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1.
Mol Genet Metab ; 106(1): 55-61, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22424739

RESUMO

BACKGROUND: Short-chain acyl-CoA dehydrogenase deficiency (SCADD) is an autosomal recessive inborn error of mitochondrial fatty acid oxidation with highly variable biochemical, genetic, and clinical characteristics. SCADD has been associated with accumulation of butyryl-CoA byproducts, including butyrylcarnitine (C4), butyrylglycine, ethylmalonic acid (EMA), and methylsuccinic acid (MS) in body fluid and tissues. Differences in genotype frequencies have been shown between patients diagnosed clinically versus those diagnosed by newborn screening. Moreover, while patients diagnosed clinically have a variable clinical presentation including developmental delay, ketotic hypoglycemia, epilepsy and behavioral disorders, studies suggest patients diagnosed by newborn screening are largely asymptomatic. Scant information is published about the biochemical, genetic and clinical outcome of SCADD patients diagnosed by newborn screening. METHODS: We collected California newborn screening, follow-up biochemical levels, and ACADS mutation data from September, 2005 through April, 2010. We retrospectively reviewed available data on SCADD cases diagnosed by newborn screening for clinical outcomes. RESULTS: During the study period, 2,632,058 newborns were screened and 76 confirmed SCADD cases were identified. No correlations between initial C4 value and follow-up biochemical markers (C4, EMA or MS levels) were found in the 76 cases studied. We found significant correlation between urine EMA versus MS, and correlation between follow-up C4 versus urine EMA. Of 22 cases where ACADS gene sequencing was performed: 7 had two or more deleterious mutations; 8 were compound heterozygotes for a deleterious mutation and common variant; 7 were homozygous for the common variant c.625G>A; and 1 was heterozygous for c.625G>A. Significant increases in mean urine EMA and MS levels were noted in patients with two or more deleterious mutations versus mutation heterozygotes or common polymorphism homozygotes. Clinical outcome data was available in 31 patients with follow-up extending from 0.5 to 60 months. None developed epilepsy or behavioral disorders, and three patients had isolated speech delay. Hypoglycemia occurred in two patients, both in the neonatal period. The first patient had concomitant meconium aspiration; the other presented with central apnea, poor feeding, and hypotonia. The latter, a c.625G>A homozygote, has had persistent elevations in both short- and medium-chain acylcarnitines; diagnostic workup in this case is extensive and ongoing. CONCLUSIONS: This study examines the largest series to date of SCADD patients identified by newborn screening. Our results suggest that confirmatory tests may be useful to differentiate patients with common variants from those with deleterious mutations. This study also provides evidence to suggest that, even when associated with deleterious mutations, SCADD diagnosed by newborn screening presents largely as a benign condition.


Assuntos
Acil Coenzima A , Erros Inatos do Metabolismo Lipídico/diagnóstico , Erros Inatos do Metabolismo Lipídico/genética , Triagem Neonatal , Acil Coenzima A/sangue , Acil Coenzima A/genética , Acil Coenzima A/urina , Acil-CoA Desidrogenase/deficiência , Acil-CoA Desidrogenase/genética , California , Carnitina/análogos & derivados , Carnitina/sangue , Carnitina/urina , Feminino , Seguimentos , Humanos , Recém-Nascido , Masculino , Malonatos/sangue , Malonatos/urina , Deleção de Sequência , Succinatos/sangue , Succinatos/urina
2.
J Urol ; 172(4 Pt 1): 1501-3, 2004 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-15371879

RESUMO

PURPOSE: We assessed the feasibility of a novel urinary test for prostate cancer based on the presence of alpha methylacyl coenzyme A racemase (AMACR) protein in voided urine specimens obtained after prostate biopsy. MATERIALS AND METHODS: Clean catch voided urine specimens were prospectively collected from 26 consecutive men immediately after transrectal ultrasound guided prostate biopsy for suspected malignancy. The presence of AMACR was evaluated in a blinded manner by Western blot analysis and correlated with biopsy results and patient clinical information. RESULTS: AMACR was detected in the urine in 18 of 26 patients (69%). AMACR was detected in all 12 patients with biopsy confirmed adenocarcinoma of the prostate (100% sensitivity, 95% CI 75 to 100), in 5 of 12 with no evidence of cancer on biopsy (58% specificity, 95% CI 29 to 78) and in 1 of 2 (50%, 95% CI 3 to 80) with atypia on biopsy. Overall AMACR detection was associated with cancer status by prostate biopsy in 21 of 26 patients (86%). CONCLUSIONS: We report the feasibility of a novel, noninvasive, nonprostate specific antigen based molecular approach to detect prostate cancer in voided urine. To our knowledge this is the first report of AMACR protein detection in the urine of patients with prostate cancer. A screening test based on urinary AMACR may develop into a useful adjunct to serum prostate specific antigen and digital rectal examination for identifying men at increased risk for harboring prostate cancer despite negative biopsy. Such a test has potential application for stratifying patients into low and high risk groups for surveillance vs repeat biopsy.


