Phenotypic characteristics of early Wolfram syndrome

Bess A. Marshall, Alexander R. Paciorkowski, James Hoekel, Roanne Karzon, Jon Wasson, Amy Viehover, Neil H. White, Joshua S. Shimony, Linda Manwaring, Paul Austin, Timothy Hullar, Tamara Hershey

Research output: Contribution to journalArticle

37 Citations (Scopus)

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.

Original languageEnglish (US)
Article number64
JournalOrphanet Journal of Rare Diseases
Volume8
Issue number1
DOIs
StatePublished - 2013
Externally publishedYes

Fingerprint

Wolfram Syndrome
Endoplasmic Reticulum Stress
Urinary Bladder
Color Vision Defects
Nocturia
Genetic Databases
Pallor
Enuresis
Diabetes Insipidus
Tungsten
Residual Volume
Hypesthesia
Smell
Optic Disk
Neurologic Manifestations
Vibration
Natural History
Hearing Loss
Age of Onset
Neuroimaging

Keywords

  • Color blindness
  • Diabetes insipidus
  • Diabetes mellitus
  • DIDMOAD
  • Hearing loss
  • Neurodegenerative disorder
  • Optic atrophy

ASJC Scopus subject areas

  • Medicine(all)
  • Genetics(clinical)
  • Pharmacology (medical)

Cite this

Marshall, B. A., Paciorkowski, A. R., Hoekel, J., Karzon, R., Wasson, J., Viehover, A., ... Hershey, T. (2013). Phenotypic characteristics of early Wolfram syndrome. Orphanet Journal of Rare Diseases, 8(1), [64]. https://doi.org/10.1186/1750-1172-8-64

Phenotypic characteristics of early Wolfram syndrome. / Marshall, Bess A.; Paciorkowski, Alexander R.; Hoekel, James; Karzon, Roanne; Wasson, Jon; Viehover, Amy; White, Neil H.; Shimony, Joshua S.; Manwaring, Linda; Austin, Paul; Hullar, Timothy; Hershey, Tamara.

In: Orphanet Journal of Rare Diseases, Vol. 8, No. 1, 64, 2013.

Research output: Contribution to journalArticle

Marshall, BA, Paciorkowski, AR, Hoekel, J, Karzon, R, Wasson, J, Viehover, A, White, NH, Shimony, JS, Manwaring, L, Austin, P, Hullar, T & Hershey, T 2013, 'Phenotypic characteristics of early Wolfram syndrome', Orphanet Journal of Rare Diseases, vol. 8, no. 1, 64. https://doi.org/10.1186/1750-1172-8-64
Marshall BA, Paciorkowski AR, Hoekel J, Karzon R, Wasson J, Viehover A et al. Phenotypic characteristics of early Wolfram syndrome. Orphanet Journal of Rare Diseases. 2013;8(1). 64. https://doi.org/10.1186/1750-1172-8-64
Marshall, Bess A. ; Paciorkowski, Alexander R. ; Hoekel, James ; Karzon, Roanne ; Wasson, Jon ; Viehover, Amy ; White, Neil H. ; Shimony, Joshua S. ; Manwaring, Linda ; Austin, Paul ; Hullar, Timothy ; Hershey, Tamara. / Phenotypic characteristics of early Wolfram syndrome. In: Orphanet Journal of Rare Diseases. 2013 ; Vol. 8, No. 1.
@article{5350f2d6949049a48e91c342dddd176f,
title = "Phenotypic characteristics of early Wolfram syndrome",
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 = "Color blindness, Diabetes insipidus, Diabetes mellitus, DIDMOAD, Hearing loss, Neurodegenerative disorder, Optic atrophy",
author = "Marshall, {Bess A.} and Paciorkowski, {Alexander R.} and James Hoekel and Roanne Karzon and Jon Wasson and Amy Viehover and White, {Neil H.} and Shimony, {Joshua S.} and Linda Manwaring and Paul Austin and Timothy Hullar and Tamara Hershey",
year = "2013",
doi = "10.1186/1750-1172-8-64",
language = "English (US)",
volume = "8",
journal = "Orphanet Journal of Rare Diseases",
issn = "1750-1172",
publisher = "BioMed Central",
number = "1",

}

TY - JOUR

T1 - Phenotypic characteristics of early Wolfram syndrome

AU - Marshall, Bess A.

AU - Paciorkowski, Alexander R.

AU - Hoekel, James

AU - Karzon, Roanne

AU - Wasson, Jon

AU - Viehover, Amy

AU - White, Neil H.

AU - Shimony, Joshua S.

AU - Manwaring, Linda

AU - Austin, Paul

AU - Hullar, Timothy

AU - Hershey, Tamara

PY - 2013

Y1 - 2013

N2 - 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.

AB - 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.

KW - Color blindness

KW - Diabetes insipidus

KW - Diabetes mellitus

KW - DIDMOAD

KW - Hearing loss

KW - Neurodegenerative disorder

KW - Optic atrophy

UR - http://www.scopus.com/inward/record.url?scp=84876679219&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84876679219&partnerID=8YFLogxK

U2 - 10.1186/1750-1172-8-64

DO - 10.1186/1750-1172-8-64

M3 - Article

C2 - 23981289

AN - SCOPUS:84876679219

VL - 8

JO - Orphanet Journal of Rare Diseases

JF - Orphanet Journal of Rare Diseases

SN - 1750-1172

IS - 1

M1 - 64

ER -