Hyperinsulinism in short-chain L-3-hydroxyacyl-CoA dehydrogenase deficiency reveals the importance of β-oxidation in insulin secretion

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.

The Foxa family of transcription factors in development and metabolism

“…The former is explained by diminished expression of the Foxa2 target genes Kir6.2 (Kcnj11) and Sur1 (Abcc8), which together comprise the K ATP glucose-sensing channel [41]. A novel Foxa2 target gene, Hadhsc, which encodes a short-chain fatty acid dehydrogenase has been identified; it is likely that loss of this gene product also contributes to the Foxa2 loxP/loxP ; Ins.Cre phenotype because humans with mutations in the orthologous gene SCHAD also have hyperinsulinemic hypoglycemia [42][43][44][45]. These results indicate that Foxa1 and Foxa2 play critical, non-redundant roles in the response of adult islets to glucose and nutrient levels.…”

Congenital Hyperinsulinism due to mutations in HNF4A and HADH

“…Mutations in the HADH gene are a rare cause of recessively inherited congenital hyperinsulinism (CHI).To date six patients have been described with hyperinsulinaemic hypoglycaemia (HH) due to homozygous mutations in this gene [13][14][15][16][17]. The mutations described so far and the clinical picture is summarized in Table 1.…”

“…Our group first described [13] an infant who presented with a hypoglycaemic seizure at 4 months of age. Investigations revealed intermittent episode of hyperinsulinaemic hypoglycaemia (HH).…”

Dominantly inherited hyperinsulinaemic hypoglycaemia

“…In all these cases, transmission can be sporadic or dominant. More recently, one other metabolic defect has been identified in recessively inherited HI: short-chain L-3-hydroxyacyl-CoA dehydrogenase (SCHAD) (Clayton et al 2001). Finally, (iii) a third mechanism has recently been reported in dominantly inherited HI, implicating the human insulin receptor gene (Hojlund et al 2004).…”