Gestacional , Hospitalização/estatística & dados numéricos , Humanos , Lactente , Recém-Nascido , Erros Inatos do Metabolismo Lipídico/diagnóstico , Masculino , Triagem Neonatal , Ontário/epidemiologia , Características de Residência , Fatores Socioeconômicos
10.
Clin Neuropathol ; 38(4): 157-167, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30738494

RESUMO

Neutral lipid storage disease with myopathy (NLSDM) is a triglyceride metabolic disorder caused by defects of adipose triglyceride lipases (ATGL). The coexistence of lipid vacuoles and rimmed vacuoles in the myofibers is a characteristic pathological change in some NLSDM cases. However, it has not been explored whether autophagic abnormalities exist in the NLSDM myofibers with rimmed vacuole. Herein, we report that 5 patients with NLSDM initially presented with muscle weakness in the right arm related to long-term physical efforts, then developed muscle weakness of other limbs. Pathogenic mutations in the PNPLA2 gene were identified in all patients. Myopathological analysis showed a coexistence of massive lipid vacuoles and rimmed vacuoles, which was not associated with the age of onset or mutation sites, but closely related to the severity of muscle degeneration. The rimmed vacuoles showed strong immunopositivity to autophagic markers, but were negative to apoptotic markers. Significant immunoreactivity of p62 was observed in the rimmed vacuoles, while the lysosomal marker LAMP1 was severely decreased. Our study expanded the clinical and genetic spectrum of NLSDM. Loss of ATGL activity in muscle fibers with rimmed vacuoles induced a marked increase in autophagic formation, but lowered down the turnover of autolysosomes due to malfunction of lysosomes.


Assuntos
Lipase/genética , Erros Inatos do Metabolismo Lipídico/genética , Músculo Esquelético/patologia , Doenças Musculares/patologia , Adulto , Apoptose/fisiologia , Autofagia , Feminino , Humanos , Eritrodermia Ictiosiforme Congênita/genética , Erros Inatos do Metabolismo Lipídico/diagnóstico , Erros Inatos do Metabolismo Lipídico/patologia , Glicoproteínas de Membrana Associadas ao Lisossomo/genética , Masculino , Pessoa de Meia-Idade , Doenças Musculares/diagnóstico , Doenças Musculares/genética , Mutação/genética , Vacúolos/genética
12.
Eur J Pediatr ; 178(3): 387-394, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30617651

