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3-hydroxyacyl-coenzyme a dehydrogenase deficiency: identification of a new mutation causing hyperinsulinemic hypoketotic hypoglycemia, altered organic acids and acylcarnitines concentrations.

ABSTRACT: The human HADH gene encodes the short-chain-L-3-hydroxyacyl-CoA dehydrogenase, the enzyme which catalyzes the third step of the β-oxidation of the fatty acids in the mitochondrial matrix. Loss-of-function mutations in the HADH gene lead to short-chain-L-3-hydroxyacyl-CoA dehydrogenase deficiency, an autosomal recessive genetic defect of unknown prevalence with a wide spectrum of phenotypic variability. As in other metabolic diseases, the diagnostic relevance of the biochemical evaluations, plasma acylcarnitines, and urinary organic acids, are crucially dependent on the clinical conditions of the patient during specimen collection.This paper describes the eighth patient carrying a HADH gene mutation, a new homozygous deletion c.565delG leading to an early stop codon (p.V116Wfs124X), in an infant with hyperinsulininemic hypoglycemia, displaying abnormal patterns of plasma acylcarnitines and urinary organic acids. We conclude that, when the residual catalytic activity of the mutated enzyme is seriously reduced, the biochemical hallmarks of the disease, namely plasma 3-hydroxybutyrylcarnitine and urinary 3-hydroxyglutaric acid, are invariably present.

SUBMITTER: Popa FI

PROVIDER: S-EPMC3509842 | biostudies-other | 2012

REPOSITORIES: biostudies-other

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3-hydroxyacyl-coenzyme a dehydrogenase deficiency: identification of a new mutation causing hyperinsulinemic hypoketotic hypoglycemia, altered organic acids and acylcarnitines concentrations.

Popa Florina Ion FI Perlini Silvia S Teofoli Francesca F Degani Daniela D Funghini Silvia S La Marca Giancarlo G Rinaldo Piero P Vincenzi Monica M Antoniazzi Franco F Boner Attilio A Camilot Marta M

JIMD reports 20110906

The human HADH gene encodes the short-chain-L-3-hydroxyacyl-CoA dehydrogenase, the enzyme which catalyzes the third step of the β-oxidation of the fatty acids in the mitochondrial matrix. Loss-of-function mutations in the HADH gene lead to short-chain-L-3-hydroxyacyl-CoA dehydrogenase deficiency, an autosomal recessive genetic defect of unknown prevalence with a wide spectrum of phenotypic variability. As in other metabolic diseases, the diagnostic relevance of the biochemical evaluations, plasm ...[more]

PMID: 23430856

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Project description:BackgroundIn addition to inborn metabolic disorders, altered metabolic profiles were reported to be associated with the risk and prognosis of some non-metabolic diseases, while as a rare metabolic disease, the overall secondary metabolic spectrum in congenital hyperinsulinemic hypoglycemia (HH) is largely undetermined. Therefore, we investigated metabolic profiles in HH patients and used ketotic hypoglycemia (KH) patients as a control cohort to unveil their distinct metabolic features.MethodsA total of 97 hypoglycemia children, including 74 with hyperinsulinemic hypoglycemia and 23 with ketotic hypoglycemia, and 170 euglycemia control subjects were studied retrospectively. Clinical and biochemical data were collected. The normoglycemic spectra of amino acids and acylcarnitines were determined by liquid chromatography tandem mass spectrometry. The serum insulin and fatty acid concentrations during standardized fasting tests in hypoglycemia patients were also collected. Receiver operating characteristic curve analysis was performed to screen potential biomarkers.ResultsAmong the normoglycemic spectra of amino acids, blood valine (p < 0.001), arginine (p < 0.001), threonine (p = 0.001), glutamate (p = 0.002), methionine (p = 0.005), ornithine (p = 0.008), leucine (p = 0.014), alanine (p = 0.017), proline (p = 0.031), citrulline (p = 0.042), aspartate (p = 0.046), and glycine (p = 0.048) levels differed significantly among the three groups. Significantly decreased levels of long- (C14:1, p < 0.001; C18, p < 0.001), medium- (C8, p < 0.001; C10, p < 0.001; C10:1, p < 0.001), and short-chain (C4-OH, p < 0.001; C5OH, p < 0.001) acylcarnitines were found in the hyperinsulinemic hypoglycemia group. Hyperinsulinemic hypoglycemia children with focal lesions and diffuse lesions had similar amino acid and acylcarnitine spectra. C10:1 < 0.09 μmol/L, threonine > 35 μmol/L, and threonine/C10:1 > 440 showed sensitivities of 81.1, 66.2, and 81.1% and specificities of 72.7, 78.3, and 81.8%, respectively, in distinguishing HH from KH.ConclusionsWe found significantly different altered serum amino acid and acylcarnitine profiles at normoglycemia, especially decreased C10:1 and increased threonine levels, between HH and KH children, which may reflect the insulin ketogenesis inhibition effect in HH patients; however, the detailed mechanisms and physiological roles remain to be studied in the future.

Dataset Information

3-hydroxyacyl-coenzyme a dehydrogenase deficiency: identification of a new mutation causing hyperinsulinemic hypoketotic hypoglycemia, altered organic acids and acylcarnitines concentrations.

Publications

3-hydroxyacyl-coenzyme a dehydrogenase deficiency: identification of a new mutation causing hyperinsulinemic hypoketotic hypoglycemia, altered organic acids and acylcarnitines concentrations.

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