Genotype-phenotype correlation of KATP channel gene defects causing permanent neonatal diabetes in Indian patients.

BACKGROUND: There are very few reports pertaining to Indian patients with neonatal diabetes mellitus (NDM). Activating or gain of function mutations of KATP channel genes namely KCNJ11 and ABCC8 are most predominant cause of permanent neonatal diabetes mellitus (PNDM). OBJECTIVES: To identify the genotype-phenotype correlation of KATP channel gene defects in a large series of (n = 181) Indian PNDM patients. METHODS: Direct sequencing of all exons of KCNJ11 and ABCC8 genes in all 181 patients with PNDM were performed. Clinical and biochemical data were collected. RESULTS: We have identified the molecular basis of KATP -NDM in 39 out of 181 patients (22%). Of these, 20 had KCNJ11 mutations and 19 had ABCC8 mutations, thus comprising 51% of KCNJ11 and 49% of ABCC8. There were four novel mutations (D1128Tfs*16, Y1287C, S1422T, and H1537R) in ABCC8 gene. Three patients with KCNJ11 mutations had developmental delay with DEND syndrome. In patients with ABCC8 mutations developmental delay was seen in seven out of 19 (36.8%). Of this, three patients (15.7%) had DEND phenotype and four (21%) had iDEND. Of the 39 patients, 33 (84%) patients were shifted to sulfonylurea therapy (glibenclamide). Of this, 19(57.5%) patients harbored KCNJ11 mutations and 14(42.1%) ABCC8 mutations. CONCLUSIONS: This is the first largest study in NDM patients in India demonstrating the importance of KATP channel gene mutation screening in PNDM and efficacy of glibenclamide for Indian patients with KATP -PNDM. The success rate of transfer is more in patients with KCNJ11 mutations compared with those with ABCC8 mutations.

Glycolate oxidase deficiency in a patient with congenital hyperinsulinism and unexplained hyperoxaluria.

BACKGROUND: A baby girl was born at 39 weeks gestation to consanguineous Asian parents. From day 1 of life she had severe hypoglycaemia with an inappropriately elevated insulin concentration consistent with congenital hyperinsulinism (CHI), confirmed by the finding of a homozygous mutation in ABCC8 (encoding the sulfonylurea receptor 1). CASE DIAGNOSIS/TREATMENT: Urine organic acid analysis showed an incidentally elevated excretion of glycolate. Whilst this was unlikely to contribute to the hypoglycaemia, hyperglycolic aciduria is a known feature of primary hyperoxaluria type 1 (PH1); therefore oxalate was also measured in urine and found to be elevated. Sequence analysis of the genes involved in PH1 and also the two other known forms of primary hyperoxaluria revealed no pathological variants. PH1 was definitively excluded by enzyme activity analysis on a liver biopsy, which confirmed normal glyoxylate aminotransferase (AGT) activity and positive AGT immunoreactivity. Glycolate oxidase (GO) deficiency was considered, and thus gene sequencing of HAO1, which encodes GO, was performed. A homozygous change (c.493G>T p.(Gly165Cys)) was found in exon 3 of HAO1, predicted to be deleterious to protein function. Further analysis of the liver biopsy demonstrated absent GO enzyme activity, confirming GO deficiency in this case. CONCLUSIONS: The results lead to the conclusion that this baby has two unrelated autosomal recessive conditions, CHI and GO deficiency, and also hyperoxaluria of unknown aetiology. Deficiency of GO is a very rare disorder with only two previously published cases. It is considered to be an essentially benign inborn error of metabolism. The present case is unique in that GO deficiency is associated with persistent hyperoxaluria.