RESUMO

Fatty acid ß-oxidation (FAO) disorders have a wide variety of symptoms, not usually evident between episodes of acute decompensations. Cardiac involvement is frequent, and severe ventricular arrhythmias are suspected of causing sudden death. Expanded newborn screening (ENS) for these disorders, hopefully, contribute to prevent potentially acute life-threatening events. In order to characterize acute decompensations observed in FAO-deficient cases identified by ENS, a retrospective analysis was performed, covering a period of 9 years. Demographic data, number/type of acute decompensations, treatment, and follow-up were considered. Eighty-three clinical charts, including 66 medium-chain acyl-CoA dehydrogenase deficiency (MCADD), 5 carnitine-uptake deficiency (CUD), 3 carnitine palmitoyltransferase I and II (CPT I/II) deficiency, 5 very long-chain acyl-CoA dehydrogenase deficiency (VLCADD), and 4 multiple acyl-CoA dehydrogenase deficiency (MADD) cases were reviewed. Nineteen patients had acute decompensations (1 CPT I, 1 CPT II, 3 MADD, 14 MCADD). Six patients developed symptoms previously to ENS diagnosis. Severe clinical manifestations included multiple organ failure, liver failure, heart failure, and sudden death. Long-chain FAO disorders had the highest number of decompensations per patient.Conclusion: Despite earlier diagnosis by ENS, sudden deaths were not avoided and acute decompensations with severe clinical manifestations still occur as well. What is Known: • Severe ventricular arrhythmias are suspected to cause unexpected death in FAO disorders. • Neonatal screening intends to reduce the incidence of severe metabolic crisis and death. What is New: • Acute severe decompensations occurred in FAO disorders diagnosed through neonatal screening. • Sudden deaths were not avoided by starting treatment precociously.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/diagnóstico , Erros Inatos do Metabolismo Lipídico/diagnóstico , Triagem Neonatal/métodos , Acil-CoA Desidrogenase/deficiência , Acil-CoA Desidrogenase de Cadeia Longa/deficiência , Erros Inatos do Metabolismo dos Aminoácidos/complicações , Erros Inatos do Metabolismo dos Aminoácidos/mortalidade , Cardiomiopatias/complicações , Cardiomiopatias/diagnóstico , Cardiomiopatias/mortalidade , Carnitina/deficiência , Carnitina O-Palmitoiltransferase/deficiência , Criança , Pré-Escolar , Diagnóstico Precoce , Feminino , Seguimentos , Humanos , Hiperamonemia/complicações , Hiperamonemia/diagnóstico , Hiperamonemia/mortalidade , Hipoglicemia/complicações , Hipoglicemia/diagnóstico , Hipoglicemia/mortalidade , Lactente , Recém-Nascido , Erros Inatos do Metabolismo Lipídico/complicações , Erros Inatos do Metabolismo Lipídico/mortalidade , Masculino , Erros Inatos do Metabolismo/complicações , Erros Inatos do Metabolismo/diagnóstico , Erros Inatos do Metabolismo/mortalidade , Doenças Mitocondriais/complicações , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/mortalidade , Deficiência Múltipla de Acil Coenzima A Desidrogenase/complicações , Deficiência Múltipla de Acil Coenzima A Desidrogenase/diagnóstico , Deficiência Múltipla de Acil Coenzima A Desidrogenase/mortalidade , Doenças Musculares/complicações , Doenças Musculares/diagnóstico , Doenças Musculares/mortalidade , Prognóstico , Estudos Retrospectivos , Índice de Gravidade de Doença
13.
Turk J Gastroenterol ; 30(1): 105-108, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30457558

RESUMO

Chanarin Dorfman syndrome is a multisystem, very rare, autosomal recessive lipid storage disorder, characterized by the accumulation of lipid vacuoles in neutrophils, and was first described by Dorfman in 1974. Due to a mutation in the ABHD5 gene of the short arm of chromosome 3, lipid is stored in the granulocytes at various sites in the human body, such as the muscle, liver, eye, ear, central nervous system, and bone marrow. Clinically, the disease is presented with ichthyosis, hearing loss, hepatomegaly, splenomegaly, cirrhosis, cataract, keratopathy, myopathy, and mental retardation. A 38-year-old male patient was referred to our Internal Medicine Clinic for consultation with laboratory findings as follows: high aspartate aminotransferase (AST; 203 U/L), alanine aminotransferase (ALT; 151 U/L), gamma-glutamyl transferase (GGT; 167 U/L), creatine kinase (CK; 1127 U/L) levels and low platelet levels (108000). After ultrasonography and gastroscopy, the patient was diagnosed with liver cirrhosis. Bilateral mixed-type hearing loss on audial tests and bilateral punctuate keratopathy, ectropion, and cataract in the left eye on ophthalmological tests were found. For the definitive diagnosis of Chanarin Dorfman syndrome, peripheral blood was examined, which revealed lipid accumulation in the neutrophils (Jordan's anomaly). We emphasize that if a patient has unusual findings, such as ichthyosis, hearing loss, hepatomegaly, splenomegaly, cirrhosis, cataract, keratopathy, myopathy, and mental retardation, the possibility of Chanarin Dorfman syndrome should be considered.


