ESPE Abstracts

Context: Neonatal hypoglycemia due to congenital hyperinsulinism (CHI) is a potentially life-threatening condition. Severe forms of CHI, caused by autosomal recessive variants in K_ATP channel subunit genes (ABCC8, KCNJ11), are more prevalent in regions with high consanguinity. These regions also have a high neonatal mortality rate with many deaths remaining unexplained.

Patients and Methods: We analyzed three patients with CHI born into three separate Kurdish consanguineous families (two families had a combined history of four unexplained neonatal deaths with seizures).

(1) A one year old girl presented at six days of life with recurrent convulsions due to hypoglycemia (blood sugar 2.05 mmol/l, insulin 58 mIU/l, C-peptide 2242 pmol/l). (2) A four year old girl with a severe developmental delay had recurrent symptomatic hypoglycemia from four days of age which was only treated with frequent feeding and starch. At three years, CHI was confirmed (blood sugar 2.78mmol/l, insulin 8.1mIU/l, C-peptide 2300pmol/l).

(3) A one year old girl presented at three weeks of age with convulsions and loss of consciousness due to blood glucose 2.5mmol/l (insulin 14.6 mIU/l, C-peptide 1580 pmol/l).

DNA was extracted from blood of the patients', their parents' and unaffected siblings'. ABCC8 and KCNJ11 genes were tested in the patients by Sanger sequencing. If potential variants were not published in the HGMD database, their pathogenicity was evaluated by their absence in the ExAC database, by predictions of in-silico programs and the American College of Medical Genetics (ACMG) standards. Thereafter, selected variants were confirmed in family members.

Results: In each of the three patients, novel pathogenic homozygous variants were found. All have heterozygous healthy parents and unaffected siblings who tested negative or heterozygous.

Patient (1) has variant p.Met1Val in KCNJ11, patient (2) has variant p. Trp514Ter in ABCC8, and patient (3) has variant p. Tyr26Ter in KCNJ11. Variants (2) and (3) cause a stop signal leading to premature protein termination.

In addition, all three variants were classified as pathogenic by all tools described above.

Conclusion: CHI caused by K_ATP channel variants was elucidated in three children, providing a highly probable explanation for their siblings who died as neonates. In regions with high consanguinity, a small but significant percentage of all unexplained neonatal deaths could be due to CHI. Future lives could be saved by the timely diagnosis of CHI when encountering a neonate with unexplained seizures or other signs of recurrent and/or persistent hypoglycemia.