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1.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(9): 1009-1013, 2020 Sep 10.
Artigo em Chinês | MEDLINE | ID: mdl-32820518

RESUMO

OBJECTIVE: To analyze the clinical and molecular characteristics of a child with very long chain acyl-CoA dehydrogenase deficiency (VLCADD). METHODS: Peripheral blood sample of the patient was collected for the extraction of genomic DNA. Next generation sequencing (NGS) was carried out for the proband. Suspected mutations were validated by Sanger sequencing. RESULTS: The patient, a 12-month-old girl, was admitted for diarrhea, vomiting, fever, poor spirit and decreased blood pressure. During the course of the disease, she also manifested hypertrophic cardiomyopathy, cardiogenic shock, elevated myocardial enzyme kinase, fever and metabolic acidosis, and had died after three days due to ventricular tachycardia and respiratory failure. Genetic testing showed that she has carried heterozygous mutations of of the ACADVL gene, namely c.664G>A (exon 8) and c.1056_1057del (exon 10). Blood screening for metabolic genetic diseases showed increased C12, C14, C16, C18, C14:1, C14:2, C16:1, C4/C3 and C8/C3, accompanied with decreased C0, C0/C16 and C8/C10. VLCADD and secondary carnitine deficiency could not be excluded, which was in keeping with the result of genetic testing. CONCLUSION: The child was diagnosed with VLCADD, which may be attributed to the compound heterozygous c.664G>A and c.1056_1057del variants of the ACADVL gene.


Assuntos
Acil-CoA Desidrogenase de Cadeia Longa/deficiência , Síndrome Congênita de Insuficiência da Medula Óssea/genética , Erros Inatos do Metabolismo Lipídico/genética , Doenças Mitocondriais/genética , Doenças Musculares/genética , Acil-CoA Desidrogenase de Cadeia Longa/genética , Feminino , Testes Genéticos , Humanos , Lactente
2.
Saudi Med J ; 41(7): 703-708, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32601637

RESUMO

OBJECTIVES: To determine the incidence of newborn screening (NBS) disorders and to study the key performance indicators of the program. METHODS: This retrospective single-center study enrolled all infants who underwent NBS from January 2012 to December 2017 at Prince Sultan Military Medical City, Riyadh, Saudi Arabia. We screened 17 NBS disorders. Blood samples were collected 24 hours after birth. If the initial result was positive, a second sample was collected. True positive cases were immediately referred for medical management. Data were extracted from laboratory computerized and non-computerized records using case report forms. RESULTS: During the study period, 56632 infants underwent NBS with a coverage rate of 100%. Thirty-eight cases were confirmed. The incidence of congenital hypothyroidism was 1:3775. The positive predictive value for the detection of congenital hypothyroidism was 11.8%. Propionic aciduria was the most common metabolic disorder, with an incidence of 1:14158. Very long-chain acyl CoA dehydrogenase deficiency and glutaric aciduria type 1 had an incidence of 1:18877 each. Phenylketonuria, biotinidase deficiency, maple syrup urine disease, and citrullinemia had an incidence of 1:28316 each. However, galactosemia and 3-methyl crotonyl carboxylase deficiency had the lowest incidence of 1:56632. CONCLUSION: The NBS coverage rate at our facility was 100%. Congenital hypothyroidism was the most frequently detected disorder with an incidence that matches worldwide figures. The incidence of other inherited disorders was consistent with regional figures.


Assuntos
Doenças do Recém-Nascido/diagnóstico , Doenças do Recém-Nascido/epidemiologia , Triagem Neonatal , Acil-CoA Desidrogenase de Cadeia Longa/deficiência , Erros Inatos do Metabolismo dos Aminoácidos/diagnóstico , Erros Inatos do Metabolismo dos Aminoácidos/epidemiologia , Biomarcadores/sangue , Encefalopatias Metabólicas/diagnóstico , Encefalopatias Metabólicas/epidemiologia , Síndrome Congênita de Insuficiência da Medula Óssea/diagnóstico , Síndrome Congênita de Insuficiência da Medula Óssea/epidemiologia , Glutaril-CoA Desidrogenase/deficiência , Humanos , Hipotireoidismo/diagnóstico , Hipotireoidismo/epidemiologia , Incidência , Recém-Nascido , Erros Inatos do Metabolismo Lipídico/diagnóstico , Erros Inatos do Metabolismo Lipídico/epidemiologia , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/epidemiologia , Doenças Musculares/diagnóstico , Doenças Musculares/epidemiologia , Valor Preditivo dos Testes , Acidemia Propiônica/diagnóstico , Acidemia Propiônica/epidemiologia , Estudos Retrospectivos , Arábia Saudita/epidemiologia , Fatores de Tempo
3.
Saudi Med J ; 41(6): 590-596, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32518924