Assuntos
Eritrodermia Ictiosiforme Congênita/diagnóstico , Erros Inatos do Metabolismo Lipídico/diagnóstico , Doenças Musculares/diagnóstico , Adulto , Catarata/etiologia , Diagnóstico Diferencial , Fibrose/etiologia , Perda Auditiva/etiologia , Hepatomegalia/etiologia , Humanos , Eritrodermia Ictiosiforme Congênita/complicações , Ictiose/etiologia , Deficiência Intelectual/etiologia , Erros Inatos do Metabolismo Lipídico/complicações , Masculino , Doenças Musculares/complicações , Doenças Musculares/etiologia , Esplenomegalia/etiologia
14.
J Hum Genet ; 64(2): 73-85, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30401918

RESUMO

Mitochondrial fatty acid oxidation disorders (FAODs) are caused by defects in ß-oxidation enzymes, including very long-chain acyl-CoA dehydrogenase (VLCAD), trifunctional protein (TFP), carnitine palmitoyltransferase-2 (CPT2), carnitine-acylcarnitine translocase (CACT) and others. During prolonged fasting, infection, or exercise, patients with FAODs present with hypoglycemia, rhabdomyolysis, cardiomyopathy, liver dysfunction, and occasionally sudden death. This article describes the diagnosis, newborn screening, and treatment of long-chain FAODs with a focus on VLCAD deficiency. VLCAD deficiency is generally classified into three phenotypes based on onset time, but the classification should be comprehensively determined based on genotype, residual enzyme activity, and clinical course, due to a lack of apparent genotype-phenotype correlation. With the expansion of newborn screening for FAODs, several issues have arisen, such as missed detection, overdiagnosis (including detection of benign/asymptomatic type), and poor prognosis of the neonatal-onset form. Meanwhile, dietary management and restriction of exercise have been unnecessary for patients with the benign/asymptomatic type of VLCAD deficiency with a high fatty acid oxidation flux score. Although L-carnitine therapy for VLCAD/TFP deficiency has been controversial, supplementation with L-carnitine may be accepted for CPT2/CACT and multiple acyl-CoA dehydrogenase deficiencies. Recently, a double-blind, randomized controlled trial of triheptanoin (seven-carbon fatty acid triglyceride) versus trioctanoin (regular medium-chain triglyceride) was conducted and demonstrated improvement of cardiac functions on triheptanoin. Additionally, although the clinical efficacy of bezafibrate remains controversial, a recent open-label clinical trial showed efficacy of this drug in improving quality of life. These drugs may be promising for the treatment of FAODs, though further studies are required.


Assuntos
Acil-CoA Desidrogenase de Cadeia Longa/deficiência , Ácidos Graxos/metabolismo , Hipolipemiantes/uso terapêutico , Erros Inatos do Metabolismo Lipídico/diagnóstico , Erros Inatos do Metabolismo Lipídico/tratamento farmacológico , Programas de Rastreamento , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/tratamento farmacológico , Doenças Musculares/diagnóstico , Doenças Musculares/tratamento farmacológico , Gerenciamento Clínico , Humanos , Erros Inatos do Metabolismo Lipídico/enzimologia , Doenças Mitocondriais/enzimologia , Doenças Musculares/enzimologia
15.
Curr Med Chem ; 26(37): 6766-6775, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-29984642

RESUMO

Sitosterolemia is a recessive inherited metabolic disorder of unknown prevalence, characterized by increased levels of plasma plant sterols. It is caused by 28 and 31 variants in ABCG5 and ABCG8 genes, respectively, and is characterized by a predisposition to hyperabsorption and accumulation of toxic levels of plant sterols in plasma. Its clinical picture is extremely heterogeneous. The main clinical features are tendinous and cutaneous xanthomas, arthritis or arthralgia, premature cardiovascular disease and atherosclerosis. These characteristics are shared with familial hypercholesterolemia (FH), making it possible for sitosterolemia to be misdiagnosed as homozygous FH, especially in pediatric patients. In such cases, a specific chromatography-based laboratory method is essential to differentiate sitosterol and cholesterol. Hematological abnormalities (hemolytic anemia and macrothrombocytopenia) may be present in 25-35% of patients, in whom it is usually associated with the main clinical features, as occurs in the 70% of the cases. In this context, the peripheral blood smear is essential and reveals giant platelets and stomatocytes. Only 21 causative variants in ABCG5/ABCG8 are associated with macrothrombocytopenia. Most physicians still do not recognize these hematological abnormalities or relate them to sitosterolemia. Patients may suffer long-term misdiagnosis of immune thrombocytopenia and be at high risk of receiving harmful therapies or of not benefitting from a low-cholesterol diet and/or from the gold standard treatment with ezetimibe. This drug reduces the levels of plasma plant sterols, provokes regression of xanthomas, and can alleviate hematological abnormalities. Finally, to identify genetic defects, recent advances in high-throughput sequencing, especially in the use of targeted sequencing of pre-specified genes, have begun to be incorporated in the first-line approach in the field of genetic disorders.


