Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Multicenter Study
. 2011 Jul;34(7):1503-10.
doi: 10.2337/dc10-1937. Epub 2011 May 20.

Diabetes and neurodegeneration in Wolfram syndrome: a multicenter study of phenotype and genotype

Julia Rohayem  1 , Christian Ehlers, Bärbel Wiedemann, Reinhard Holl, Konrad Oexle, Olga Kordonouri, Giuseppina Salzano, Thomas Meissner, Walter Burger, Edith Schober, Angela Huebner, Min Ae Lee-Kirsch; Wolfram Syndrome Diabetes Writing Group
Collaborators, Affiliations
Multicenter Study

Diabetes and neurodegeneration in Wolfram syndrome: a multicenter study of phenotype and genotype

Julia Rohayem et al. Diabetes Care. 2011 Jul.

Abstract

Objective: To describe the diabetes phenotype in Wolfram syndrome compared with type 1 diabetes, to investigate the effect of glycemic control on the neurodegenerative process, and to assess the genotype-phenotype correlation.

Research design and methods: The clinical data of 50 patients with Wolfram syndrome-related diabetes (WSD) were reviewed and compared with the data of 24,164 patients with type 1 diabetes. Patients with a mean HbA1c during childhood and adolescence of ≤7.5 and >7.5% were compared with respect to the occurrence of additional Wolfram syndrome symptoms. The wolframin (WFS1) gene was screened for mutations in 39 patients. WFS1 genotypes were examined for correlation with age at onset of diabetes.

Results: WSD was diagnosed earlier than type 1 diabetes (5.4±3.8 vs. 7.9±4.2 years; P<0.001) with a lower prevalence of ketoacidosis (7 vs. 20%; P=0.049). Mean duration of remission in WSD was 2.3±2.4 vs. 1.6±2.1 in type 1 diabetes (NS). Severe hypoglycemia occurred in 37 vs. 7.9% (P<0.001). Neurologic disease progression was faster in the WSD group with a mean HbA1c>7.5% (P=0.031). Thirteen novel WSF1 mutations were identified. Predicted functional consequence of WFS1 mutations correlated with age at WSD onset (P=0.028).

Conclusions: Endoplasmic reticulum stress-mediated decline of β-cells in WSD occurs earlier in life than autoimmune-mediated β-cell destruction in type 1 diabetes. This study establishes a role for WFS1 in determining the age at onset of diabetes in Wolfram syndrome and identifies glucose toxicity as an accelerating feature in the progression of disease.

PubMed Disclaimer

Figures

Figure 1
Figure 1
A: A schematic presentation of the wolframin protein and analysis of genotype-genotype correlation shows the relative positions of WFS1 mutations within the wolframin polypeptide chain with the five transmembrane domains indicated (adapted from Gene Reviews, University of Washington, Seattle, WA). Mutations are color-coded according to their mutation categories: group 1 (red), group 2 (blue), and group 3 (green). Unclassifiable variants are indicated in black; novel mutations are indicated in boldface. B: Genotype–phenotype correlation; the differences in mean age at WSD onset between group 1 (3.7 ± 1.7 years), 2 (5.8 ± 2.6 years), and 3 (7.5 ± 6.0 years) are significant (ANOVA, P = 0.028).
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Collier DA, Barrett TG, Curtis D, et al. Linkage of Wolfram syndrome to chromosome 4p16.1 and evidence for heterogeneity. Am J Hum Genet 1996;59:855–863 - PMC - PubMed
    1. Strom TM, Hörtnagel K, Hofmann S, et al. Diabetes insipidus, diabetes mellitus, optic atrophy and deafness (DIDMOAD) caused by mutations in a novel gene (wolframin) coding for a predicted transmembrane protein. Hum Mol Genet 1998;7:2021–2028 - PubMed
    1. Malhotra JD, Kaufman RJ. Endoplasmic reticulum stress and oxidative stress: a vicious cycle or a double-edged sword? Antioxid Redox Signal 2007;9:2277–2293 - PubMed
    1. Lin JH, Walter P, Yen TS. Endoplasmic reticulum stress in disease pathogenesis. Annu Rev Pathol 2008;3:399–425 - PMC - PubMed
    1. Harding HP, Ron D. Endoplasmic reticulum stress and the development of diabetes: a review. Diabetes 2002;51(Suppl. 3):S455–S461 - PubMed

Publication types