Phenotypic characteristics of early Wolfram syndrome

Abstract

BackgroundWolfram 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.MethodsEighteen 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.ResultsSeventeen (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.ConclusionsWFS 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.

A calcium-dependent protease as a potential therapeutic target for Wolfram syndrome

“…Insulin-dependent diabetes usually occurs as the initial manifestation during the first decade of life, whereas the diagnosis of Wolfram syndrome is invariably later, with onset of symptoms in the second and ensuing decades (7,10,11). Two causative genes for this genetic disorder have been identified and named Wolfram syndrome 1 (WFS1) and Wolfram syndrome 2 (WFS2) (12,13).…”

Diabetes mellitus y atrofia óptica: estudio del síndrome de Wolfram

“…Muchos pacientes con SW pueden permanecer sin diagnóstico hasta la adultez debido al mal diagnóstico de diabetes tipo 1 y a la interpretación errónea de los síntomas clínicos de las alteraciones neurodegenerativas, sobre todo en etapas tempranas, al atribuirlos a complicaciones de la diabetes 43 . Hasta la fecha no existe ninguna intervención que altere la progresión de la enfermedad o prolongue la expectativa de vida en el SW, pero el reconocimiento temprano de este síndro-me y sus complicaciones puede incrementar la calidad de vida de quienes la padecen al permitir intervenciones tempranas para los componentes de este síndrome 22 . Aunque el SW es una enfermedad rara, deberá sospecharse en todos aquellos casos de diabetes mellitus con síntomas de atrofia óptica progresiva, pérdida auditiva, diabetes insípida, síntomas psiquiá-tricos o alteraciones del tracto urinario 43,61 .…”

“…En el SW, la deficiencia de wolframina causa hiperactivación y un alza sin control de vías de señalización celular que causan la muerte por apoptosis en las células sensibles 11,19 . Estudios clínicos y genéticos han demostrado que la disfunción heredada o adquirida del RE es causante o contribuyente para la aparición de enfermedades mucho más comunes que el SW, como la diabetes mellitus tipo 1 y tipo 2, la obesidad, la aterosclerosis, la dislipidemia, la esteatosis hepática, la enfermedad inflamatoria intestinal, muchos tipos distintos de cán-cer y enfermedades neurodegenerativas como la enfermedad de Alzheimer, la corea de Huntington y enfermedades por priones, por lo que el RE se convierte en un blanco terapéutico atractivo para estas enfermedades 10,[20][21][22][23] ; sin embargo, el SW es considerado como el prototipo de las enfermedades del RE.…”

When is it MODY? Challenges in the Interpretation of Sequence Variants in MODY Genes

“…Autosomal recessive or compound heterozygous mutations in the wolframin gene, WFS1, which encodes an ER transmembrane protein, give rise to Wolfram syndrome [104]. The most prominent clinical features of Wolfram syndrome include juvenile insulindependent diabetes, optic atrophy, and deafness [105,106]. Shang and colleagues created insulinproducing C-peptide-positive beta-cells from skin fibroblasts of patients with Wolfram syndrome and control subjects [99].…”