Assuntos
Doenças Cardiovasculares , Hipercolesterolemia , Enteropatias , Erros Inatos do Metabolismo Lipídico , Fitosteróis/efeitos adversos , Animais , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/metabolismo , Humanos , Hipercolesterolemia/sangue , Hipercolesterolemia/diagnóstico , Hipercolesterolemia/metabolismo , Enteropatias/sangue , Enteropatias/diagnóstico , Enteropatias/metabolismo , Erros Inatos do Metabolismo Lipídico/sangue , Erros Inatos do Metabolismo Lipídico/diagnóstico , Erros Inatos do Metabolismo Lipídico/metabolismo , Fitosteróis/sangue , Fitosteróis/metabolismo
16.
BMC Med Genet ; 19(1): 172, 2018 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-30223778

RESUMO

BACKGROUND: PNPLA2 gene mutations cause neutral lipid storage disease with myopathy (NLSD-M) or cardiomyopathies. The clinical phenotype, blood test results, imaging examination and gene analysis can be used to improve the understanding of NLSD-M, reduce the misdiagnosis rate and prevent physical disability and even premature death. CASE PRESENTATION: We report a Chinese child with NLSD-M presenting with marked asymmetric skeletal myopathy and hypertrophic cardiomyopathy. Blood biochemical tests revealed increased creatine kinase levels, and echocardiography revealed a diffuse and thick left ventricular wall. Gene analysis revealed a homozygous mutation c.155C > G (p.Thr52Arg) in PNPLA2. CONCLUSIONS: An understanding of the characteristic features is essential for the early diagnosis of NLSD-M. Our data expand the allelic spectrum of PNPLA2 mutations, providing further evidence for genetic and clinical NLSD-M heterogeneity in younger individuals.


Assuntos
Cardiomegalia/genética , Cardiomiopatias/genética , Lipase/genética , Erros Inatos do Metabolismo Lipídico/genética , Doenças Musculares/genética , Sequência de Bases , Cardiomegalia/diagnóstico , Cardiomegalia/enzimologia , Cardiomegalia/patologia , Cardiomiopatias/diagnóstico , Cardiomiopatias/enzimologia , Cardiomiopatias/patologia , Criança , Creatina Quinase/sangue , Creatina Quinase/genética , Análise Mutacional de DNA , Diagnóstico Precoce , Expressão Gênica , Ventrículos do Coração/enzimologia , Ventrículos do Coração/patologia , Humanos , Lipase/deficiência , Erros Inatos do Metabolismo Lipídico/diagnóstico , Erros Inatos do Metabolismo Lipídico/enzimologia , Erros Inatos do Metabolismo Lipídico/patologia , Masculino , Doenças Musculares/diagnóstico , Doenças Musculares/enzimologia , Doenças Musculares/patologia , Mutação
17.
J Inherit Metab Dis ; 41(6): 1169-1178, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30194637

