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1.
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
2.
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
3.
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
4.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(4): 310-313, 2019 Apr 10.
Artigo em Chinês | MEDLINE | ID: mdl-30950014

RESUMO

OBJECTIVE: To explore the clinical features and variations of ACADVL gene in 9 neonates with very long chain acyl-coenzyme A dehydrogenase deficiency (VLCADD). METHODS: VLCADD was suspected based on the results of neonatal screening by tandem mass spectrometry (MS-MS), with tetradecenoylcarnitine ± tetradecenoylcarnitine/octanoylcarnitine (C14: 1 ± C14: 1/C8) as the mark indexes. Infants with positive outcome were confirmed by sequencing of the ACADVL gene. RESULTS: Among 9 VLCADD cases, one case lost during follow-up, the observed phenotypes comprised 2 with severe early-onset form, 1 with hepatic form and 5 with late-onset form. Optimal outcome was acquired for all patients except the 2 early-onset cases. In total 16 ACADVL variations were detected among the 9 infants, which included 8 novel variations (c.96-105del GCCCGGCCCT, c.541C>T, c.863T>G, c.878+1G>C, c.895A>G, c.1238T>C, c.1276G>A, and c.1505T>A) and 11 missense variations. There were 9 genotypic combinations, including 1 homozygote and 8 compound heterozygotes. Except for two patients carrying null variations, all had a good outcome. CONCLUSION: VLCADD is relatively rare in southern China, for which late-onset form is common. Carriers of null variations of the ACADVL gene may have relatively poorer clinical outcome. Above results will provide valuable information for the diagnosis and management of VLCADD.


Assuntos
Acil-CoA Desidrogenase de Cadeia Longa/deficiência , Erros Inatos do Metabolismo Lipídico/genética , Doenças Mitocondriais/genética , Doenças Musculares/genética , Acil-CoA Desidrogenase de Cadeia Longa/genética , Carnitina , China , Humanos , Recém-Nascido , Triagem Neonatal
5.
Dis Markers ; 2019: 2984747, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30881520

RESUMO

Because tandem mass spectrometry- (MS/MS-) based newborn screening identifies many suspicious cases of fatty acid oxidation and carnitine cycle disorders, a simple, noninvasive test is required to confirm the diagnosis. We have developed a novel method to evaluate the metabolic defects in peripheral blood mononuclear cells loaded with deuterium-labeled fatty acids directly using the ratios of acylcarnitines determined by flow injection MS/MS. We have identified diagnostic indices for the disorders as follows: decreased ratios of d27-C14-acylcarnitine/d31-C16-acylcarnitine and d23-C12-acylcarnitine/d31-C16-acylcarnitine for carnitine palmitoyltransferase-II (CPT-II) deficiency, decreased ratios of d23-C12-acylcarnitine/d27-C14-acylcarnitine for very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency, and increased ratios of d29-C16-OH-acylcarnitine/d31-C16-acylcarnitine for trifunctional protein (TFP) deficiency, together with increased ratios of d7-C4-acylcarnitine/d31-C16-acylcarnitine for carnitine palmitoyltransferase-I deficiency. The decreased ratios of d1-acetylcarnitine/d31-C16-acylcarnitine could be indicative of ß-oxidation ability in patients with CPT-II, VLCAD, and TFP deficiencies. Overall, our data showed that the present method was valuable for establishing a rapid diagnosis of fatty acid oxidation disorders and carnitine cycle disorders and for complementing gene analysis because our diagnostic indices may overcome the weaknesses of conventional enzyme activity measurements using fibroblasts or mononuclear cells with assumedly uncertain viability.


Assuntos
Acil-CoA Desidrogenase de Cadeia Longa/deficiência , Cardiomiopatias/sangue , Ácidos Graxos/metabolismo , Erros Inatos do Metabolismo Lipídico/sangue , Espectrometria de Massas/métodos , Doenças Mitocondriais/sangue , Miopatias Mitocondriais/sangue , Proteína Mitocondrial Trifuncional/deficiência , Técnicas de Diagnóstico Molecular/métodos , Monócitos/química , Doenças Musculares/sangue , Doenças do Sistema Nervoso/sangue , Rabdomiólise/sangue , Acil-CoA Desidrogenase de Cadeia Longa/sangue , Adulto , Biomarcadores/sangue , Carnitina/análogos & derivados , Carnitina/química , Carnitina O-Palmitoiltransferase/deficiência , Deutério/química , Humanos , Lactente , Proteína Mitocondrial Trifuncional/sangue , Monócitos/metabolismo , Oxirredução
6.
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
7.
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
8.
Pediatr Blood Cancer ; 66(4): e27591, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30588737

