Wolfram syndrome in the Japanese population; molecular analysis of WFS1 gene and characterization of clinical features.

Kimie Matsunaga,Yukari Kora,Hiroshi Inoue,Shin Amemiya,Yukio Tanizawa,Yoshitomo Oka,Shigetaka Sugihara,Yuichiro Yamada,Yasuharu Ohta,Akihiko Taguchi,Katsuya Tanabe,Yuzo Nakao,Yasuhiko Wada,Yasuhiko Wada,Shigeru Okuya,Masaru Akiyama,Naoko Okayama,Shiro Maeda

doi:10.1371/journal.pone.0106906

Abstract

BackgroundWolfram syndrome (WFS) is a recessive neurologic and endocrinologic degenerative disorder, and is also known as DIDMOAD (Diabetes Insipidus, early-onset Diabetes Mellitus, progressive Optic Atrophy and Deafness) syndrome. Most affected individuals carry recessive mutations in the Wolfram syndrome 1 gene (WFS1). However, the phenotypic pleiomorphism, rarity and molecular complexity of this disease complicate our efforts to understand WFS. To address this limitation, we aimed to describe complications and to elucidate the contributions of WFS1 mutations to clinical manifestations in Japanese patients with WFS.MethodologyThe minimal ascertainment criterion for diagnosing WFS was having both early onset diabetes mellitus and bilateral optic atrophy. Genetic analysis for WFS1 was performed by direct sequencing.Principal FindingsSixty-seven patients were identified nationally for a prevalence of one per 710,000, with 33 patients (49%) having all 4 components of DIDMOAD. In 40 subjects who agreed to participate in this investigation from 30 unrelated families, the earliest manifestation was DM at a median age of 8.7 years, followed by OA at a median age of 15.8 years. However, either OA or DI was the first diagnosed feature in 6 subjects. In 10, features other than DM predated OA. Twenty-seven patients (67.5%) had a broad spectrum of recessive mutations in WFS1. Two patients had mutations in only one allele. Eleven patients (27.5%) had intact WFS1 alleles. Ages at onset of both DM and OA in patients with recessive WFS1 mutations were indistinguishable from those in patients without WFS1 mutations. In the patients with predicted complete loss-of-function mutations, ages at the onsets of both DM and OA were significantly earlier than those in patients with predicted partial-loss-of function mutations.Conclusion/SignificanceThis study emphasizes the clinical and genetic heterogeneity in patients with WFS. Genotype-phenotype correlations may exist in patients with WFS1 mutations, as demonstrated by the disease onset.

Highlights

Wolfram syndrome (WFS:OMIM 222300) was first described by Wolfram and Wagener in 1938 as the association of childhoodonset diabetes and optic atrophy [1]
WFS is a rare hereditary recessive disorder associated with multiple clinical manifestations
The current study documented the following observations; 1) WFS was confirmed to be rare with the prevalence being 1/710,000 in the Japanese population

Summary

Introduction

Wolfram syndrome (WFS:OMIM 222300) was first described by Wolfram and Wagener in 1938 as the association of childhoodonset diabetes and optic atrophy [1] It is recognized as a recessive neurologic and endocrinologic degenerative disorder defined by the association of early onset insulin dependent diabetes mellitus and progressive bilateral optic atrophy [2]. Wolfram syndrome (WFS) is a recessive neurologic and endocrinologic degenerative disorder, and is known as DIDMOAD (Diabetes Insipidus, early-onset Diabetes Mellitus, progressive Optic Atrophy and Deafness) syndrome. The phenotypic pleiomorphism, rarity and molecular complexity of this disease complicate our efforts to understand WFS To address this limitation, we aimed to describe complications and to elucidate the contributions of WFS1 mutations to clinical manifestations in Japanese patients with WFS

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Conclusion