RESUMO

OBJECTIVES: To describe the clinical and molecular characteristics of patients with very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency.   Methods: A retrospective observational cross-sectional analysis was conducted on all patients with VLCAD deficiency at  (Genetic/Metabolic Section), Prince Sultan Military Medical City (PSMMC), Riyadh, Saudi Arabia from 2000 to 2019. Demographic, clinical, and laboratory data were abstracted from the electronic hospital records using a case report form. Results: A total of 14 children were analyzed. Six presented with hypoglycemia, 4 with cardiomyopathy, and 10 had rhabdomyolysis. Five patients had early onset severe phenotype, while 9 had mild form. The molecular study revealed homozygous mutations in ACADVL in all 14 patients. Three variants were not reported before. All patients were treated with medium-chain triglyceride and carnitine. Ten patients are alive and have normal development, while 4 died. Conclusion: Most of the patients in this cohort presented in the neonatal period either by newborn screening or clinically with hypoglycemia, cardiomyopathy, and rhabdomyolysis. The new molecular variants detected in this study broaden the genetic spectrum of VLCAD deficiency in Saudi Arabia.


Assuntos
Acil-CoA Desidrogenase de Cadeia Longa/deficiência , Síndrome Congênita de Insuficiência da Medula Óssea , Erros Inatos do Metabolismo Lipídico , Doenças Mitocondriais , Doenças Musculares , Acil-CoA Desidrogenase de Cadeia Longa/genética , Cardiomiopatias/etiologia , Carnitina/uso terapêutico , Estudos de Coortes , Síndrome Congênita de Insuficiência da Medula Óssea/diagnóstico , Síndrome Congênita de Insuficiência da Medula Óssea/tratamento farmacológico , Síndrome Congênita de Insuficiência da Medula Óssea/genética , Estudos Transversais , Homozigoto , Humanos , Hipoglicemia/etiologia , Recém-Nascido , Erros Inatos do Metabolismo Lipídico/diagnóstico , Erros Inatos do Metabolismo Lipídico/tratamento farmacológico , Erros Inatos do Metabolismo Lipídico/genética , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/tratamento farmacológico , Doenças Mitocondriais/genética , Doenças Musculares/diagnóstico , Doenças Musculares/tratamento farmacológico , Doenças Musculares/genética , Mutação , Triagem Neonatal , Rabdomiólise/etiologia , Arábia Saudita , Triglicerídeos/uso terapêutico
4.
Int J Mol Sci ; 21(7)2020 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-32276429

RESUMO

Patients with very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) can present with life-threatening cardiac arrhythmias. The pathophysiological mechanism is unknown. We reprogrammed fibroblasts from one mildly and one severely affected VLCADD patient, into human induced pluripotent stem cells (hiPSCs) and differentiated these into cardiomyocytes (VLCADD-CMs). VLCADD-CMs displayed shorter action potentials (APs), more delayed afterdepolarizations (DADs) and higher systolic and diastolic intracellular Ca2+ concentration ([Ca2+]i) than control CMs. The mitochondrial booster resveratrol mitigated the biochemical, electrophysiological and [Ca2+]i changes in the mild but not in the severe VLCADD-CMs. Accumulation of potentially toxic intermediates of fatty acid oxidation was blocked by substrate reduction with etomoxir. Incubation with etomoxir led to marked prolongation of AP duration and reduced DADs and [Ca2+]i in both VLCADD-CMs. These results provide compelling evidence that reduced accumulation of fatty acid oxidation intermediates, either by enhanced fatty acid oxidation flux through increased mitochondria biogenesis (resveratrol) or by inhibition of fatty acid transport into the mitochondria (etomoxir), rescues pro-arrhythmia defects in VLCADD-CMs and open doors for new treatments.


Assuntos
Acil-CoA Desidrogenase de Cadeia Longa/deficiência , Arritmias Cardíacas/prevenção & controle , Síndrome Congênita de Insuficiência da Medula Óssea/fisiopatologia , Compostos de Epóxi/farmacologia , Ácidos Graxos/química , Erros Inatos do Metabolismo Lipídico/fisiopatologia , Mitocôndrias/fisiologia , Doenças Mitocondriais/fisiopatologia , Doenças Musculares/fisiopatologia , Miócitos Cardíacos/fisiologia , Resveratrol/farmacologia , Potenciais de Ação , Arritmias Cardíacas/etiologia , Eletrofisiologia Cardíaca , Síndrome Congênita de Insuficiência da Medula Óssea/complicações , Ácidos Graxos/metabolismo , Humanos , Células-Tronco Pluripotentes Induzidas , Erros Inatos do Metabolismo Lipídico/complicações , Doenças Mitocondriais/complicações , Doenças Musculares/complicações , Miócitos Cardíacos/efeitos dos fármacos , Oxirredução
5.
Biochim Biophys Acta Mol Basis Dis ; 1866(6): 165725, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32061778