RESUMO

Very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) is the most common defect of mitochondrial ß-oxidation of long-chain fatty acids. However, the unambiguous diagnosis of true VLCADD patients may be challenging, and a high rate of false positive individuals identified by newborn screening undergo confirmation diagnostics. In this study, we show the outcome of enzyme testing in lymphocytes as a confirmatory tool in newborns identified by screening, and the correlation with molecular sequencing of the ACADVL gene. From April 2013 to March 2017, in 403 individuals with characteristic acylcarnitine profiles indicative of VLCADD, palmitoyl-CoA oxidation was measured followed by molecular genetic analysis in most of the patients with residual activity (RA) <50%. In almost 50% of the samples (209/403) the RA was >50%, one-third of the individuals (125/403) displayed a RA of 30-50% and 69/403 individuals showed a residual activity of 0-30%. Sequencing of the ACADVL gene revealed that all individuals with activities below 24% were true VLCADD patients, individuals with residual activities between 24 and 27% carried either one or two mutations. Twenty new mutations could be identified and functionally classified based on their effect on enzyme function. Finally, we observed an up-regulation of MCAD-activity in many patients. However, this did not correlate with the degree of VLCAD RA. Although the likely clinical phenotype cannot be fully foreseen by genetic and functional tests as it depends on many factors, our data demonstrate the strength of this functional enzyme test in lymphocytes as a quick and reliable method for confirmation diagnostics of VLCADD.


Assuntos
Acil-CoA Desidrogenase de Cadeia Longa/deficiência , Erros Inatos do Metabolismo Lipídico/diagnóstico , Erros Inatos do Metabolismo Lipídico/genética , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/genética , Doenças Musculares/diagnóstico , Doenças Musculares/genética , Mutação , Acil-CoA Desidrogenase de Cadeia Longa/genética , Cromatografia Líquida de Alta Pressão , Triagem de Portadores Genéticos , Genótipo , Humanos , Recém-Nascido , Literatura de Revisão como Assunto , Espectrometria de Massas em Tandem
18.
Prog Lipid Res ; 72: 1-17, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30099045

RESUMO

Lipid storage myopathies (LSMs) are a heterogeneous group of genetic disorders that present with abnormal lipid storage in multiple body organs, typically muscle. Patients can clinically present with cardiomyopathy, skeletal muscle weakness, myalgia, and extreme fatigue. An early diagnosis is crucial, as some LSMs can be managed by simple nutraceutical supplementation. For example, high dosage l-carnitine is an effective intervention for patients with Primary Carnitine Deficiency (PCD). This review discusses the clinical features and management practices of PCD as well as Neutral Lipid Storage Disease (NLSD) and Multiple Acyl-CoA Dehydrogenase Deficiency (MADD). We provide a detailed summary of current clinical management strategies, highlighting issues of high-risk contraindicated treatments with case study examples not previously reviewed. Additionally, we outline current preclinical studies providing disease mechanistic insight. Lastly, we propose that a number of other conditions involving lipid metabolic dysfunction that are not classified as LSMs may share common features. These include Neurofibromatosis Type 1 (NF1) and autoimmune myopathies, including Polymyositis (PM), Dermatomyositis (DM), and Inclusion Body Myositis (IBM).


Assuntos
Erros Inatos do Metabolismo Lipídico/terapia , Metabolismo dos Lipídeos , Doenças Musculares/terapia , Triglicerídeos/metabolismo , Cardiomiopatias/diagnóstico , Cardiomiopatias/metabolismo , Cardiomiopatias/terapia , Carnitina/deficiência , Carnitina/metabolismo , Humanos , Hiperamonemia/diagnóstico , Hiperamonemia/metabolismo , Hiperamonemia/terapia , Erros Inatos do Metabolismo Lipídico/diagnóstico , Erros Inatos do Metabolismo Lipídico/metabolismo , Modelos Biológicos , Doenças Musculares/diagnóstico , Doenças Musculares/metabolismo
19.
Arch Med Res ; 49(3): 205-212, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-30119976

RESUMO

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 Jovem
20.
Clín. investig. arterioscler. (Ed. impr.) ; 30(4): 170-178, jul.-ago. 2018. tab, graf
Artigo em Espanhol | IBECS | ID: ibc-175432