RESUMO

BACKGROUND: Sideroblastic anemia represents a heterogeneous group of inherited or acquired diseases with disrupted erythroblast iron utilization, ineffective erythropoiesis, and variable systemic iron overload. In a cohort of 421 patients with multisystem mitochondrial diseases, refractory anemia was found in 8 children. RESULTS: Five children had sideroblastic anemia with increased numbers of ring sideroblasts >15%. Two of the children had a fatal course of MLASA1 syndrome (mitochondrial myopathy, lactic acidosis, and sideroblastic anemia [SA]) due to a homozygous, 6-kb deletion in the PUS1 gene, part of the six-member family of pseudouridine synthases (pseudouridylases). Large homozygous deletions represent a novel cause of presumed PUS1-loss-of-function phenotype. The other three children with SA had Pearson syndrome (PS) due to mtDNA deletions of 4 to 8 kb; two of these children showed early onset of PS and died due to repeated sepsis; the other child had later onset of PS and survived as the hematological parameters normalized and the disease transitioned to Kearns-Sayre syndrome. In addition, anemia without ring sideroblasts was found in three other patients with mitochondrial disorders, including two children with later onset of PS and one child with failure to thrive, microcephaly, developmental delay, hypertrophic cardiomyopathy, and renal tubular acidosis due to the heterozygous mutations c.610A>G (p.Asn204Asp) and c.674C>T (p.Pro225Leu) in the COX10 gene encoding the cytochrome c oxidase assembly factor. CONCLUSIONS: Sideroblastic anemia was found in fewer than 1.2% of patients with multisystem mitochondrial disease, and it was usually associated with an unfavorable prognosis.


Assuntos
Acil-CoA Desidrogenase de Cadeia Longa/deficiência , Anemia Sideroblástica , Sobrecarga de Ferro , Erros Inatos do Metabolismo Lipídico , Síndrome MELAS , Doenças Mitocondriais , Doenças Musculares , Acil-CoA Desidrogenase de Cadeia Longa/genética , Acil-CoA Desidrogenase de Cadeia Longa/metabolismo , Anemia Sideroblástica/genética , Anemia Sideroblástica/metabolismo , Anemia Sideroblástica/patologia , Criança , Pré-Escolar , Feminino , Humanos , Sobrecarga de Ferro/genética , Sobrecarga de Ferro/metabolismo , Sobrecarga de Ferro/patologia , Erros Inatos do Metabolismo Lipídico/genética , Erros Inatos do Metabolismo Lipídico/metabolismo , Erros Inatos do Metabolismo Lipídico/patologia , Síndrome MELAS/genética , Síndrome MELAS/metabolismo , Masculino , Doenças Mitocondriais/genética , Doenças Mitocondriais/metabolismo , Doenças Mitocondriais/patologia , Doenças Musculares/genética , Doenças Musculares/metabolismo , Doenças Musculares/patologia
9.
Environ Sci Pollut Res Int ; 25(32): 32506-32514, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30238259

RESUMO

Benzene is an environmental and occupational contaminant. Health hazards associated with occupational benzene exposure is a major public health problem in China. In this study, we analyzed metabolite profiles among plasma samples collected from benzene-exposed workers with low white blood cell count (BLWs) and healthy controls using high-performance liquid chromatography-time-of-flight mass spectrometry. To screen potential benzene hematotoxicity biomarkers and metabolic pathways, principal component analysis was used to examine metabolite profile changes in plasma samples. The alterations in fatty acid oxidation (FAO) pathway were consistent with our previous findings in a mouse model; hence, two key genes were selected and verified in WBC samples. A total of nine identified metabolites were significantly changed in BLWs, which were involved in glutathione metabolism, porphyrin metabolism, lipid metabolism pathway, and FAO metabolism. Furthermore, compared with healthy controls, the mRNA expressions of carnitine acyltransferase (CRAT) and ACADVL were significantly increased in BLWs. Particularly, WBC counts was negatively correlated with the expression of AVADVL in BLWs. These aberrant metabolites could act as potential biomarkers for benzene hematotoxicity. In addition, fatty acid oxidation pathway may play a critical role in the development of hematotoxicity caused by benzene.