RESUMO

PURPOSE: Newborns who test positive for very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) in newborn screening may have a severe phenotype with early onset of life-threatening symptoms but may also have an attenuated phenotype and never become symptomatic. The objective of this study is to investigate whether metabolomic profiles in dried bloodspots (DBS) of newborns allow early phenotypic prediction, permitting tailored treatment and follow-up. METHODS: A metabolic fingerprint was generated by direct infusion high resolution mass spectrometry in DBS of VLCADD patients (n = 15) and matched controls. Multivariate analysis of the metabolomic profiles was applied to differentiate subgroups. RESULTS: Concentration of six acylcarnitine species differed significantly between patients and controls. The concentration of C18:2- and C20:0-carnitine, 13,14-dihydroretinol and deoxycytidine monophosphate allowed separation between mild and severe patients. Two patients who could not be prognosticated on early clinical symptoms, were correctly fitted for severity in the score plot based on the untargeted metabolomics. CONCLUSION: Distinctive metabolomic profiles in DBS of newborns with VLCADD may allow phenotypic prognostication. The full potential of this approach as well as the underlying biochemical mechanisms need further investigation.


Assuntos
Acil-CoA Desidrogenase de Cadeia Longa/deficiência , Carnitina/análogos & derivados , Síndrome Congênita de Insuficiência da Medula Óssea/sangue , Erros Inatos do Metabolismo Lipídico/sangue , Metabolômica , Doenças Mitocondriais/sangue , Doenças Musculares/sangue , Triagem Neonatal , Acil-CoA Desidrogenase de Cadeia Longa/sangue , Acil-CoA Desidrogenase de Cadeia Longa/genética , Carnitina/metabolismo , Criança , Pré-Escolar , Síndrome Congênita de Insuficiência da Medula Óssea/patologia , Teste em Amostras de Sangue Seco/métodos , Feminino , Humanos , Lactente , Recém-Nascido , Erros Inatos do Metabolismo Lipídico/patologia , Masculino , Espectrometria de Massas , Doenças Mitocondriais/patologia , Doenças Musculares/patologia , Fenótipo
7.
Clin Chim Acta ; 503: 218-222, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31794763

RESUMO

Very long-chain acyl-coenzyme A dehydrogenase deficiency (VLCAD deficiency), a rare autosomal recessive disorder, is characterized by hypoketotic hypoglycemia, cardiomyopathy, liver damage, and myopathy. VLCAD deficiency is caused by defects of ACADVL gene, which encodes VLCAD protein. The aim of this study was to determine the clinical, biochemical, prognosis and mutation spectrum of patients with VLCAD deficiency in mainland China. A total of Six families visited us, four patients (2 boys and 2 girls) were admitted in hospital due to liver dysfunction, hypoglycemia, and positive newborn screen result. The parents of the other two patients (2 girls) visited us for genetic consultation after their children's death. All the six patients had elevated level of serum tetradecenoylcarnitine (C14:1-carnitine), four of them showed decreased free carnitine (C0) level, and three had dicarboxylic aciduria. Eight types of mutations of the ACADVL gene were detected, three of them are novel, including c.563G > A (p.G188D) c.1387G > A (p.G463R) and c.1582_1586del (p.L529Sfs*31). The p.R450H mutation accounts for 9/52 alleles (5/40 in previous study of 20 unrelated patients, and 4/12 in this study) of genetically diagnosed Chinese VLCAD deficiency cases. The four alive patients (Patient 1-4) responded well to diet prevention and drug therapy with stable hepatic dysfunction condition. In conclusion, we describe three novel mutations of the ACADVL gene among six unrelated families with VLCAD deficiency. Moreover, we suggest that the p.R450H may be a potential hotspot mutation in the Chinese population.


Assuntos
Acil-CoA Desidrogenase de Cadeia Longa/deficiência , Síndrome Congênita de Insuficiência da Medula Óssea/genética , Erros Inatos do Metabolismo Lipídico/genética , Doenças Mitocondriais/genética , Doenças Musculares/genética , Mutação , Acil-CoA Desidrogenase de Cadeia Longa/genética , Grupo com Ancestrais do Continente Asiático , Carnitina/análogos & derivados , Carnitina/metabolismo , China , Síndrome Congênita de Insuficiência da Medula Óssea/patologia , Síndrome Congênita de Insuficiência da Medula Óssea/terapia , Feminino , Humanos , Hipoglicemia , Recém-Nascido , Erros Inatos do Metabolismo Lipídico/patologia , Erros Inatos do Metabolismo Lipídico/terapia , Hepatopatias , Masculino , Doenças Mitocondriais/patologia , Doenças Mitocondriais/terapia , Doenças Musculares/patologia , Doenças Musculares/terapia
8.
Toxicol In Vitro ; 62: 104665, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31629068

