Hyperinsulinism caused by paternal-specific inheritance of a recessive mutation in the sulfonylurea-receptor gene

Neonatal hyperinsulinism (HI) is a genetic disorder of pancreatic beta-cell s characterized by failure to suppress insulin secretion in the presence of hypoglycemia, resulting in brain damage or death if not adequately treated . Germline mutations in four genes have been associated with HI. Some patie nts have focal regions of beta-cell proliferation (focal HI). Seventy HI pr obands in whom at least one SUR-1 mutation was identified were studied. Cli nical data from patients with two SUR-1 mutant alleles were compared with t hose from patients with single paternally inherited mutations. Thirty-seven probands were homozygous or compound heterozygous for SUR-1 mutations. In 33 probands, only a single mutation was identified, and in 31, the parental origin of the proband could be determined; in 29, the mutation was on the paternal allele (P < 0.0002). For three of these, pancreatic tissue was ava ilable and showed focal beta-cell hyperplasia. DNA extracted from the focal lesion and adjacent normal pancreas revealed loss of the maternal chromoso me 11p15, resulting in reduction to homozygosity for the SUR-1 mutation wit hin the focal lesion only. Using the Tdt-mediated dUTP nick end labeling (T UNEL) reaction, apoptotic beta-cells were identified exclusively within the focal region. At diagnosis,disease severity was similar in patients with p aternally inherited mutations and those with two mutations. For patients wh o did not undergo surgery, those with only paternal mutations entered clini cal remission within 16 +/- 6.2 months, compared with 48 +/- 23 months for those with two SUR-1 mutations (P = 0.001). In conclusion, we identified a novel mechanism to explain the pathophysiology of focal HT and provide evid ence to suggest that this entity may be self-limiting, since affected beta- cells undergo apoptosis.