Hyperinsulinism and treatable congenital disorders of glycosylation (CDG)

Jaak Jaeken

Centre for Metabolic Diseases

UniversityHospital Gasthuisberg, Leuven

Hyperinsulinism has been reported in several disorders of protein N-glycosylation more specifically in CDG-Ia, CDG-Ib, CDG-Ic and CDG-Ih (1). Its mechanism is unclear but it is possibly a compensatory phenomenon secondary to receptor hypoglycosylation. The same mechanism might underly increases of other hormones (growth hormone, LH, FSH, TSH) reported in CDG (2). Only in CDG-Ib, the hyperinsulinism is associated with hypoglycemia casting doubt on whether it is the (only) cause of this hypoglycemia. CDG-Ib is a defect in the first step of the mannose pathway (phosphomannose isomerase (PMI)) and has been reported in some 30 patients (3). It is a hepatic-intestinal disorder (liver fibrosis and steatosis, protein-losing enteropathy) without significant neurological abnormalities. Up to now it was the only well treatable CDG: oral mannose (+/- 170 mg/kg per 4 hours) restores the metabolic pathway by its transformation into mannose 6-phosphate and corrects the clinical symptomatology of this otherwise lethal disease. However recently two patients have been reported with an early diagnosis of CDG-Ib (2 months) in whom mannose therapy was not able to prevent development of liver fibrosis (3). Complete loss of PMI activity has an embryonic lethal outcome in mice (4).

Very recently a promotor mutation has been identified in the mannosyltransferase-encoding gene PIGM causing a novel CDG, glycosylphosphatidylinositol deficiency (5). This disorder causes disrupted binding of the transcription factor Sp1 resulting in histone hypoacetylation at the PIGM promotor. The histone deacetylase inhibitor phenylbutyrate increased PIGM transcription and caused complete cessation of longstanding intractable seizures in a child with this disorder (6).

This seems to be the second CDG, among the some 35 known CDG, amenable to efficient treatment.

References

  1. Jaeken J, Matthijs G. Congenital disorders of glycosylation: a rapidly expanding disease family. Ann Rev Genomics Hum Genet 2007; 8: 261-278.
  2. de Zegher F, Jaeken J. Endocrinology of the carbohydrate-deficient glycoprotein syndrome type 1 from birth through adolescence. Pediatr Res 1995; 37: 395-401.
  3. Mention K, Lacaille F, Valayannopoulos V et al. Development of liver disease despite mannose treatment in two patients with CDG-Ib.Mol Genet Metab 2007, Oct 16 Epub ahead of print.
  4. DeRossi C, Bode L, Eklund EA et al. Ablation ofmouse phosphomannose isomerase (Mpi) causes mannose 6-phosphate accumulation, toxicity and embryonic lethality. J Biol Chem 2006; 281: 5916-5927.
  5. Almeida AM, Murakami Y, Layton DM, et al. Hypomorphic promotor mutation in PIGM causes inherited glycosylphosphatidylinositol deficiency. Nat Med 2006; 12: 846-851.
  6. Almeida AM, Murakami Y, Baker A, et al. Targeted therapy for inherited GPI deficiency. N Engl J Med 2007: 356: 1641-1647.