RESUMO

cis-5-Tetradecenoic (cis-5) and myristic (Myr) acids predominantly accumulate in patients affected by very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency. They commonly manifest myopathy with muscular pain and rhabdomyolysis, whose underlying mechanisms are poorly known. Thus, in the present study we investigated the effects of cis-5 and Myr on mitochondrial bioenergetics and Ca2+ homeostasis in rat skeletal muscle. cis-5 and Myr decreased ADP-stimulated (state 3) and CCCP-stimulated (uncoupled) respiration, especially when mitochondria were supported by NADH-linked as compared to FADH2-linked substrates. In contrast, these fatty acids increased resting respiration (state 4). Similar effects were observed in skeletal muscle fibers therefore validating the data obtained with isolated mitochondria. Furthermore, cis-5 and Myr markedly decreased mitochondrial membrane potential and Ca2+ retention capacity that were avoided by cyclosporin A plus ADP and ruthenium red, indicating that cis-5 and Myr induce mitochondrial permeability transition (MPT). Finally, docosanoic acid did not disturb mitochondrial homeostasis, indicating selective effects for Myr and cis-5. Taken together, our findings indicate that major long-chain fatty acids accumulating in VLCAD deficiency behave as metabolic inhibitors, uncouplers of oxidative phosphorylation and MPT inducers. It is presumed that these pathomechanisms contribute to the muscular symptoms and rhabdomyolysis observed in patients affected by VLCAD deficiency.


Assuntos
Acil-CoA Desidrogenase de Cadeia Longa/deficiência , Síndrome Congênita de Insuficiência da Medula Óssea/metabolismo , Erros Inatos do Metabolismo Lipídico/metabolismo , Mitocôndrias/efeitos dos fármacos , Doenças Mitocondriais/metabolismo , Músculo Esquelético/efeitos dos fármacos , Doenças Musculares/metabolismo , Ácidos Mirísticos/toxicidade , Acil-CoA Desidrogenase de Cadeia Longa/metabolismo , Animais , Cálcio/metabolismo , Metabolismo Energético/efeitos dos fármacos , Homeostase/efeitos dos fármacos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/fisiologia , Músculo Esquelético/metabolismo , Consumo de Oxigênio/efeitos dos fármacos , Permeabilidade/efeitos dos fármacos , Ratos Wistar
9.
J Pediatr Hematol Oncol ; 42(2): 113-117, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31205222

RESUMO

Eltrombopag (ELT) is a thrombopoietin receptor activator that has shown efficacy in chronic immune thrombocytopenia. We report the outcome of ELT therapy in 4 children who were treated for rare hematologic disorders, including Pearson syndrome, DiGeorge syndrome, posttransplant allogeneic poor graft function (PGF), and Wiskott-Aldrich syndrome. The ELT tolerance in the analyzed group was good, with the exception of the child with Pearson syndrome, who experienced an exacerbation of cataracts and had to discontinue treatment. Thromboembolic events were observed in one child, who continued ELT therapy despite achieving normalized platelet counts. Independence from PLT transfusions was observed at the 4-week timepoint of therapy in patients with DiGeorge syndrome and PGF who responded to ELT. Discontinuation of therapy was successful in one child, who sustained the normal CBC values afterward. In 2 patients, an increase in neutrophil counts was observed during ELT therapy without additional intervention, and a positive correlation between neutrophil and platelet values during ELT therapy was observed in the child with PGF. ELT is effective in rare pediatric disorders, but response patterns are determined by the underlying disease. ELT shows promising results in patients, but constitutional hematopoiesis defects reduce the chances of a response.


