title: Diabetes and neurodegeneration in Wolfram syndrome: a multicenter study of phenotype and genotype.
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.
  
  
  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.
authors: Children’s Hospital, Technical University Dresden, Dresden, Germany. julia.rohayem@uniklinikum-dresden.de
authors: Julia
authors: J
authors: Rohayem
authors: Christian
authors: C
authors: Ehlers
authors: Bärbel
authors: B
authors: Wiedemann
authors: Reinhard
authors: R
authors: Holl
authors: Konrad
authors: K
authors: Oexle
authors: Olga
authors: O
authors: Kordonouri
authors: Giuseppina
authors: G
authors: Salzano
authors: Thomas
authors: T
authors: Meissner
authors: Walter
authors: W
authors: Burger
authors: Edith
authors: E
authors: Schober
authors: Angela
authors: A
authors: Huebner
authors: Min Ae
authors: MA
authors: Lee-Kirsch
references: Diabetologia. 2005 Nov;48(11):2313-21
references: 16215705
references: Annu Rev Pathol. 2008;3:399-425
references: 18039139
references: Diabetes Care. 1989 Feb;12(2):135-8
references: 2649325
references: Am J Physiol Endocrinol Metab. 2008 Mar;294(3):E540-50
references: 18198352
references: Adv Exp Med Biol. 2010;654:447-62
references: 20217509
references: Diabetes. 2001 Jun;50(6):1290-301
references: 11375329
references: Diabetes Care. 1986 Jul-Aug;9(4):405-8
references: 3461931
references: Endocr Rev. 2008 Feb;29(1):42-61
references: 18048764
references: Am J Med Genet A. 2007 Jul 15;143A(14):1605-12
references: 17568405
references: Lancet. 1990 Sep 15;336(8716):667-9
references: 1975860
references: Hum Mol Genet. 1998 Dec;7(13):2021-8
references: 9817917
references: Diabetes Care. 1995 Dec;18(12):1566-70
references: 8722052
references: J Clin Invest. 2010 Mar;120(3):744-55
references: 20160352
references: Hum Mol Genet. 2003 Aug 15;12(16):2003-12
references: 12913071
references: Diabetes Care. 2007 Sep;30(9):2327-30
references: 17536072
references: Lancet. 1995 Dec 2;346(8988):1458-63
references: 7490992
references: Hum Mutat. 2005 Jan;25(1):99-100
references: 15605410
references: Acta Paediatr Scand Suppl. 1977;(264):1-16
references: 270276
references: Hum Mol Genet. 2004 Jun 1;13(11):1159-70
references: 15056606
references: Diabetes. 2002 Dec;51 Suppl 3:S455-61
references: 12475790
references: Antioxid Redox Signal. 2007 Dec;9(12):2277-93
references: 17979528
references: Hum Mutat. 2003 Oct;22(4):275-87
references: 12955714
references: Free Radic Biol Med. 2006 Jul 15;41(2):177-84
references: 16814095
references: Arch Neurol. 1977 Dec;34(12):759-65
references: 588096
references: Am J Hum Genet. 1996 Oct;59(4):855-63
references: 8808601