Assuntos
Benzeno/toxicidade , Ácidos Graxos/sangue , Contagem de Leucócitos , Exposição Ocupacional/efeitos adversos , Acil-CoA Desidrogenase de Cadeia Longa/sangue , Acil-CoA Desidrogenase de Cadeia Longa/deficiência , Adulto , Animais , Grupo com Ancestrais do Continente Asiático , Biomarcadores/sangue , Carnitina Aciltransferases/sangue , China , Feminino , Glutationa/sangue , Hemolíticos , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolismo dos Lipídeos/genética , Erros Inatos do Metabolismo Lipídico/sangue , Masculino , Espectrometria de Massas , Metaboloma , Metabolômica/métodos , Camundongos , Doenças Mitocondriais/sangue , Doenças Musculares/sangue , Exposição Ocupacional/análise , Oxirredução , Porfirinas/sangue , RNA Mensageiro/metabolismo
10.
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
12.
Mol Genet Metab ; 125(1-2): 144-152, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30031688

RESUMO

Despite judicious monitoring and care, patients with fatty acid oxidation disorders may experience metabolic decompensation due to infection which may result in rhabdomyolysis, cardiomyopathy, hypoglycemia and liver dysfunction and failure. Since clinical studies on metabolic decompensation are dangerous, we employed a preclinical model of metabolic decompensation due to infection. By infecting mice with mouse adapted influenza and using a pair-feeding strategy in a mouse model of long-chain fatty acid oxidation (Acadvl-/-), our goals were to isolate the effects of infection on tissue acylcarnitines and determine how they relate to their plasma counterparts. Applying statistical data reduction techniques (Partial Least Squares-Discriminant Analysis), we were able to identify critical acylcarnitines that were driving differentiation of our experimental groups for all the tissues studied. While plasma displayed increases in metabolites directly related to mouse VLCAD deficiency (e.g. C16 and C18), organs like the heart, muscle and liver also showed involvement of alternative pathways (e.g. medium-chain FAO and ketogenesis), suggesting adaptive measures. Matched correlation analyses showed strong correlations (r > 0.7) between plasma and tissue levels for a small number of metabolites. Overall, our results demonstrate that infection as a stress produces perturbations in metabolism in Acadvl-/- that differ greatly from WT infected and Acadvl-/- pair-fed controls. This model system will be useful for studying the effects of infection on tissue metabolism as well as evaluating interventions aimed at modulating the effects of metabolic decompensation.


Assuntos
Acil-CoA Desidrogenase de Cadeia Longa/deficiência , Carnitina/análogos & derivados , Ácidos Graxos/metabolismo , Erros Inatos do Metabolismo Lipídico/genética , Doenças Metabólicas/genética , Doenças Mitocondriais/genética , Doenças Musculares/genética , Acil-CoA Desidrogenase de Cadeia Longa/genética , Animais , Cardiomiopatias/genética , Cardiomiopatias/metabolismo , Cardiomiopatias/patologia , Carnitina/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Hipoglicemia/genética , Hipoglicemia/metabolismo , Hipoglicemia/patologia , Peroxidação de Lipídeos/genética , Fígado/metabolismo , Fígado/fisiologia , Falência Hepática/genética , Falência Hepática/metabolismo , Falência Hepática/patologia , Doenças Metabólicas/metabolismo , Doenças Metabólicas/patologia , Camundongos , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Miocárdio/patologia , Oxirredução
13.
Clin Lab ; 64(3): 375-377, 2018 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-29739102

RESUMO

BACKGROUND: The detection of sideroblastic anemia in a newborn may suggest developing Pearson syndrome. The prognosis of these patients is severe and death occurs in the first 3 years of life, so it is important to find new ways of diagnosis. Case Presentation: In the case of our patient the diagnosis was supported only at the age of 5 months, highlighting the difficulties of diagnosis at this age. CONCLUSIONS: The diagnosis of Pearson syndrome with neonatal onset is difficult to sustain or even impossible at that age. This diagnosis can be confirmed and supported during disease progression.


