Heterogeneity in phenotype of hyperinsulinism caused by activating glucokinase mutations: a novel mutation and its functional characterization.

BACKGROUND: Mutations in the GCK gene lead to different forms of glucokinase (GCK)-disease, activating mutations cause hyperinsulinaemic hypoglycaemia while inactivating mutations cause monogenic diabetes. Hyperinsulinism (HI) is a heterogeneous condition with a significant genetic component. The major causes are channelopathies, the other forms are rare and being caused by mutations in genes such as GCK. OBJECTIVE: To describe the clinical and genetic presentation of four families with activating GCK mutations, and to explore the pathogenicity of the novel mutation identified through functional studies. RESULTS: Four cases of HI with mutations in GCK were identified. These include one novel mutation (p.Trp99Cys). Functional analysis of the purified mutant fusion protein glutathione-S-transferase (GST)-GCK-p.Trp99Cys demonstrated that p.Trp99Cys is an activating mutation as it induces a higher affinity for glucose and increases the relative activity index more than 11 times. Moreover, the thermal stability of the mutant protein was similar to that of its wild type. All patients were responsive to diazoxide treatment. One of the mutations arose de novo, and two were dominantly inherited, although only one of them from an HI affected parent. The age of presentation in our cases varied widely from the neonatal period to adulthood. CONCLUSION: The clinical phenotype of the GCK activating mutation carriers was heterogeneous, the severity of symptoms and age at presentation varied markedly between affected individuals, even within the same family. The novel activating GCK mutation (p.Trp99Cys) has a strong activating effect in vitro although it has been identified in one case of a milder and late-onset form of HI.

Incidence of childhood-onset type 1 diabetes in Biscay, Spain, 1990-2013.

OBJECTIVE: To identify the incidence rate (IR) and epidemiologic trends of childhood type 1 diabetes mellitus (T1DM) in children aged 0 to 14-yr-old from 1990 to 2013, in the north of Spain (Biscay). SUBJECTS AND METHODS: A prospective-retrospective study was performed. Capture-recapture method was used: primary cases were ascertained from hospital register and a secondary independent data source was obtained from diabetes associations and public health plan database. Age and sex-standardized incidence rates were calculated using direct method, assuming an equal distribution in each age/sex group. In order to identify and analyse trends the period studied was divided into two (1990-2001 and 2002-2013) 11-year periods. The 95% confidence interval (CI) was estimated assuming the Poisson distribution. RESULTS: A total of 399 new cases were identified throughout the study. Mean age at diagnosis was 8.9 ± 3.7 yr. Completeness of ascertainment was 99.1%. Mean annual age-standardized IR was 10.7 (95% CI: 9.6-11.7). The mean incidence for the 0-4, 5-9 and 10-14 age groups was 5.1, 14.6 and 13.2 per 100,000 children/yr, respectively. The incidence rate trend in the whole group was not statistically significant. In the 10-14 age group we found a yearly average increase (2.5% [CI 95% 0.4-4.6]; P < 0.05) and analysing by sex, this statistically significant incidence trend was observed only in boys. We did not find a seasonal onset pattern. CONCLUSIONS: The IR did not increase in this population during the period studied unlike the results in other Spanish regions and European Countries.