Assuntos
Acil Coenzima A/urina , Adenocarcinoma/diagnóstico , Biomarcadores Tumorais/urina , Metilação de DNA , Neoplasias da Próstata/diagnóstico , Adenocarcinoma/patologia , Adenocarcinoma/urina , Idoso , Biópsia , Western Blotting , Estudos de Viabilidade , Humanos , Masculino , Pessoa de Meia-Idade , Lesões Pré-Cancerosas/diagnóstico , Lesões Pré-Cancerosas/patologia , Lesões Pré-Cancerosas/urina , Valor Preditivo dos Testes , Estudos Prospectivos , Próstata/metabolismo , Próstata/patologia , Neoplasias da Próstata/patologia , Neoplasias da Próstata/urina , Racemases e Epimerases
3.
Acta Paediatr Scand ; 75(4): 676-81, 1986 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-3751563

RESUMO

A boy with riboflavin-responsive beta-oxidation deficiency (multiple acyl-CoA dehydrogenation deficiency) was assessed clinically and biochemically after 3 years of continuous riboflavin medication. He was diagnosed at the age of three years after an attack of a Reye's syndrome-like disease. During the 3 years of assessment he has experienced no serious disease; although short episodes of fatigue and loss of appetite have been noted. His mental and physical development has been normal. Biochemically the abnormal excretion of organic acid metabolites, characteristic of the acyl-CoA dehydrogenation deficiency, has been continuously present. Quantitatively there has been a trend to a more simple picture with ethylmalonic acid as the predominant metabolite. However, because of the large within-day variation in the excretion of all the metabolites, changes following diet and riboflavin trials must be interpreted with caution in these patients.


Assuntos
Ácidos Graxos Dessaturases/deficiência , Riboflavina/uso terapêutico , Acil Coenzima A/urina , Criança , Glutationa Redutase/sangue , Humanos , Masculino , Síndrome de Reye/diagnóstico , Síndrome de Reye/enzimologia
4.
Eur J Pediatr ; 144(6): 586-9, 1986 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-3709573

RESUMO

Two patients have been studied in whom the activity of the short chain-length-specific mitochondrial 3-ketothiolase was found to be deficient. Use of a range of 3-ketoacyl-CoA substrates showed that the other 3-ketothiolase isoenzymes were normal in each case. Both patients had episodic ketosis and metabolic acidosis. One patient had substantial evidence of damage to the central nervous system and two siblings who had died of the disease. The organic aciduria was characterized by the excretion of 2-methyl-3-hydroxybutyric acid and tiglyglycine. In one patient the organic aciduria was very subtle and was masked during the presence of ketosis, but it was clarified by an isoleucine load after recovery from ketosis.


Assuntos
Acetil-CoA C-Aciltransferase/deficiência , Aciltransferases/deficiência , Ácido 3-Hidroxibutírico , Acetilcoenzima A/análogos & derivados , Acetilcoenzima A/metabolismo , Acetil-CoA C-Aciltransferase/metabolismo , Acil Coenzima A/urina , Criança , Feminino , Fibroblastos/enzimologia , Glicina/análogos & derivados , Glicina/urina , Humanos , Hidroxibutiratos/urina , Lactente , Isoleucina , Cetose/metabolismo , Masculino , Valeratos/metabolismo
5.
J Clin Invest ; 73(6): 1785-8, 1984 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-6725560

RESUMO

Treatment with L-carnitine greatly enhanced the formation and excretion of short-chain acylcarnitines in three patients with propionic acidemia and in three normal controls. The use of fast atom bombardment mass spectrometry and linked scanning at constant magnetic (B) to electric (E) field ratio identified the acylcarnitine as propionylcarnitine in patients with propionic acidemia. The normal children excreted mostly acetylcarnitine. Propionic acidemia and other organic acidurias are characterized by the intramitochondrial accumulation of short-chain acyl-Coenzyme A (CoA) compounds. The substrate specificity of the carnitine acetyltransferase enzyme and its steady state nature appears to facilitate elimination of propionyl groups while restoring the acyl-CoA:free CoA ratio in the mitochondrion. We suggest that L-carnitine may be a useful therapeutic approach for elimination of toxic acyl CoA compounds in several of these disorders.


Assuntos
Acil Coenzima A/urina , Carboxiliases/deficiência , Carnitina/análogos & derivados , Adolescente , Carnitina/metabolismo , Carnitina/urina , Criança , Pré-Escolar , Humanos , Lactente , Masculino , Espectrometria de Massas/métodos , Erros Inatos do Metabolismo/metabolismo , Metilmalonil-CoA Descarboxilase , Propionatos/metabolismo
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