2-Ethylhydracrylic Aciduria in Short/Branched-Chain Acyl-CoA Dehydrogenase Deficiency: Application to Diagnosis and Implications for the R-Pathway of Isoleucine Oxidation

Korman, Stanley H.; Andresen, Brage S.; Zeharia, Avraham; Gutman, Alisa; Boneh, Avihu; Pitt, James

doi:10.1373/clinchem.2004.043265

Cited by 35 publications

(35 citation statements)

References 33 publications

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“…In the present study, we employed an enzyme assay using 2-methylbutyryl-CoA as substrate to further demonstrate SBCADD in fibroblasts from patient 2, his affected younger sister, and in a new unrelated patient (patient 1) in whom we suspected SBCADD because 2-methylbutyrylglycine was present in his urine. From a diagnostic point of view, it is notable that all patients diagnosed after clinical presentation, including the two patients described in the present study, have exhibited 2-methylbutyrylglycine in their urine (Andresen et al 2000;Gibson et al 2000;Korman et al 2005). In contrast, MS/MS analysis of the newborn blood spot from patient 1 showed a ''high normal'' acylcarnitine profile, with C5-carnitine being below the current cutoff.…”

Section: Discussionmentioning

confidence: 54%

“…Little is known about the clinical presentation of this disease, as it has so far been described only in a limited number of patients. Because SBCADD may cause accumulation of C5-carnitine in blood, the enzymatic defect can be identified by tandem mass spectrometry (MS/MS) analysis of blood spots in newborn screening (Korman et al 2005;Matern et al 2003). With the expanding use of routine MS/MS-based newborn screening, it is likely that the number of individuals diagnosed with SBCADD will increase.…”

Section: Introductionmentioning

confidence: 99%

“…Urine acylglycine analysis, which is not widely available, can differentiate isovalerylglycine from methylbutyrylglycine, and therefore, may be helpful in the diagnosis, but a definitive diagnosis of SBCADD requires identification and characterization of mutations in the SBCAD gene. Seven mutations in the SBCAD gene have been reported so far (Andresen et al 2000;Gibson et al 2000;Korman et al 2005;Matern et al 2003), but only three of these have been demonstrated experimentally to be deleterious.…”

Section: Introductionmentioning

confidence: 99%

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Short/branched-chain acyl-CoA dehydrogenase deficiency due to an IVS3+3A>G mutation that causes exon skipping

et al. 2005

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Short/branched-chain acyl-CoA dehydrogenase deficiency (SBCADD) is an autosomal recessive disorder of L: -isoleucine catabolism. Little is known about the clinical presentation associated with this enzyme defect, as it has been reported in only a limited number of patients. Because the presence of C5-carnitine in blood may indicate SBCADD, the disorder may be detected by MS/MS-based routine newborn screening. It is, therefore, important to gain more knowledge about the clinical presentation and the mutational spectrum of SBCADD. In the present study, we have studied two unrelated families with SBCADD, both with seizures and psychomotor delay as the main clinical features. One family illustrates the fact that affected individuals may also remain asymptomatic. In addition, the normal level of newborn blood spot C5-acylcarnitine in one patient underscores the fact that newborn screening by MS/MS currently lacks sensitivity in detecting SBCADD. Until now, seven mutations in the SBCAD gene have been reported, but only three have been tested experimentally. Here, we identify and characterize an IVS3+3A>G mutation (c.303+3A>G) in the SBCAD gene, and provide evidence that this mutation is disease-causing in both families. Using a minigene approach, we show that the IVS3+3A>G mutation causes exon 3 skipping, despite the fact that it does not appear to disrupt the consensus sequence of the 5' splice site. Based on these results and numerous literature examples, we suggest that this type of mutation (IVS+3A>G) induces missplicing only when in the context of non-consensus (weak) 5' splice sites. Statistical analysis of the sequences shows that the wild-type versions of 5' splice sites in which +3A>G mutations cause exon skipping and disease are weaker on average than a random set of 5' splice sites. This finding is relevant to the interpretation of the functional consequences of this type of mutation in other disease genes.

