Wolfram syndrome (WS) is a rare neurodegenerative disorder characterized by juvenile-onset diabetes mellitus and optic atrophy. Our aim was to describe the nature and the frequency of the neurologic manifestations, which had been poorly studied until now.
We performed a detailed clinical study with genotype-phenotype correlation in a series of 59 patients with WS.
The onset of neurologic symptoms, with a median age of 15 years, was much earlier than previously reported. Cognitive impairment, which was not frequent in previous reports, was observed in 32% of patients with neurologic signs. Like epilepsy, it was mainly found in patients who developed neurologic signs before 15 years of age. In contrast to previous series, we also found malformations of cortical development on magnetic resonance imaging in epileptic children and white matter involvement, including diffuse leukoencephalopathy, in adult patients. We identified 109 mutated alleles corresponding to 56 different mutations of the WFS1 gene, among which 10 were novel. Homozygosity or compound heterozygosity for missense mutation does not seem to influence the age of onset and the occurrence of neurologic complications. However, an interesting point concerns a possible correlation between the location of the mutations and the development of the neurologic manifestations.
This series concerns the largest cohort of WS patients reported to date. It illustrates the wide variety of neurologic signs in this syndrome and the necessity of rapid therapeutic coverage to improve the prognosis.
"In addition, as central nervous system atrophy is found in WS patients , , , possible central degeneration in Wfs1−/− mice could contribute to the changes observed in VEP analysis, independently from retinal dysfunctions. Wfs1 mRNA was shown to be enriched in excitatory neuronal cells of layer2/3 of the visual cortex in a subset of excitatory neurons responsive to selective visual stimuli . "
[Show abstract][Hide abstract] ABSTRACT: Wolfram syndrome is an early onset genetic disease (1/180,000) featuring diabetes mellitus and optic neuropathy, associated to mutations in the WFS1 gene. Wfs1-/- mouse model shows pancreatic beta cell atrophy, but its visual performance has not been investigated, prompting us to study its visual function and histopathology of the retina and optic nerve. Electroretinogram and visual evoked potentials (VEPs) were performed in Wfs1-/- and Wfs1+/+ mice at 3, 6, 9 and 12 months of age. Fundi were pictured with Micron III apparatus. Retinal ganglion cell (RGC) abundance was determined from Brn3a immunolabeling of retinal sections. RGC axonal loss was quantified by electron microscopy in transversal optic nerve sections. Endoplasmic reticulum stress was assessed using immunoglobulin binding protein (BiP), protein disulfide isomerase (PDI) and inositol-requiring enzyme 1 alpha (Ire1α) markers. Electroretinograms amplitudes were slightly reduced and latencies increased with time in Wfs1-/- mice. Similarly, VEPs showed decreased N+P amplitudes and increased N-wave latency. Analysis of unfolded protein response signaling revealed an activation of endoplasmic reticulum stress in Wfs1-/- mutant mouse retinas. Altogether, progressive VEPs alterations with minimal neuronal cell loss suggest functional alteration of the action potential in the Wfs1-/- optic pathways.
PLoS ONE 05/2014; 9(5):e97222. DOI:10.1371/journal.pone.0097222 · 3.23 Impact Factor
"These included dysfunction of the brainstem and cerebellum, peripheral neuropathy, cognitive decline, and epilepsy. Additionally, renal tract abnormalities, psychiatric symptoms , and gastrointestinal anomalies were also present in some individuals (Chaussenot et al., 2011). "
[Show abstract][Hide abstract] ABSTRACT: Mitochondrial dysfunction in Wolfram Syndrome (WS) is controversial and optic neuropathy, a cardinal clinical manifestation, is poorly characterized. We here describe the histopathological features in postmortem retinas and optic nerves (ONs) from one patient with WS testing the hypothesis that mitochondrial dysfunction underlies the pathology. Eyes and retrobulbar ONs were obtained at autopsy from a WS patient, and compared with those of a Leber hereditary optic neuropathy (LHON) patient and one healthy control. Retinas were stained with hematoxylin & eosin for general morphology and ONs were immunostained for myelin basic protein (MBP). Immunostained ONs were examined in four "quadrants": superior, inferior, nasal, and temporal. The WS retinas displayed a severe loss of retinal ganglion cells in the macular region similar to the LHON retina, but not in the control. The WS ONs, immunostained for MBP, revealed a zone of degeneration in the inferior and temporal quadrants. This pattern was similar to that seen in the LHON ONs but not in the control. Thus, the WS patient displayed a distinct pattern of optic atrophy observed bilaterally in the temporal and inferior quadrants of the ONs. This arrangement of axonal degeneration, involving primarily the papillomacular bundle, closely resembled LHON and other mitochondrial optic neuropathies, supporting that mitochondrial dysfunction underlies its pathogenesis.
"However, the order in which symptoms emerge over time in WFS has been difficult to discern. A recent paper surveying (but not directly assessing) 59 subjects with WFS ranging in age from 5 to 54 found that some individuals are reported to have optic atrophy prior to the diagnosis of diabetes mellitus . These investigators did not test each subject directly, and did not assess olfaction or color vision, so it is not clear whether these features were also present prior to diabetes. "
[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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.
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.
Hanne Struyfs, Wim Van Hecke, Jelle Veraart, Jan Sijbers, Sylvie Slaets, Maya De Belder, Laura Wuyts, Benjamin Peters, Kristel Sleegers, Caroline Robberecht, Christine Van Broeckhoven, Frank De Belder, Paul M Parizel, Sebastiaan Engelborghs
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