Clinical Characteristics of Wolfram Syndrome in Chinese Population and a Novel Frameshift Mutation in WFS1.

Lian Duan,An-Li Tong,Jiang-Feng Mao,Xiao-Feng Chai,Qian Li,Feng Gu,Miao Yu,Tao Yuan

doi:10.3389/fendo.2018.00018

Abstract

Wolfram syndrome (WS) is a rare, degenerative, and hereditary disorder characterized by ear diabetes mellitus (DM) and optic atrophy (OA). We aim to characterize clinical features in Chinese patients who had been poorly studied until now. We performed a retrospective review of patients with WS seen in the Peking Union Medical College Hospital from 2002 to 2017. Data including demographic data, clinical presentations, examination results, family history, and genetic analysis were described. Six patients with WS were identified, meeting the diagnostic criteria of the coincidence of DM and OA before 15 years old or the existence of two WFS1 mutations. All were male, with the median age of 14.5 years (range 10-19 years). Blood glucose impairment, OA, and diabetes insipidus were present in all (100%), hearing impairment in four (66.7%), urological abnormalities in four (66.7%), neurological abnormalities in one (16.7%), and endocrine disorder in one (16.7%). Rare presentation includes cataract, glaucoma, and spina bifida occulta. Diabetes was insulin-dependent and not ketosis onset, with antibody to glutamic acid decarboxylase and islet cell negative. Genetic analysis revealed mutations in WFS1 in three patients. A novel frameshift mutation (p.Asp151Glufs*93) was identified in exon 4 of WFS1. Our series of WS patients indicated that WS is a degenerative disease with a wide and variable spectrum, characterized by ear non-autoimmune DM and bilateral OA. Genetic analysis is recommended when suspected of WS.

Highlights

Wolfram syndrome (WS) is a rare, degenerative, and hereditary disease described by Wolfram and Wagener in 1938 for the first time
Loss-of-function mutation in WFS1 is related to autosome-recessive WS, a mutation in WFS1 was believed to be a cause of autosome-dominant optic atrophy (OA), hearing impairment, and diabetes [14, 15]
One patient clinically suspected of WS, presenting polydipsia, polyuria, and hearing impairment, was excluded because of lack of co-occurrences of diabetes mellitus (DM) and OA as well as WFS1 mutation

Summary

Introduction

Wolfram syndrome (WS) is a rare, degenerative, and hereditary disease described by Wolfram and Wagener in 1938 for the first time. WFS1 was identified as the first causative gene of WS in 1998, mutated in almost all patients [3, 4]. CISD2 was described as the second responsible gene in some Jordanian families in 2007 [5, 6]. WFS1 encodes Wolframin, an endoplasmic reticulum (ER) transmembrane protein, generally expressed in a variety of tissues, highly in pancreatic β-cells and brain [4]. CISD2 encodes Endoplasmic Reticulum Intermembrane Small protein, involved in mitochondrial disorder, associated with a variant feature of gastrointestinal ulcer and bleeding tendency without DI [12, 13]. Approximately 350 mutations in WFS1 and 3 mutations in CISD2 are reported in HGMD database. Previous studies implicate that the classification of WFS1 mutations may predict the onset age of symptoms [16]. The underlying mechanisms of WS as well as associations between genotype and phenotype remain to be further elucidated

Methods

Results

Discussion

Conclusion