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Section: Discussionmentioning

confidence: 54%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Short/branched-chain acyl-CoA dehydrogenase deficiency due to an IVS3+3A>G mutation that causes exon skipping

et al. 2005

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“…Acylcarnitines were determined by electrospray–tandem mass spectrometry in plasma or dry bloodspots (Micromass, Waters, Milford, MA, USA) [7]. Organic acids in urine were determined qualitatively by gas chromatography–mass spectrometry (GC-MS) (Agilent, Santa Clara, CA, USA) [8].…”

Section: Methodsmentioning

confidence: 99%

The Relationship between Mitochondrial Respiratory Chain Activities in Muscle and Metabolites in Plasma and Urine: A Retrospective Study

Alban

Fatale

Joulani

et al. 2017

JCM

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The relationship between 114 cases with decreased enzymatic activities of mitochondrial respiratory chain (MRC) complexes I-V (C I-V) in muscle and metabolites in urine and plasma was retrospectively examined. Less than 35% disclosed abnormal plasma amino acids and acylcarnitines, with elevated alanine and low free carnitine or elevated C4-OH-carnitine as the most common findings, respectively. Abnormal urine organic acids (OA) were detected in 82% of all cases. In CI and CII defects, lactic acid (LA) in combination with other metabolites was the most common finding. 3-Methylglutaconic (3MGA) acid was more frequent in CIV and CV, while Tyrosine metabolites, mainly 4-hydroxyphenyllactate, were common in CI and IV defects. Ketones were present in all groups but more prominent in combined deficiencies. There was a significant strong correlation between elevated urinary LA and plasma lactate but none between urine Tyrosine metabolites and plasma Tyrosine or urinary LA and plasma Alanine. All except one of 14 cases showed elevated FGF21, but correlation with urine OA was weak. Although this study is limited, we conclude that urine organic acid test in combination with plasma FGF21 determination are valuable tools in the diagnosis of mitochondrial diseases.

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“…C16 [8-10, 13, 14, 18, 19, 57, 72, 81] C0 [8-10, 13, 14, 18, 19, 57, 81] C18:1 [9,10,72] C18 [8-10, 13, 14, 18, 19, 57, 72, 80] C0/C16+C18 [8,14,15,18,19,57,81] Enzymatic assay and molecular studies [57,81,82].…”

Section: Cpt-ia 60052cpt-ib 601987mentioning

confidence: 99%

Tandem Mass Spectrometry Newborn Screening for Inborn Errors of Intermediary Metabolism: Abnormal Profile Interpretation

Fernández-Lainez¹,

Aguilar-Lemus²,

Vela-Amieva³

et al. 2012

CMC

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Expanded newborn screening for inherited metabolic disorders using tandem mass spectrometry was introduced in 1990's and is widely used around the world. In contrast to conventional screening methods, tandem mass spectrometry does not measure single analytes but identifies and quantifies metabolite profiles; one single blood spot analyzed provides information of about 60 metabolites including amino acids, acylcarnitines and related ratios that enable the diagnosis of approximately 50 different diseases. However, the interpretation of these profiles can become quite complex. The aim of this work is to present in an easy and practical manner a comprehensive compilation of information needed for tandem mass neonatal screening profile interpretation, and basic actions for immediate follow up of abnormal results, including the tests that are required for confirmatory purposes. Other conditions not attributable to metabolic disorders which can lead to an abnormal profile of these markers are also described as well as a series of general recommendations which would be useful for health professionals who are beginning newborn screening for inborn errors of intermediary metabolism using tandem mass spectrometry.

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2-Ethylhydracrylic Aciduria in Short/Branched-Chain Acyl-CoA Dehydrogenase Deficiency: Application to Diagnosis and Implications for the R-Pathway of Isoleucine Oxidation

Cited by 35 publications

References 33 publications

Short/branched-chain acyl-CoA dehydrogenase deficiency due to an IVS3+3A>G mutation that causes exon skipping

Short/branched-chain acyl-CoA dehydrogenase deficiency due to an IVS3+3A>G mutation that causes exon skipping

The Relationship between Mitochondrial Respiratory Chain Activities in Muscle and Metabolites in Plasma and Urine: A Retrospective Study

Tandem Mass Spectrometry Newborn Screening for Inborn Errors of Intermediary Metabolism: Abnormal Profile Interpretation

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