Assuntos
Acil-CoA Desidrogenase de Cadeia Longa/deficiência , Erros Inatos do Metabolismo Lipídico/diagnóstico , Erros Inatos do Metabolismo Lipídico/terapia , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/terapia , Doenças Musculares/diagnóstico , Doenças Musculares/terapia , Acil-CoA Desidrogenase de Cadeia Longa/genética , Transfusão de Sangue , Transplante de Medula Óssea , Testes Genéticos , Humanos , Lactente , Erros Inatos do Metabolismo Lipídico/genética , Masculino , Doenças Mitocondriais/genética , Doenças Musculares/genética
14.
Medicine (Baltimore) ; 97(20): e10813, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29768383

RESUMO

RATIONALE: Infantile-onset hypertrophic cardiomyopathy (HCMP) should be considered a largely genetic condition, although its onset is most often triggered by infection. Very long chain acyl-CoA dehydrogenase (VLCAD) deficiency is a rare autosomal recessive inborn error of mitochondrial fatty acid ß-oxidation that often causes severe cardiomyopathy and/or sudden death during the neonatal period. PATIENT CONCERNS: Herein, we report an infant with VLCAD deficiency who presented with severe cardiac manifestations, including massive pericardial effusion and HCMP. The subject's older sister died of unknown causes at three days of age; however, the subject exhibited a normal tandem mass-spectrometry profile during the neonatal period. DIAGNOSES: During her later cardiac presentation, the subject's C-14 and C-18 levels became elevated, and she was determined, via the conducted molecular analysis, to harbor a novel homozygous frameshift mutation (c.103_112dup) in ACADVL. INTERVENTIONS: After VLCAD deficiency diagnosis, the subject was treated with the administration of a medium chain triglyceride formula and fluid therapy. OUTCOMES: The subject's cardiac status was markedly improved by the dietary intervention and fluid therapy. LESSONS: This report highlights that genetic mutations should be investigated as possible causes of infantile-onset HCMP, and that early diagnosis and intervention can prevent mortality for patients with VLCAD deficiency.


Assuntos
Acil-CoA Desidrogenase de Cadeia Longa/deficiência , Mutação da Fase de Leitura , Hipertrofia Ventricular Esquerda/etiologia , Erros Inatos do Metabolismo Lipídico/diagnóstico , Erros Inatos do Metabolismo Lipídico/genética , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/genética , Doenças Musculares/diagnóstico , Doenças Musculares/genética , Derrame Pericárdico/etiologia , Acil-CoA Desidrogenase de Cadeia Longa/genética , Diagnóstico Tardio , Feminino , Hidratação , Humanos , Hipertrofia Ventricular Esquerda/terapia , Lactente , Erros Inatos do Metabolismo Lipídico/complicações , Erros Inatos do Metabolismo Lipídico/terapia , Doenças Mitocondriais/complicações , Doenças Mitocondriais/terapia , Doenças Musculares/complicações , Doenças Musculares/terapia , Derrame Pericárdico/terapia , Triglicerídeos/uso terapêutico
16.
Clin Chim Acta ; 481: 156-160, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29534959

RESUMO

Single large-scale mitochondrial DNA deletions disorders are classified into three main phenotypes with frequent clinical overlap: Pearson marrow-pancreas syndrome (PMS), Kearns-Sayre syndrome (KSS) and chronic progressive external ophtalmoplegia (PEO). So far, only few anecdotal studies have reported on the urinary organic acids profile in this disease class. In this single-center retrospective study, we performed quantitative evaluation of urinary organic acids in a series of 15 pediatric patients, 7 with PMS and 8 with KSS. PMS patients showed an organic acids profile almost constantly altered, whereas KSS patients frequently presented with normal profiles. Lactate, 3-hydroxybutyrate, 3-hydroxyisobutyrate, fumarate, pyruvate, 2-hydroxybutyrate, 2-ethyl-3-hydroxypropionate, and 3-methylglutaconate represented the most frequent metabolites observed in PMS urine. We also found novel metabolites, 3-methylglutarate, tiglylglycine and 2-methyl-2,3-dihydroxybutyrate, so far never reported in this disease. Interestingly, patients with a disease onset as PMS evolving overtime into KSS phenotype, presented persistent and more pronounced alterations of organic acid signature than in patients with a pure KSS phenotype. Our study shows that the quantitative analysis of urinary organic acid profile represents a helpful tool for the diagnosis of PMS and for the differential diagnosis with other inherited diseases causing abnormal organic acidurias.


