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Mitochondrial involvement and erythronic acid as a novel biomarker in transaldolase deficiency.

ABSTRACT: Sedoheptulose, arabitol, ribitol, and erythritol have been identified as key diagnostic metabolites in TALDO deficiency.Urine from 6 TALDO-deficient patients and TALDO-deficient knock-out mice were analyzed using ¹H-NMR spectroscopy and GC-mass spectrometry.Our data confirm the known metabolic characteristics in TALDO-deficient patients. The ?-furanose form was the major sedoheptulose anomer in TALDO-deficient patients. Erythronic acid was identified as a major abnormal metabolite in all patients and in knock-out TALDO mice implicating an as yet unknown biochemical pathway in this disease. A putative sequence of enzymatic reactions leading to the formation of erythronic acid is presented. The urinary concentration of the citric acid cycle intermediates 2-oxoglutaric acid and fumaric acid was increased in the majority of TALDO-deficient patients but not in the knock-out mice.Erythronic acid is a novel and major hallmark in TALDO deficiency. The pathway leading to its production may play a role in healthy humans as well. In TALDO-deficient patients, there is an increased flux through this pathway. The finding of increased citric acid cycle intermediates hints toward a disturbed mitochondrial metabolism in TALDO deficiency.

SUBMITTER: Engelke UF

PROVIDER: S-EPMC3117462 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

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Mitochondrial involvement and erythronic acid as a novel biomarker in transaldolase deficiency.

Engelke Udo F H UF Zijlstra Fokje S M FS Mochel Fanny F Valayannopoulos Vassili V Rabier Daniel D Kluijtmans Leo A J LA Perl András A Verhoeven-Duif Nanda M NM de Lonlay Pascale P Wamelink Mirjam M C MM Jakobs Cornelis C Morava Eva E Wevers Ron A RA

Biochimica et biophysica acta 20100618 11

<h4>Background</h4>Sedoheptulose, arabitol, ribitol, and erythritol have been identified as key diagnostic metabolites in TALDO deficiency.<h4>Method</h4>Urine from 6 TALDO-deficient patients and TALDO-deficient knock-out mice were analyzed using ¹H-NMR spectroscopy and GC-mass spectrometry.<h4>Results</h4>Our data confirm the known metabolic characteristics in TALDO-deficient patients. The β-furanose form was the major sedoheptulose anomer in TALDO-deficient patients. Erythronic acid was identi ...[more]

PMID: 20600873

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Project description:ObjectiveShort-chain enoyl-CoA hydratase (ECHS1) is a multifunctional mitochondrial matrix enzyme that is involved in the oxidation of fatty acids and essential amino acids such as valine. Here, we describe the broad phenotypic spectrum and pathobiochemistry of individuals with autosomal-recessive ECHS1 deficiency.MethodsUsing exome sequencing, we identified ten unrelated individuals carrying compound heterozygous or homozygous mutations in ECHS1. Functional investigations in patient-derived fibroblast cell lines included immunoblotting, enzyme activity measurement, and a palmitate loading assay.ResultsPatients showed a heterogeneous phenotype with disease onset in the first year of life and course ranging from neonatal death to survival into adulthood. The most prominent clinical features were encephalopathy (10/10), deafness (9/9), epilepsy (6/9), optic atrophy (6/10), and cardiomyopathy (4/10). Serum lactate was elevated and brain magnetic resonance imaging showed white matter changes or a Leigh-like pattern resembling disorders of mitochondrial energy metabolism. Analysis of patients' fibroblast cell lines (6/10) provided further evidence for the pathogenicity of the respective mutations by showing reduced ECHS1 protein levels and reduced 2-enoyl-CoA hydratase activity. While serum acylcarnitine profiles were largely normal, in vitro palmitate loading of patient fibroblasts revealed increased butyrylcarnitine, unmasking the functional defect in mitochondrial β-oxidation of short-chain fatty acids. Urinary excretion of 2-methyl-2,3-dihydroxybutyrate - a potential derivative of acryloyl-CoA in the valine catabolic pathway - was significantly increased, indicating impaired valine oxidation.InterpretationIn conclusion, we define the phenotypic spectrum of a new syndrome caused by ECHS1 deficiency. We speculate that both the β-oxidation defect and the block in l-valine metabolism, with accumulation of toxic methacrylyl-CoA and acryloyl-CoA, contribute to the disorder that may be amenable to metabolic treatment approaches.

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Mitochondrial involvement and erythronic acid as a novel biomarker in transaldolase deficiency.

Publications

Mitochondrial involvement and erythronic acid as a novel biomarker in transaldolase deficiency.

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