Assuntos
Acil-CoA Desidrogenase de Cadeia Longa/deficiência , Benzoatos/uso terapêutico , Síndrome Congênita de Insuficiência da Medula Óssea/tratamento farmacológico , Síndrome de DiGeorge/tratamento farmacológico , Rejeição de Enxerto/tratamento farmacológico , Hidrazinas/uso terapêutico , Erros Inatos do Metabolismo Lipídico/tratamento farmacológico , Doenças Mitocondriais/tratamento farmacológico , Doenças Musculares/tratamento farmacológico , Pirazóis/uso terapêutico , Receptores de Trombopoetina/agonistas , Trombocitopenia/tratamento farmacológico , Síndrome de Wiskott-Aldrich/tratamento farmacológico , Adolescente , Criança , Pré-Escolar , Síndrome Congênita de Insuficiência da Medula Óssea/complicações , Síndrome Congênita de Insuficiência da Medula Óssea/patologia , Síndrome de DiGeorge/complicações , Síndrome de DiGeorge/patologia , Feminino , Rejeição de Enxerto/etiologia , Rejeição de Enxerto/patologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Erros Inatos do Metabolismo Lipídico/complicações , Erros Inatos do Metabolismo Lipídico/patologia , Masculino , Doenças Mitocondriais/complicações , Doenças Mitocondriais/patologia , Doenças Musculares/complicações , Doenças Musculares/patologia , Prognóstico , Trombocitopenia/complicações , Trombocitopenia/patologia , Síndrome de Wiskott-Aldrich/complicações , Síndrome de Wiskott-Aldrich/patologia
10.
Pediatr Ann ; 48(11): e441-e447, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31710363

RESUMO

Exocrine pancreatic insufficiency in children can lead to lifelong complications related to malnutrition and poor growth. The clinical presentation can be subtle in the early stages of insufficiency as the large functional capacity of the pancreas is gradually lost. The pediatrician plays a crucial role in the early identification of these children to ensure a timely referral so that a diagnosis can be made and therapy initiated. Early nutritional therapy allows for prevention and correction of deficiencies, which leads to improved outcomes and survival. When insufficiency is suspected, the workup should start with an indirect test of exocrine pancreatic function, such as fecal elastase, to establish the diagnosis. Once a diagnosis is established, further testing to delineate the etiology should be pursued, with cystic fibrosis being high on the differential list and assessed for with a sweat test. Assessment of anthropometry at every visit is key, as is monitoring of laboratory parameters and physical examination findings that are suggestive of malabsorption and malnutrition. The mainstay of management is administration of exogenous pancreatic enzymes to facilitate digestion and absorption. [Pediatr Ann. 2019;48(11):e441-e447.].


Assuntos
Transtornos da Nutrição Infantil/etiologia , Insuficiência Pancreática Exócrina/diagnóstico , Acil-CoA Desidrogenase de Cadeia Longa/deficiência , Anus Imperfurado/complicações , Criança , Transtornos da Nutrição Infantil/diagnóstico , Transtornos da Nutrição Infantil/terapia , Quimotripsina/metabolismo , Síndrome Congênita de Insuficiência da Medula Óssea/complicações , Fibrose Cística/complicações , Gorduras na Dieta/metabolismo , Displasia Ectodérmica/complicações , Terapia de Reposição de Enzimas , Insuficiência Pancreática Exócrina/etiologia , Insuficiência Pancreática Exócrina/terapia , Fezes/enzimologia , Transtornos do Crescimento/complicações , Perda Auditiva Neurossensorial/complicações , Humanos , Hipotireoidismo/complicações , Deficiência Intelectual/complicações , Erros Inatos do Metabolismo Lipídico/complicações , Doenças Mitocondriais/complicações , Doenças Musculares/complicações , Nariz/anormalidades , Avaliação Nutricional , Pâncreas/diagnóstico por imagem , Pâncreas/fisiologia , Pancreatopatias/complicações , Elastase Pancreática/metabolismo , Testes de Função Pancreática , Pancreatite Crônica/complicações , Pancreatite Crônica/etiologia , Síndrome de Shwachman-Diamond/complicações , Esteatorreia/etiologia , Tripsinogênio/sangue
11.
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 , Síndrome Congênita de Insuficiência da Medula Óssea/diagnóstico , 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 , Síndrome Congênita de Insuficiência da Medula Óssea/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
12.
Med J Malaysia ; 74(5): 454-455, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31649231

RESUMO

Neonatal death due to inborn error of metabolism (IEM) is rare in Malaysia. We report a sudden neonate death just a few hours after being discharged from the hospital. The deceased was a two-day-old baby boy and was asymptomatic until his demise. He was fed with expressed breast milk and formula milk. Autopsy revealed fatty changes of the liver and an enlarged heart. Laboratory investigation confirmed very long chain Acyl-CoA dehydrogenase deficiency which resulted in his death. Autopsy of sudden unexpected death in neonate should include investigation for inborn error of metabolism. Fatty liver and enlarged heart could give a clue for the diagnosis.


