Visuomotor Performance in KCNJ11-Related Neonatal Diabetes Is Impaired in Children With DEND-Associated Mutations and May Be Improved by Early Treatment With Sulfonylureas

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

OBJECTIVE

To assess performance on an age-standardized neuromotor coordination task among sulfonylurea-treated KCNJ11-related neonatal diabetic patients.

RESEARCH DESIGN AND METHODS

Nineteen children carrying KCNJ11 mutations associated with isolated diabetes (R201H; n = 8), diabetes with neurodevelopmental impairment (V59M or V59A [V59M/A]; n = 8), or diabetes not consistently associated with neurodevelopmental disability (Y330C, E322K, or R201C; n = 3) were studied using the age-standardized Beery-Buktenica Developmental Test of Visual-Motor Integration (VMI).

RESULTS

Although R201H subjects tested in the normal range (median standard score = 107), children with V59M/A mutations had significantly lower than expected VMI standard scores (median = 49). The scores for all three groups were significantly different from each other ( P = 0.0017). The age of sulfonylurea initiation was inversely correlated with VMI scores in the V59M/A group ( P < 0.05).

CONCLUSIONS

Neurodevelopmental disability in KCNJ11-related diabetes includes visuomotor problems that may be ameliorated by early sulfonylurea treatment. Comprehensive longitudinal assessment on larger samples will be imperative.

Related collections

Most cited references 14

Record: found
Abstract: found
Article: not found

Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes.

Anna L. Gloyn, Ewan Pearson, Jennifer F Antcliff … (2004)

Patients with permanent neonatal diabetes usually present within the first three months of life and require insulin treatment. In most, the cause is unknown. Because ATP-sensitive potassium (K(ATP)) channels mediate glucose-stimulated insulin secretion from the pancreatic beta cells, we hypothesized that activating mutations in the gene encoding the Kir6.2 subunit of this channel (KCNJ11) cause neonatal diabetes. We sequenced the KCNJ11 gene in 29 patients with permanent neonatal diabetes. The insulin secretory response to intravenous glucagon, glucose, and the sulfonylurea tolbutamide was assessed in patients who had mutations in the gene. Six novel, heterozygous missense mutations were identified in 10 of the 29 patients. In two patients the diabetes was familial, and in eight it arose from a spontaneous mutation. Their neonatal diabetes was characterized by ketoacidosis or marked hyperglycemia and was treated with insulin. Patients did not secrete insulin in response to glucose or glucagon but did secrete insulin in response to tolbutamide. Four of the patients also had severe developmental delay and muscle weakness; three of them also had epilepsy and mild dysmorphic features. When the most common mutation in Kir6.2 was coexpressed with sulfonylurea receptor 1 in Xenopus laevis oocytes, the ability of ATP to block mutant K(ATP) channels was greatly reduced. Heterozygous activating mutations in the gene encoding Kir6.2 cause permanent neonatal diabetes and may also be associated with developmental delay, muscle weakness, and epilepsy. Identification of the genetic cause of permanent neonatal diabetes may facilitate the treatment of this disease with sulfonylureas. Copyright 2004 Massachusetts Medical Society

0 comments Cited 277 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Switching from insulin to oral sulfonylureas in patients with diabetes due to Kir6.2 mutations.

Ewan Pearson, Isabelle Flechtner, Pål R. Njølstad … (2006)

Heterozygous activating mutations in KCNJ11, encoding the Kir6.2 subunit of the ATP-sensitive potassium (K(ATP)) channel, cause 30 to 58 percent of cases of diabetes diagnosed in patients under six months of age. Patients present with ketoacidosis or severe hyperglycemia and are treated with insulin. Diabetes results from impaired insulin secretion caused by a failure of the beta-cell K(ATP) channel to close in response to increased intracellular ATP. Sulfonylureas close the K(ATP) channel by an ATP-independent route. We assessed glycemic control in 49 consecutive patients with Kir6.2 mutations who received appropriate doses of sulfonylureas and, in smaller subgroups, investigated the insulin secretory responses to intravenous and oral glucose, a mixed meal, and glucagon. The response of mutant K(ATP) channels to the sulfonylurea tolbutamide was assayed in xenopus oocytes. A total of 44 patients (90 percent) successfully discontinued insulin after receiving sulfonylureas. The extent of the tolbutamide blockade of K(ATP) channels in vitro reflected the response seen in patients. Glycated hemoglobin levels improved in all patients who switched to sulfonylurea therapy (from 8.1 percent before treatment to 6.4 percent after 12 weeks of treatment, P<0.001). Improved glycemic control was sustained at one year. Sulfonylurea treatment increased insulin secretion, which was more highly stimulated by oral glucose or a mixed meal than by intravenous glucose. Exogenous glucagon increased insulin secretion only in the presence of sulfonylureas. Sulfonylurea therapy is safe in the short term for patients with diabetes caused by KCNJ11 mutations and is probably more effective than insulin therapy. This pharmacogenetic response to sulfonylureas may result from the closing of mutant K(ATP) channels, thereby increasing insulin secretion in response to incretins and glucose metabolism. (ClinicalTrials.gov number, NCT00334711 [ClinicalTrials.gov].). Copyright 2006 Massachusetts Medical Society.

