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Open Access Research

Phenotypic characteristics of early Wolfram syndrome

Bess A Marshall115*, M Alan Permutt2, Alexander R Paciorkowski345, James Hoekel1146, Roanne Karzon1478, Jon Wasson2, Amy Viehover19, Neil H White1142, Joshua S Shimony10, Linda Manwaring1, Paul Austin1112, Timothy E Hullar7, Tamara Hershey10139 and the Washington University Wolfram Study Group

Author Affiliations

1 Department of Pediatrics, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, USA

2 Department of Internal Medicine, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, USA

3 Department of Neurology, Center for Neural Development and Disease, University of Rochester Medical Center, Rochester, NY, USA

4 Department of Pediatrics, Center for Neural Development and Disease, University of Rochester Medical Center, Rochester, NY, USA

5 Department of Biomedical Genetics, Center for Neural Development and Disease, University of Rochester Medical Center, Rochester, NY, USA

6 Department of Ophthalmology, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, USA

7 Department of Otolaryngology-Head and Neck Surgery, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, USA

8 Department of Audiology, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, USA

9 Department of Neurology, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, USA

10 Department of Mallinckrodt Institute of Radiology, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, USA

11 Department of Surgery, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, USA

12 Department of Urology, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, USA

13 Department of Psychiatry, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, USA

14 St. Louis Children’s Hospital, One Children’s Place, St. Louis, MO 63110, USA

15 Department of Pediatrics, Division of Endocrinology and Diabetes, One Children’s Place, Campus Box 8116, St. Louis, MO 63110, USA

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Orphanet Journal of Rare Diseases 2013, 8:64  doi:10.1186/1750-1172-8-64

Published: 27 April 2013

Abstract

Background

Wolfram Syndrome (WFS:OMIM 222300) is an autosomal recessive, progressive, neurologic and endocrinologic degenerative disorder caused by mutations in the WFS1 gene, encoding the endoplasmic reticulum (ER) protein wolframin, thought to be involved in the regulation of ER stress. This paper reports a cross section of data from the Washington University WFS Research Clinic, a longitudinal study to collect detailed phenotypic data on a group of young subjects in preparation for studies of therapeutic interventions.

Methods

Eighteen subjects (ages 5.9–25.8, mean 14.2 years) with genetically confirmed WFS were identified through the Washington University International Wolfram Registry. Examinations included: general medical, neurologic, ophthalmologic, audiologic, vestibular, and urologic exams, cognitive testing and neuroimaging.

Results

Seventeen (94%) had diabetes mellitus with the average age of diabetes onset of 6.3 ± 3.5 years. Diabetes insipidus was diagnosed in 13 (72%) at an average age of 10.6 ± 3.3 years. Seventeen (94%) had optic disc pallor and defects in color vision, 14 (78%) had hearing loss and 13 (72%) had olfactory defects, eight (44%) had impaired vibration sensation. Enuresis was reported by four (22%) and nocturia by three (17%). Of the 11 tested for bladder emptying, five (45%) had elevated post-void residual bladder volume.

Conclusions

WFS causes multiple endocrine and neurologic deficits detectable on exam, even early in the course of the disease. Defects in olfaction have been underappreciated. The proposed mechanism of these deficits in WFS is ER stress-induced damage to neuronal and hormone-producing cells. This group of subjects with detailed clinical phenotyping provides a pool for testing proposed treatments for ER stress. Longitudinal follow-up is necessary for establishing the natural history and identifying potential biomarkers of progression.

Keywords:
Diabetes mellitus; DIDMOAD; Diabetes insipidus; Hearing loss; Optic atrophy; Color blindness; Neurodegenerative disorder