Marked clinical heterogeneity in congenital hyperinsulinism due to a novel homozygous ABCC8 mutation

Abstract

Background:The most severe forms of congenital hyperinsulinism (CHI) are caused by inactivating mutations of two KATP channel genes, KCNJ11 and ABCC8.Unresponsiveness to diazoxide and need for subtotal pancreatectomy can usually be predicted by genetic form, particularly biallelic mutations in KATP channel genes. A few reports indicated marked clinical heterogeneity in siblings with identical biallelic mutations in ABCC8. The clinical heterogeneity in biallelic KATP CHI was speculated to be caused by epigenetic and environmental factors or related to differences in splicing factor machinery.Objective: To elucidate the clinical pathophysiology, especially heterogeneity, among three cases with CHI caused by a homogenous novel mutation. Patients and Methods:We report a case series that includes two siblings and one unrelated individual with CHI caused by a homogenous 1-bp deletion around the splice acceptor site at the exon 35 mutation of ABCC8, which exhibited markedly distinct phenotypes. To assess the effect of the mutation on splicing, we performed digital droplet polymerase chain reaction (ddPCR) on normal pancreas tissue and a patient's lymphocytes.Results: ddPCR of ABCC8 cDNA revealed that expression of exon 35 and its upstream and downstream regions did not differ. These data suggested that clinical heterogeneity may not be caused by differences in splicing factor machinery. Conclusion:The phenotypic variation in homozygotes could not be explained by splicing abnormalities. Though early genetic diagnosis of KATP CHI could contribute to selecting appropriate therapeutic options, more deliberate selection of therapeutic options in diffuse CHI due to biallelic ABCC8 mutations may be required.

Clinical management of diazoxide-unresponsive congenital hyperinsulinism: a single-center experience

“…None of the patients had a family history of gestational diabetes or diabetes mellitus in first-or second-degree relatives. Patient 1's older sister had an ABCC8-associated CHI (7); however, patients 1 and 2 were unrelated. The clinical courses of all four patients are illustrated in Supplementary Fig.…”

“…A large for gestational age (birth weight, 4,380 g + 3.7 SD; height, 52.5 cm + 2.2 SD at 38 wk 4 d of gestation) male neonate born to consanguineous Kurdish parents presented with hypoglycemia (blood glucose: BG, 1 mg/dL; immunoreactive insulin: IRI, 8.6 μIU/mL) at 3 h of age (7). He required an infusion of high-concentration glucose (glucose infusion rate, GIR, 13.6 mg/kg/min), continuous intravenous infusion of glucagon (30 μg/kg/h), DZX (15 mg/kg/d), and continuous tube feeding of breast milk to maintain BG above 3.5 mmol/L.…”

KATP channel mutations in congenital hyperinsulinism: Progress and challenges towards mechanism-based therapies

“…Definitive demonstration that a variation in these regions reduce transcript number would be very difficult. Several studies have presented in vitro evidence that genetic variations could disrupt splicing of SUR1 transcripts, especially variants located near the ABCC8 intron-exon boundaries, using a combination of bioinformatics and expression of mini-genes containing the variants or digital droplet PCR of patient lymphocytes (31, [48][49][50][51].…”

Congenital Hyperinsulinaemic Hypoglycaemia—A Review and Case Presentation

“…The K ATP channel consists of four sulphonylurea receptor 1 (SUR1) subunits, encoded by ABCC8, and four inward-rectifier potassium channel (Kir6.2) subunits, encoded by KCNJ11 [ 9 ]. The most severe forms of HH are caused by an inactivating mutation of the ABCC9 and KCNJ11 genes, which together are responsible for 36–70% of CHI cases [ 10 , 11 ].…”