0 comments Cited 241 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Activating mutations in Kir6.2 and neonatal diabetes: new clinical syndromes, new scientific insights, and new therapy.

Andrew Hattersley, Frances M. Ashcroft, Peter Kahn (2005)

Closure of ATP-sensitive K(+) channels (K(ATP) channels) in response to metabolically generated ATP or binding of sulfonylurea drugs stimulates insulin release from pancreatic beta-cells. Heterozygous gain-of-function mutations in the KCJN11 gene encoding the Kir6.2 subunit of this channel are found in approximately 47% of patients diagnosed with permanent diabetes at transient neonatal diabetes > permanent neonatal diabetes > DEND syndrome channels. Sulfonylureas still close mutated K(ATP) channels, and many patients can discontinue insulin injections and show improved glycemic control when treated with high-dose sulfonylurea tablets. In conclusion, the finding that Kir6.2 mutations can cause neonatal diabetes has enabled a new therapeutic approach and shed new light on the structure and function of the Kir6.2 subunit of the K(ATP) channel.

0 comments Cited 87 times – based on 0 reviews      Review now

Bookmark

All references

Author and article information

Journal

Journal ID (nlm-ta): Diabetes Care

Journal ID (iso-abbrev): Diabetes Care

Journal ID (hwp): diacare

Journal ID (pmc): dcare

Journal ID (publisher-id): Diabetes Care

Title: Diabetes Care

Publisher: American Diabetes Association

ISSN (Print): 0149-5992

ISSN (Electronic): 1935-5548

Publication date (Print): October 2012

Publication date (Electronic): 11 September 2012

Volume: 35

Issue: 10

Pages: 2086-2088

Affiliations

[1] ¹Section of Developmental and Behavioral Pediatrics and John P. Kennedy Jr. Intellectual and Developmental Disabilities Research Center, Department of Pediatrics, Comer Children’s Hospital and Pritzer School of Medicine, The University of Chicago, Chicago, Illinois

[2] ²Section of Pediatric Sleep Medicine, Department of Pediatrics, Comer Children’s Hospital and Pritzer School of Medicine, The University of Chicago, Chicago, Illinois

[3] ³Section of Adult and Pediatric Endocrinology, Diabetes and Metabolism, Department of Medicine, The University of Chicago, Chicago, Illinois

Author notes

Corresponding author: Siri Atma W. Greeley, sgreeley@ 123456uchicago.edu .

S.A.W.G. and M.E.M. contributed equally to this study.

Article

Publisher ID: 2225

DOI: 10.2337/dc11-2225

PMC ID: 3447845

PubMed ID: 22855734

SO-VID: f5c10654-d140-4a90-8d21-a1ea386082b8

License:

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

Visuomotor Performance in KCNJ11-Related Neonatal Diabetes Is Impaired in Children With DEND-Associated Mutations and May Be Improved by Early Treatment With Sulfonylureas

Read this article at

Abstract

OBJECTIVE

RESEARCH DESIGN AND METHODS

RESULTS

CONCLUSIONS

Related collections

Journal of the ASEAN Federation of Endocrine Societies

Most cited references 14

Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes.

Switching from insulin to oral sulfonylureas in patients with diabetes due to Kir6.2 mutations.

Activating mutations in Kir6.2 and neonatal diabetes: new clinical syndromes, new scientific insights, and new therapy.

Author and article information

Journal

Affiliations

Author notes

Article

History

Categories

Comments

Comment on this article

Similar content 417

Cited by 21

Most referenced authors 674