RESUMO

Introducción: La hipercolesterolemia familiar (HF) infantil está infradiagnosticada y su diagnóstico no es fácil en la práctica clínica. El objetivo fue evaluar qué características clínicas, bioquímicas y de imagen vascular pueden ayudarnos a detectar a niños/as y adolescentes con hipercolesterolemia afectados de HF. Métodos: Doscientos veintidós niños y adolescentes de entre 4 y 18 años fueron reclutados para participar en un proyecto de detección precoz de HF (proyecto DECOPIN). La HF se diagnosticó por criterios genéticos o clínicos. Se definió hipercolesterolemia poligénica (HP) cuando el c-LDL >135mg/dl pero sin criterios clínicos ni genéticos de HF. Participantes con c-LDL < 135mg/dl se incluyeron en el grupo control (GC). Se recogieron la historia familiar, los datos antropométricos y las variables clínicas. Se analizaron parámetros bioquímicos y lipídicos. Se determinó el grosor íntima-media carotídeo (GIMc) y los tendones de Aquiles por ecografía. Resultados: Noventa y un niños fueron diagnosticados de HF y 23 de HP, y 108 como GC. El grupo HF presentó mayores concentraciones de CT, c-LDL, índice ApoB/ApoA1 e índice colesterol año. El c-HDL fue menor en grupo HF que en el GC. Si bien el c-LDL fue el parámetro más definitorio de HF, el índice ApoB/ApoA1 > 0,82 fue el que de forma aislada mostró mayor sensibilidad y especificad para predecir la presencia de mutación en el grupo de niños HF. El grosor de los tendones de Aquiles no mostró diferencias entre grupos. El GIMc fue mayor en los niños HF sin diferencias significativas. Conclusiones: Los niveles de c-LDL son el marcador de HF. Un índice ApoB/ApoA1 > 0,82 puede ser una herramienta útil para decidir el estudio genético en niños con sospecha de HF


Background: Familial hypercholesterolaemia (FH) in children is under-detected and is difficult to diagnose in clinical practice. The aim of this study was to evaluate clinical, biochemical and vascular imaging variables in order to detect children and adolescents with FH. Methods: A total of 222 children aged 4-18 years old were recruited to participate in a project for the early detection of FH (The DECOPIN Project). They were distributed into 3groups: FH, if genetic study or clinical criteria were positive (n=91); Polygenic hypercholesterolaemia (PH) if LDL-Cholesterol >135mg/dL without FH criteria (n=23), and Control group (CG) if LDL-C <135mg/dL (n=108). Data were collected from family history, anthropometric data, and clinical variables. The usual biochemical parameters, including a complete lipid profile were analysed. The carotid intima-media thickness (cIMT) and thickness of Achilles tendons were determined using ultrasound in all participants. Results: A total of 91 children had a diagnosis of FH, 23 with PH, and 108 with CG. Children with FH had higher concentrations of total cholesterol, LDL-C, ApoB/ApoA1 ratio, and cholesterol-year score, than the other groups. HDL-C was lower in the FH group than in the CG. Thickness of the Achilles tendon and cIMT did not show any differences between groups, although a greater cIMT trend was observed in the FH group. ApoB/ApoA1 ratio >0.82 was the parameter with the highest sensitivity and specificity to predict the presence of mutation in children with FH. Conclusions: Although LDL-C is the main biochemical parameter used to define FH, the ApoB/ApoA1 ratio (>0.82) may be a useful tool to identify children with FH and a positive mutation


Assuntos
Humanos , Masculino , Feminino , Pré-Escolar , Criança , Adolescente , Hiperlipoproteinemia Tipo II/diagnóstico , Lipoproteínas LDL/análise , LDL-Colesterol/uso terapêutico , Apolipoproteínas B/genética , Hiperlipoproteinemia Tipo II/metabolismo , Hiperlipoproteinemia Tipo II/fisiopatologia , Erros Inatos do Metabolismo Lipídico/diagnóstico , Criança , Biomarcadores/análise
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