A Challenging Form of Non-autoimmune Insulin-Dependent Diabetes in a Wolfram Syndrome Patient with a Novel Sequence Variant.

Liliana P Paris

doi:10.4172/2155-6156.1000561

Abstract

Wolfram syndrome type 1 is a rare, autosomal recessive, neurodegenerative disorder that is diagnosed when insulin-dependent diabetes of non-auto-immune origin and optic atrophy are concomitantly present. Wolfram syndrome is also designated by DIDMOAD that stands for its most frequent manifestations: diabetes insipidus, diabetes mellitus, optic atrophy and deafness. With disease progression, patients also commonly develop severe neurological and genito-urinary tract abnormalities. When compared to the general type 1 diabetic population, patients with Wolfram Syndrome have been reported to have a form of diabetes that is more easily controlled and with less microvascular complications, such as diabetic retinopathy.We report a case of Wolfram syndrome in a 16-year-old male patient who presented with progressive optic atrophy and severe diabetes with very challenging glycemic control despite intensive therapy since diagnosis at the age of 6. Despite inadequate metabolic control he did not develop any diabetic microvascular complications during the 10-year follow-up period. To further investigate potential causes for this metabolic idiosyncrasy, we performed genetic analyses that revealed a novel combination of homozygous sequence variants that are likely the cause of the syndrome in this family. The identified genotype included a novel sequence variant in the Wolfram syndrome type 1 gene along with a previously described one, which had initially been associated with isolated low frequency sensorineural hearing loss (LFSNHL). Interestingly, our patient did not show any abnormal findings with audiometry testing.

Highlights

Wolfram syndrome (WS) is a rare multisystem neurodegenerative disorder of autosomal recessive origin that minimally requires the presence of two diagnostic criteria, insulin-dependent diabetes mellitus and progressive optic nerve atrophy [1]
The sequence variants identified were the following: (1) A novel missense variant c1066T>C, in exon 8; (2) A previously described variant c482G>A, in exon 5, initially associated with low frequency sensorineural hearing loss (LFSNHL) [15] and later described in the 1000 Genomes Project [16] and interpreted as benign by Shearer et al [17]. His mother and his 19-year-old sister were heterozygous for the same sequence variants in the WFS1 gene, while the 11-yearold brother did not present any variations (Figure 2). These findings highly suggest that (1) both sequence variants must be located on the same chromosome and that (2) the presence of the two haplotypes in homozygosity is the cause for Wolfram syndrome in this family
In the present study we report a 16 year-old patient with Wolfram syndrome with a therapeutically challenging form of non-autoimmune diabetes associated with a novel sequence variant in the WFS1 gene

Summary

Introduction

Wolfram syndrome (WS) is a rare multisystem neurodegenerative disorder of autosomal recessive origin that minimally requires the presence of two diagnostic criteria, insulin-dependent diabetes mellitus (of non autoimmune origin) and progressive optic nerve atrophy [1]. In this study we identify a novel WFS1 missense sequence variant in a WS patient and describe its associated progressive clinical picture (over a 10-year follow-up period) in a 16-year old patient who developed an especially challenging form of insulin-dependent diabetes at the age of 6. (2) A previously described variant c482G>A (pArg161Gln), in exon 5, initially associated with low frequency sensorineural hearing loss (LFSNHL) [15] and later described in the 1000 Genomes Project [16] and interpreted as benign by Shearer et al [17] His mother and his 19-year-old sister were heterozygous for the same sequence variants in the WFS1 gene, while the 11-yearold brother did not present any variations (Figure 2). These findings highly suggest that (1) both sequence variants must be located on the same chromosome (haplotype) and that (2) the presence of the two haplotypes in homozygosity is the cause for Wolfram syndrome in this family

Findings

Discussion

Conclusion