Diabetes and Neurodegeneration in Wolfram Syndrome

Abstract

OBJECTIVETo 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 METHODSThe 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.RESULTSWSD 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).CONCLUSIONSEndoplasmic 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.

Genotypic classification of patients with Wolfram syndrome: insights into the natural history of the disease and correlation with phenotype

“…36 We analyzed as mutations (i) c.2020G→A (p.Gly674Arg), considered either a mutation 37 or a polymorphism, 38 and (ii) c.1367G→A (p.Arg456His), considered either a mutation 34 or a polymorphism, [31][32][33]39,40 because both are predicted to produce deleterious proteins by Condel 41 and PolyPhen-2. 42 c.2020G→A is also considered a mutation in the LOVD-WFS1 database.…”

“…The genotyping methods of Cano et al 33 and Chaussenot et al 30 were based on mutation types and differ from each other only in genotype naming. The genotyping method of Rohayem et al 34 was based on the effect of mutations on the function of WFS1. In the analysis performed, a significant correlation was found only for DM and OA with both methodologies, similar to the findings in the original publications of Cano et al 33 and Chaussenot et al 30 and expanding the findings in Rohayem et al 34 By contrast, a significant correlation for DI and HD (see Supplementary Figures S3a and Supplementary Table S8 online) was observed when grouped into three genotypic classes and for DM and DI when grouped into five genotypic classes (Figure 4 and see Supplementary Table S8 online) with the approach described here.…”

“…Chaussenot et al 30 showed no association between the effect of the genotype in the neurological signs observed in patients with WS. Rohayem et al 34 showed that the age at onset of DM in patients carrying predicted complete loss of function mutations is lower than those carrying predicted partial or minor loss of function mutations.…”

Wolfram syndrome: Are we aware of the severe hypoglycemic unawareness?

“…In keeping with the above theory, the manifestations of neurogenic bladder and severe hypoglycemia with unawareness emerged after less than 2 years of poor diabetes control, in contrast with the appearance of autonomic symptoms after much longer periods of poor control in young subjects with type 1 diabetes. Thus, this rapid and substantial deterioration in glucose control was likely an important factor in the development and quick progression of her hypoglycemia unawareness [8].…”

“…Loss of this function by alteration of the WFS1 gene is thought to result in chronic ER stress leading to apoptosis in pancreatic beta cells, neuroendocrine cells, and neuronal cells. Together, these processes result in a progressive decline of endocrine and neuroendocrine function [8]. The WFS1 gene also plays a key role in intracellular calcium homeostasis and cAMP mediated signaling.…”