Neurologic Features and Genotype-Phenotype Correlation in Wolfram Syndrome

Department of Medical Genetics, Archet 2 Hospital, CHU of Nice, France.
Annals of Neurology (Impact Factor: 9.98). 03/2011; 69(3):501-8. DOI: 10.1002/ana.22160
Source: PubMed


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.

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    • "DID- MOAD is taken from major characteristics of the disease including diabetes insipidus, diabetes mellitus (DM), optic atrophy and deafness (Domenech et al., 2004; Cano et al., 2007). It is observed mostly in the first decade of life manifesting as juvenile-onset DM and optic atrophy, which are the minimum criteria for diagnosis (Chaussenot et al., 2011). Other features including deafness, abnormalities of urinary tract, psychiatric disorders, ataxia, peripheral neuropathy, and other endocrine disturbances may appear during the second decade (Gomez-Zaera et al., 2001; Gasparin et al., 2009; Kytovuori et al., 2013). "
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    ABSTRACT: Wolfram syndrome is one of the rare autosomal recessive, progressive, neurodegenerative disorders, characterized by diabetes mellitus and optic atrophy. Several other features are observed in patients including deafness, ataxia, and peripheral neuropathy. A gene called WFS1 is identified on chromosome 4p, responsible for Wolfram syndrome. We investigated a family consisted of parents and 8 children, which 5 of them have been diagnosed for Wolfram syndrome. WFS1 gene in all family members was sequenced for causative mutations. A mutation (c.376G>A, p.A126T) was found in all affected members in homozygous state and in both parents in heterozygous state. The bioinformatics analysis showed the deleterious effects of this nucleotide change on the structure and function of the protein product. As all of the patients in the family showed the homozygote mutation, and parents were both heterozygote, this mutation is probably the cause of the disease. We identified this mutation in homozygous state for the first time as Wolfram syndrome causation. We also showed that this mutation probably doesn't cause deafness in affected individuals.
    Full-text · Article · Feb 2016 · European journal of medical genetics
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    • "In addition, as central nervous system atrophy is found in WS patients [3], [33], [34], 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 [35]. "
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    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.
    Full-text · Article · May 2014 · PLoS ONE
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    • "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). "
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    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.
    Full-text · Article · Jun 2013 · Mitochondrion
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