Hyperinsulinism in short-chain L-3-hydroxyacyl-CoA dehydrogenase deficiency reveals the importance of beta-oxidation in insulin secretion.
J Clin Invest
; 108(3): 457-65, 2001 Aug.
Article
em En
| MEDLINE
| ID: mdl-11489939
ABSTRACT
A female infant of nonconsanguineous Indian parents presented at 4 months with a hypoglycemic convulsion. Further episodes of hypoketotic hypoglycemia were associated with inappropriately elevated plasma insulin concentrations. However, unlike other children with hyperinsulinism, this patient had a persistently elevated blood spot hydroxybutyrylcarnitine concentration when fed, as well as when fasted. Measurement of the activity of L-3-hydroxyacyl-CoA dehydrogenase in cultured skin fibroblasts with acetoacetyl-CoA substrate showed reduced activity. In fibroblast mitochondria, the activity was less than 5% that of controls. Sequencing of the short-chain L-3-hydroxyacyl-CoA dehydrogenase (SCHAD) genomic DNA from the fibroblasts showed a homozygous mutation (C773T) changing proline to leucine at amino acid 258. Analysis of blood from the parents showed they were heterozygous for this mutation. Western blot studies showed undetectable levels of immunoreactive SCHAD protein in the child's fibroblasts. Expression studies showed that the P258L enzyme had no catalytic activity. We conclude that C773T is a disease-causing SCHAD mutation. This is the first defect in fatty acid beta-oxidation that has been associated with hyperinsulinism and raises interesting questions about the ways in which changes in fatty acid and ketone body metabolism modulate insulin secretion by the beta cell. The patient's hyperinsulinism was easily controlled with diazoxide and chlorothiazide.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Carnitina
/
Mutação Puntual
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3-Hidroxiacil-CoA Desidrogenases
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Hiperinsulinismo
/
Insulina
Tipo de estudo:
Etiology_studies
/
Prognostic_studies
Limite:
Animals
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Female
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Humans
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Infant
Idioma:
En
Revista:
J Clin Invest
Ano de publicação:
2001
Tipo de documento:
Article
País de afiliação:
Reino Unido