Compound Heterozygosity for the Common Sulfonylurea Receptor Mutations Can Cause Mild Diazoxide-Sensitive Hyperinsulinism

Abstract

Persistent hyperinsulinemic hypoglycemia of infancy (PHHI) is a disorder characterized by dysregulation of insulin secretion and prolonged hypoglycemia. Mutations in the genes of both subunits of the P-cell KATP channel, Kir 6.2 (potassium channel) and SUR1 (sulfonylurea receptor) have been associated with the autosomal recessive form of this disorder. It was previously demonstrated that patients harboring SURI mutations often do not respond well to diazoxide. A patient is reported of compound heterozygosity for the 2 most common mutations previously reported to be associated with PHHI in Ashkenazi Jews; splice mutation of intron 32 (3993-9G->A) and deletion of phenylalanine at position 1388. Relatively low glucose utilization (<10 mg/kg/min) was needed to maintain blood glucose concentrations. In addition, treatment with diazoxide was highly effective. We suggest that diazoxide unresponsiveness is not always present in patients with SURI mutations and that the probable cause of the milder phenotype in this compund heterozygote state is the splice mutation.

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References

1. Stanley CA . Hyperinsulinism in infants and children. Pediatr Clin North Am. 1997;44:363-374.

2. Sempoux C , Guiot Y , Lefevre A , et al. Neonatal hyperinsulinemic hypoglycemia: heterogeneity of the syndrome and keys for differential diagnosis. J Clin Endocrinol Metab. 1998;83: 1455-1461.

3. Thomas PM , Cote CJ , Wohlik N , et al. Mutations in the sulfonylurea receptor gene in familial hyperinsuliniemic hypoglycemia of infancy. Science. 1995;268:426-429.

4. Nestorowicz A , Wilson BA , Schoor KP , et al. Mutations in the sulfonylurea receptor gene are associated with familial hyperinsulinism in Ashkenazi Jews. Hum Mol Genet. 1996;5:1813-1822.

5. Nestorowicz A , Inagaki N , Gonoi T , et al. A nonesense mutation in the inward rectifier potassium channel gene, Kir 6.2, is associated with familial hyperinsulinism. Diabetes. 1997;46:1743-1748.

6. Thornton PS , Sumner AE , Ruchelli ED , et al. Familial and sporadic hyperinsulinism: histopathologic findings and segregation analysis support a single autosomal recessive disorder. J Pediatr 1991;119:721-724.

7. Glaser B , Kesavan P , Heyman M , et al. Familial hyperinsulinism caused by an activating glucokinase mutation. N Engl J Med. 1998;338:226-230.

8. Kukuvitis A , Deal C , Arbour L , Polychronakos C . An autosomal dominant form of familial persistent hyperinsulinemic hypoglycemia of infancy, not linked to the sulfonylurea receptor locus. J Clin Endocrinol Metab. 1997;82:1192-1194.

9. Stanley CA , Lieu YK , Hsu BY , et al. Hyperinsulinism and hyperammonemia in infants with regulatory mutations of the glutamate dehydrogenase gene. N Engl J Med. 1998;338:1352-1357.

10.

10. Touati G , Poggi-Travert F , Ogier de Baulny H , et al. Long-term treatment of persistent hyperinsulinaemic hypoglycaemia of infancy with diazoxide: a retrospective review of 77 cases and analysis of efficacy-predicting criteria. Eur J Pediatr 1998;157:628-633.

11.

11. Spitz L , Bhargava RK , Grant DB , Leonard JV . Surgical treatment of hyperinsulinaemic hypoglycaemia in infancy and childhood. Arch Dis Child. 1992;67:201-205.

12.

12. Shyng SL , Ferrigni T , Shepard JB , et al. Functional analysis of novel mutations in the sulfonylurea receptor 1 associated with persistent hyperinsulinemic hypoglycemia of infancy. Diabetes. 1998;47:1145-1151.

13.

13. Thornton PS , Satin-Smith MS , Herold K , et al. Familial hyperinsulinism with apparent autosomal dominant inheritence: clinical and genetic differences from the autosomal recessive variant. J Pediatr 1998;131:9-14.

14.

14. Nestorowicz A , Glaser B , Wilson B , et al. Genetic heterogeneity in familial hyperinsulinism. Hum Mol Genet. 1998;7:1119-1128.

15.

15. Glaser B , Furth J , Stanley CA , et al. Intragenic single nucleotide polymorphism haplotype analysis of SURI mutations in familial hyperinsulinism. Hum Mut. 1999;14:23-29.