Clinical and Laboratory Observation
Hyperinsulinism of infancy associated with a novel splice site mutation in the SCHAD gene

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Fatty acids play an important role in regulating insulin secretion, but the mechanisms are unclear. We report a case of a novel splice site mutation in the short-chain 3-hydroxyacyl-CoA dehydrogenase (SCHAD) gene associated with hyperinsulinism. This mutation resulted in a nearly complete absence of immunoreactive protein and a decrease in fibroblast SCHAD activity.

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Clinical Case History

This child was born to consanguineous first cousin parents, with a birth weight of 3.1 kg. At 4 months of age he presented with hypoglycemia and seizures. Investigations showed an increased glucose clearance rate (7 mg/kg per minute) and a biochemical picture consistent with hyperinsulinemic hypo–fatty acidemic hypoketotic hypoglycemia. This patient responded to 5 mg/kg per day diazoxide and 7.5 mg/kg per day chlorothiazide.

Measurement of 3-Hydroxyacyl-CoA Dehydrogenase Activity

Short-, medium-, and long-chain 3-hydroxyacyl-CoA dehydrogenase

Results

The results of the diagnostic fast were similar to the first patient we described.5 During one fast with a blood glucose level of 1.9 mmol/L, insulin level was <1 mU/L and NEFA (1.49 mmol/L) and 3-hydroxybutyrtae (0.53 mmol/L) were elevated. During a second fast with a blood glucose level of 2.9 mmol/L, the insulin level was elevated at 3.0 mU/L, with suppressed NEFA (0.50 mmol/L) and ketones (<0.05 mmol/L).

Hydroxybutyrylcarnitine was persistently elevated (0.70 to 1.69 μmol/L). Urine organic

Discussion

This is the third reported case of a mutation in the SCHAD gene in a patient with hyperinsulinism. All reported cases have presented with increased 3-hydroxyglutarate in urine and hydroxybutyrylcarnitine in blood, diagnostically useful markers for SCHAD deficiency. The clinical presentation is heterogeneous, with either mild late onset hypoglycaemia or severe neonatal hypoglycaemia.5, 7

The mechanism of how a defect in SCHAD leads to dysregulated insulin secretion is unclear at present. In the

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    Citation Excerpt :

    This enzyme is now known as hydroxyl acyl-coenzyme A dehydrogenase (HADH). The inhibition of HADH, due to a mutation in its gene, may also cause protein-induced HH [61–64]. Patients may present in the neonatal period or more commonly later in life with hypoglycemia and increased hydroxybutyrylcarnitine and urine 3-hydroxyglutarate.

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Supported by the NHS Executive R & D funding (Research at the Institute of Child Health and Great Ormond Street Hospital for Children NHS Trust).

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