Assuntos
Acil-CoA Desidrogenase de Cadeia Longa/deficiência , DNA Mitocondrial/genética , Síndrome de Kearns-Sayre/urina , Erros Inatos do Metabolismo Lipídico/urina , Doenças Mitocondriais/urina , Doenças Musculares/urina , Ácido 3-Hidroxibutírico/urina , Acil-CoA Desidrogenase de Cadeia Longa/genética , Acil-CoA Desidrogenase de Cadeia Longa/urina , Adolescente , Criança , Pré-Escolar , Fumaratos/urina , Glutaratos/urina , Humanos , Hidroxibutiratos/urina , Lactente , Síndrome de Kearns-Sayre/diagnóstico , Síndrome de Kearns-Sayre/genética , Ácido Láctico/urina , Erros Inatos do Metabolismo Lipídico/diagnóstico , Erros Inatos do Metabolismo Lipídico/genética , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/genética , Doenças Musculares/diagnóstico , Doenças Musculares/genética , Ácido Pirúvico/urina , Estudos Retrospectivos , Valeratos/urina
17.
FEBS J ; 285(8): 1437-1455, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29476646

RESUMO

We studied the effects of the major long-chain fatty acids accumulating in very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency, namely cis-5-tetradecenoic acid (Cis-5) and myristic acid (Myr), on important mitochondrial functions in isolated mitochondria from cardiac fibers and cardiomyocytes of juvenile rats. Cis-5 and Myr at pathological concentrations markedly reduced mitochondrial membrane potential (ΔΨm ), matrix NAD(P)H pool, Ca2+ retention capacity, ADP- (state 3) and carbonyl cyanide 3-chlorophenyl hydrazine-stimulated (uncoupled) respiration, and ATP generation. By contrast, these fatty acids increased resting (state 4) respiration (uncoupling effect) with the involvement of the adenine nucleotide translocator because carboxyatractyloside significantly attenuated the increased state 4 respiration provoked by Cis-5 and Myr. Furthermore, the classical inhibitors of mitochondrial permeability transition (MPT) pore cyclosporin A plus ADP, as well as the Ca2+ uptake blocker ruthenium red, fully prevented the Cis-5- and Myr-induced decrease in ΔΨm in Ca2+ -loaded mitochondria, suggesting, respectively, the induction of MPT pore opening and the contribution of Ca2+ toward these effects. The findings of the present study indicate that the major long-chain fatty acids that accumulate in VLCAD deficiency disrupt mitochondrial bioenergetics and Ca2+ homeostasis, acting as uncouplers and metabolic inhibitors of oxidative phosphorylation, as well as inducers of MPT pore opening, in the heart at pathological relevant concentrations. It is therefore presumed that a disturbance of bioenergetics and Ca2+ homeostasis may contribute to the cardiac manifestations observed in VLCAD deficiency.


Assuntos
Acil-CoA Desidrogenase de Cadeia Longa/deficiência , Cálcio/metabolismo , Metabolismo Energético , Homeostase , Erros Inatos do Metabolismo Lipídico/metabolismo , Mitocôndrias Cardíacas/metabolismo , Doenças Mitocondriais/metabolismo , Doenças Musculares/metabolismo , Miocárdio/metabolismo , Acil-CoA Desidrogenase de Cadeia Longa/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Linhagem Celular , Ácidos Graxos/metabolismo , Potencial da Membrana Mitocondrial , Miocárdio/citologia , Fosforilação Oxidativa , Consumo de Oxigênio , Ratos Wistar
18.
Sci Rep ; 8(1): 3254, 2018 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-29459657

RESUMO

Children diagnosed with Long-Chain-3-Hydroxy-Acyl-CoA-Dehydrogenase-Deficiency (LCHADD) or Very-Long-Chain-3-Hydroxy-Acyl-CoA-Dehydrogenase-Deficiency (VLCADD) frequently present with hypertrophic cardiomyopathy or muscle weakness which is caused by the accumulation of fatty acid metabolites due to inactivating mutations in the mitochondrial trifunctional protein. By analyzing mitochondrial morphology we uncovered that mutations within the HADHA or the ACADVL gene not only affect fatty acid oxidation, but also cause significant changes in the DNM1L/MFN2 ratio leading to the significant accumulation of truncated and punctate mitochondria in contrast to network-like mitochondrial morphology in controls. These striking morphological abnormalities correlate with changes in OXPHOS, an imbalance in ROS levels, reduced mitochondrial respiration, reduced growth rates and significantly increased glucose uptake per cell, suggesting that HADHA and ACADVL mutations shift cellular energy household into glycolysis. Experiments using the NOX2-specific inhibitor Phox-I2 suggest that NOX2 is activated by accumulating long-chain fatty acids and generates ROS, which in turn changes mitochondrial morphology and activity. We thereby provide novel insights into the cellular energy household of cells from LCHADD/VLCADD patients and demonstrate for the first time a connection between fatty acid metabolism, mitochondrial morphology and ROS in patients with these rare genetic disorders.