Assuntos
Acil-CoA Desidrogenase de Cadeia Longa/deficiência , Acil-CoA Desidrogenase/deficiência , Síndrome Congênita de Insuficiência da Medula Óssea/complicações , Fígado Gorduroso/diagnóstico , Erros Inatos do Metabolismo Lipídico/complicações , Doenças Mitocondriais/complicações , Doenças Musculares/complicações , Acil-CoA Desidrogenase/metabolismo , Acil-CoA Desidrogenase de Cadeia Longa/metabolismo , Síndrome Congênita de Insuficiência da Medula Óssea/diagnóstico , Síndrome Congênita de Insuficiência da Medula Óssea/metabolismo , Evolução Fatal , Fígado Gorduroso/etiologia , Fígado Gorduroso/metabolismo , Humanos , Recém-Nascido , Erros Inatos do Metabolismo Lipídico/diagnóstico , Erros Inatos do Metabolismo Lipídico/metabolismo , Masculino , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/metabolismo , Doenças Musculares/diagnóstico , Doenças Musculares/metabolismo
13.
PLoS One ; 14(9): e0221829, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31479473

RESUMO

Mitochondrial DNA (mtDNA) genome integrity is essential for proper mitochondrial respiratory chain function to generate cellular energy. Nuclear genes encode several proteins that function at the mtDNA replication fork, including mitochondrial single-stranded DNA-binding protein (SSBP1), which is a tetrameric protein that binds and protects single-stranded mtDNA (ssDNA). Recently, two studies have reported pathogenic variants in SSBP1 associated with hearing loss, optic atrophy, and retinal degeneration. Here, we report a 14-year-old Chinese boy with severe and progressive mitochondrial disease manifestations across the full Pearson, Kearns-Sayre, and Leigh syndromes spectrum, including infantile anemia and bone marrow failure, growth failure, ptosis, ophthalmoplegia, ataxia, severe retinal dystrophy of the rod-cone type, sensorineural hearing loss, chronic kidney disease, multiple endocrine deficiencies, and metabolic strokes. mtDNA genome sequencing identified a single large-scale 5 kilobase mtDNA deletion (m.8629_14068del5440), present at 68% and 16% heteroplasmy in the proband's fibroblast cell line and blood, respectively, suggestive of a mtDNA maintenance defect. On trio whole exome blood sequencing, the proband was found to harbor a novel de novo heterozygous mutation c.79G>A (p.E27K) in SSBP1. Size exclusion chromatography of p.E27K SSBP1 revealed it remains a stable tetramer. However, differential scanning fluorimetry demonstrated p.E27K SSBP1 relative to wild type had modestly decreased thermostability. Functional assays also revealed p.E27K SSBP1 had altered DNA binding. Molecular modeling of SSBP1 tetramers with varying combinations of mutant subunits predicted general changes in surface accessible charges, strength of inter-subunit interactions, and protein dynamics. Overall, the observed changes in protein dynamics and DNA binding behavior suggest that p.E27K SSBP1 can interfere with DNA replication and precipitate the introduction of large-scale mtDNA deletions. Thus, a single large-scale mtDNA deletion (SLSMD) with manifestations across the clinical spectrum of Pearson, Kearns-Sayre, and Leigh syndromes may result from a nuclear gene disorder disrupting mitochondrial DNA replication.


Assuntos
Acil-CoA Desidrogenase de Cadeia Longa/deficiência , Síndrome Congênita de Insuficiência da Medula Óssea/genética , DNA Mitocondrial/genética , Proteínas de Ligação a DNA/genética , Síndrome de Kearns-Sayre/genética , Doença de Leigh/genética , Erros Inatos do Metabolismo Lipídico/genética , Doenças Mitocondriais/genética , Proteínas Mitocondriais/genética , Doenças Musculares/genética , Mutação , Acil-CoA Desidrogenase de Cadeia Longa/genética , Adolescente , Sequência de Aminoácidos , Linhagem Celular , Criança , Síndrome Congênita de Insuficiência da Medula Óssea/complicações , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/metabolismo , Heterozigoto , Humanos , Síndrome de Kearns-Sayre/complicações , Doença de Leigh/complicações , Erros Inatos do Metabolismo Lipídico/complicações , Masculino , Doenças Mitocondriais/complicações , Proteínas Mitocondriais/química , Proteínas Mitocondriais/metabolismo , Simulação de Dinâmica Molecular , Doenças Musculares/complicações , Fenótipo , Estabilidade Proteica , Estrutura Quaternária de Proteína , Deleção de Sequência , Sequenciamento Completo do Exoma
14.
Biochim Biophys Acta Mol Cell Biol Lipids ; 1864(11): 1591-1605, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31394165