Assuntos
Acil-CoA Desidrogenase de Cadeia Longa/deficiência , Cardiomiopatia Hipertrófica/patologia , Mitocôndrias/enzimologia , Doenças Mitocondriais/patologia , Dinâmica Mitocondrial , Subunidade alfa da Proteína Mitocondrial Trifuncional/deficiência , Debilidade Muscular/patologia , Acil-CoA Desidrogenase de Cadeia Longa/metabolismo , Cardiomiopatia Hipertrófica/genética , Respiração Celular , GTP Fosfo-Hidrolases/análise , Glicólise , Humanos , Proteínas Associadas aos Microtúbulos/análise , Mitocôndrias/fisiologia , Mitocôndrias/ultraestrutura , Doenças Mitocondriais/genética , Proteínas Mitocondriais/análise , Subunidade alfa da Proteína Mitocondrial Trifuncional/metabolismo , Debilidade Muscular/genética , Fosforilação Oxidativa
19.
J Pediatr Endocrinol Metab ; 31(3): 297-304, 2018 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-29425111

RESUMO

BACKGROUND: Children with long-chain fatty acid ß-oxidation disorders (LCFAOD) presenting with clinical symptoms are treated with a specialist infant formula, with medium chain triglyceride (MCT) mainly replacing long chain triglyceride (LCT). It is essential that the safety and efficacy of any new specialist formula designed for LCFAOD be tested in infants and children. METHODS: In an open-label, 21-day, phase I trial, we studied the safety of a new MCT-based formula (feed 1) in six well-controlled children (three male), aged 7-13 years (median 9 years) with LCFAOD (very long chain acyl CoA dehydrogenase deficiency [VLCADD], n=2; long chain 3-hydroxyacyl CoA dehydrogenase deficiency [LCHADD], n=2; carnitine acyl carnitine translocase deficiency [CACTD], n=2). Feed 1 (Lipistart; Vitaflo) contained 30% energy from MCT, 7.5% LCT and 3% linoleic acid and it was compared with a conventional MCT feed (Monogen; Nutricia) (feed 2) containing 17% energy from MCT, 3% LCT and 1.1% linoleic acid. Subjects consumed feed 2 for 7 days then feed 1 for 7 days and finally resumed feed 2 for 7 days. Vital signs, blood biochemistry, ECG, weight, height, food/feed intake and symptoms were monitored. RESULTS: Five subjects completed the study. Their median daily volume of both feeds was 720 mL (range 500-1900 mL/day). Feed 1 was associated with minimal changes in tolerance, free fatty acids (FFA), acylcarnitines, 3-hydroxybutyrate (3-HB), creatine kinase (CK), blood glucose, liver enzymes and no change in an electrocardiogram (ECG). No child complained of muscle pain or symptoms associated with LCFAOD on either feed. CONCLUSIONS: This is the first safety trial reported of an MCT formula specifically designed for infants and children with LCFAOD. In this short-term study, it appeared safe and well tolerated in this challenging group.


Assuntos
3-Hidroxiacil-CoA Desidrogenases/deficiência , Acil-CoA Desidrogenase de Cadeia Longa/deficiência , Carnitina Aciltransferases/deficiência , Erros Inatos do Metabolismo Lipídico/dietoterapia , Doenças Mitocondriais/dietoterapia , Doenças Musculares/dietoterapia , Triglicerídeos/administração & dosagem , Adolescente , Criança , Feminino , Humanos , Masculino , Triglicerídeos/efeitos adversos
20.
Paediatr Anaesth ; 28(3): 296-297, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29316010

RESUMO

We report the case of a 3-year-old boy with very long-chain acyl-coenzyme A dehydrogenase deficiency presenting for adenotonsillectomy who was successfully and safely managed with a balanced anesthetic including sevoflurane. The anesthetic management is described, and the controversy surrounding volatile anesthetics in these patients is discussed.


Assuntos
Acil-CoA Desidrogenase de Cadeia Longa/deficiência , Anestesia por Inalação/métodos , Erros Inatos do Metabolismo Lipídico/complicações , Doenças Mitocondriais/complicações , Doenças Musculares/complicações , Adenoidectomia , Anestésicos Inalatórios , Pré-Escolar , Humanos , Masculino , Éteres Metílicos , Assistência Perioperatória , Pré-Medicação , Sevoflurano , Tonsilectomia
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