RESUMO

Medium-chain-triglycerides (MCT) are widely applied in the treatment of long-chain fatty acid oxidation disorders (lcFAOD). Long-term treatment with MCT led to a sexually dimorphic response in the mouse model of very-long-chain-acyl-CoA-dehydrogenase-deficiency (VLCAD-/-) with the subsequent development of a metabolic syndrome in female mice. In order to evaluate the molecular mechanisms responsible for this sex specific response we performed a comprehensive metabolic phenotyping, SILAC-based quantitative proteomics and characterized the involved signaling pathways by western blot analysis and gene expression. WT and VLCAD-/- mice showed strong sex-dependent differences in basal metabolism and expression of proteins involved in the distinct metabolic pathways, even more prominent after treatment with octanoate. The investigation of molecular mechanisms responsible for the sexual dimorphisms delineated the selective activation of the ERK/mTORc1 signaling pathway leading to an increased biosynthesis and elongation of fatty acids in VLCAD-/- females. In contrast, octanoate induced the activation of ERK/PPARγ pathway and the subsequent upregulation of peroxisomal ߭oxidation in males. We here provide first evidence that sex has to be considered as important variable in disease phenotype. These findings may have implications on treatment strategies in the different sexes.


Assuntos
Acil-CoA Desidrogenase de Cadeia Longa/deficiência , Acil-CoA Desidrogenase de Cadeia Longa/metabolismo , Síndrome Congênita de Insuficiência da Medula Óssea/metabolismo , Ácidos Graxos/metabolismo , Erros Inatos do Metabolismo Lipídico/metabolismo , Doenças Mitocondriais/metabolismo , Doenças Musculares/metabolismo , Acil-CoA Desidrogenase de Cadeia Longa/genética , Animais , Caprilatos/metabolismo , Caprilatos/uso terapêutico , Síndrome Congênita de Insuficiência da Medula Óssea/genética , Síndrome Congênita de Insuficiência da Medula Óssea/terapia , Feminino , Deleção de Genes , Humanos , Erros Inatos do Metabolismo Lipídico/genética , Erros Inatos do Metabolismo Lipídico/terapia , Sistema de Sinalização das MAP Quinases , Masculino , Camundongos , Doenças Mitocondriais/genética , Doenças Mitocondriais/terapia , Doenças Musculares/genética , Doenças Musculares/terapia , Oxirredução , PPAR gama/metabolismo , Fatores Sexuais , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo
15.
Eur J Hum Genet ; 27(12): 1821-1826, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31358953

RESUMO

Rapid genomic testing is a valuable new diagnostic tool for acutely unwell infants, however exome sequencing does not deliver clinical-grade mitochondrial genome sequencing and may fail to diagnose mitochondrial disorders caused by mitochondrial DNA (mtDNA) variants. Rapid mitochondrial genome sequencing and analysis are not routinely available in rapid genomic diagnosis programmes. We present two critically ill neonates with transfusion-dependent anaemia and persistent lactic acidosis who underwent rapid mitochondrial genome sequencing in tandem with exome sequencing as part of an exome sequencing-based rapid genomic diagnosis programme. No diagnostic variants were identified on examination of the nuclear exome data for either infant. Mitochondrial genome sequencing identified a large mtDNA deletion in both infants, diagnosing Pearson syndrome within 74 and 55 h, respectively. Early diagnosis in the third week of life allowed the avoidance of a range of other investigations and appropriate treatment planning. Rapid mitochondrial genome analysis provides additional diagnostic and clinical utility and should be considered as an adjunct to exome sequencing in rapid genomic diagnosis programmes.


Assuntos
Acil-CoA Desidrogenase de Cadeia Longa/deficiência , Síndrome Congênita de Insuficiência da Medula Óssea/genética , Diagnóstico Precoce , Genoma Mitocondrial/genética , Erros Inatos do Metabolismo Lipídico/genética , Doenças Mitocondriais/genética , Doenças Musculares/genética , Acil-CoA Desidrogenase de Cadeia Longa/genética , Síndrome Congênita de Insuficiência da Medula Óssea/diagnóstico , DNA Mitocondrial/genética , Exoma/genética , Feminino , Testes Genéticos , Humanos , Recém-Nascido , Terapia Intensiva Neonatal , Erros Inatos do Metabolismo Lipídico/diagnóstico , Masculino , Mitocôndrias/genética , Doenças Mitocondriais/diagnóstico , Doenças Musculares/diagnóstico , Sequenciamento Completo do Exoma/normas , Sequenciamento Completo do Genoma
16.
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 , Síndrome Congênita de Insuficiência da Medula Óssea/diagnóstico , Letargia/etiologia , Erros Inatos do Metabolismo Lipídico/diagnóstico , Doenças Mitocondriais/diagnóstico , Hipotonia Muscular/etiologia , Doenças Musculares/diagnóstico , Síndrome Congênita de Insuficiência da Medula Óssea/terapia , Diagnóstico Diferencial , Humanos , Hipotermia/etiologia , Recém-Nascido , Erros Inatos do Metabolismo Lipídico/terapia , Masculino , Doenças Mitocondriais/terapia , Doenças Musculares/terapia
17.
J Pediatr Health Care ; 33(5): 568-577, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31248636

RESUMO

The exponential rate at which genetic testing has been integrated into routine and high-risk obstetric care has been exciting to watch. With this technical explosion, however, the knowledge surrounding the benefits and limitations of prenatal genetic and newborn screening can be overlooked by both parents and providers. The following case exemplifies how a couple with infertility who underwent comprehensive prenatal expanded genetic carrier screening and parental karyotype experienced the benefits and limitations of such testing. It guides the reader through diagnostic testing for an infant, born to a father with a balanced translocation, who presented with an abnormal newborn screening result for an inherited metabolic disorder of fatty acid oxidation metabolism, very-long-chain acyl-coenzyme dehydrogenase deficiency, for which the prenatal expanded carrier screening result was negative.


Assuntos
Testes Genéticos , Diagnóstico Pré-Natal , Acil-CoA Desidrogenase de Cadeia Longa/deficiência , Acil-CoA Desidrogenase de Cadeia Longa/genética , Síndrome Congênita de Insuficiência da Medula Óssea/diagnóstico , Síndrome Congênita de Insuficiência da Medula Óssea/genética , Reações Falso-Negativas , Feminino , Triagem de Portadores Genéticos/métodos , Aconselhamento Genético , Testes Genéticos/métodos , Humanos , Recém-Nascido , Cariotipagem , Erros Inatos do Metabolismo Lipídico/diagnóstico , Erros Inatos do Metabolismo Lipídico/genética , Masculino , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/genética , Doenças Musculares/diagnóstico , Doenças Musculares/genética , Teste Pré-Natal não Invasivo/métodos , Cuidado Pré-Concepcional , Diagnóstico Pré-Natal/métodos
18.
J Inherit Metab Dis ; 42(5): 870-877, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30993714

RESUMO

Very-long chain acyl-CoA dehydrogenase (VLCAD) deficiency (VLCADD) is an autosomal recessive disorder of fatty acid oxidation. Fatty acids are a major source of energy during catabolic stress, so the absence of VLCAD can result in a metabolic crises and respiratory insufficiency. The etiology of this respiratory insufficiency is unclear. Thus, our aims were: (1) to characterize respiratory pathophysiology in VLCADD mice (VLCAD-/- ), and (2) to determine if AAV9-mediated gene therapy improves respiratory function. For the first aim, VLCAD-/- and wild-type (WT) mice underwent an exercise/fast "stress protocol" and awake spontaneous breathing was evaluated using whole-body plethysmography (WBP) both at baseline and during a hypercapnic respiratory challenge (FiO2 : 0.21; FiCO2 : 0.07; nitrogen balance). During hypercapnia, VLCAD -/- mice had a significantly lower frequency, tidal volume, minute ventilation, and peak inspiratory and expiratory flow, all of which indicate respiratory insufficiency. Histologically, the cardiac and respiratory muscles of stressed VLCAD -/- animals had an accumulation of intramyocellular lipids. For the second aim, a single systemic injection of AAV9-VLCAD gene therapy improved this respiratory pathology by normalizing breathing frequency and enhancing peak inspiratory flow. In addition, following gene therapy, there was a moderate reduction of lipid accumulation in the respiratory muscles. Furthermore, VLCAD protein expression was robust in cardiac and respiratory muscle. This was confirmed by immuno-staining with anti-human VLCAD antibody. In summary, stress with exercise and fasting induces respiratory insufficiency in VLCAD-/- mice and a single injection with AAV9-VLCAD gene therapy ameliorates breathing.


Assuntos
Acil-CoA Desidrogenase de Cadeia Longa/deficiência , Síndrome Congênita de Insuficiência da Medula Óssea/terapia , Terapia Genética , Erros Inatos do Metabolismo Lipídico/terapia , Doenças Mitocondriais/terapia , Doenças Musculares/terapia , Insuficiência Respiratória/terapia , Acil-CoA Desidrogenase de Cadeia Longa/genética , Animais , Carnitina/sangue , Síndrome Congênita de Insuficiência da Medula Óssea/genética , Dependovirus/genética , Feminino , Expressão Gênica , Vetores Genéticos , Metabolismo dos Lipídeos , Erros Inatos do Metabolismo Lipídico/genética , Fígado/metabolismo , Masculino , Camundongos , Camundongos Knockout , Doenças Mitocondriais/genética , Doenças Musculares/genética , Insuficiência Respiratória/etiologia , Transdução Genética
19.
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 , Síndrome Congênita de Insuficiência da Medula Óssea , Humanos , Recém-Nascido , Triagem Neonatal
20.
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 , Síndrome Congênita de Insuficiência da Medula Óssea , 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
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