Ophthalmologic correlates of disease severity in children and adolescents with Wolfram syndrome

Hoekel, James; Chisholm, Smith Ann; Al‐Lozi, Amal; Hershey, Tamara; Tychsen, Lawrence

doi:10.1016/j.jaapos.2014.07.162

Cited by 47 publications

(53 citation statements)

References 24 publications

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“…Visual field (VF) demonstrated the presence of a central scotoma only in 2 WS cases, whereas for other WS patients visual field defects were heterogenous, again not suggesting a classical mitochondrial pattern 34 . The neuro-ophthalmological phenotype has been poorly defined in WS until recently [35][36][37] . Grenier and colleagues 22 evaluated OCT findings in 15 WS cases.…”

Section: Discussionmentioning

confidence: 99%

Calcium mishandling in absence of primary mitochondrial dysfunction drives cellular pathology in Wolfram Syndrome

Morgia

Maresca

Amore

et al. 2020

Sci Rep

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Wolfram syndrome (WS) is a recessive multisystem disorder defined by the association of diabetes mellitus and optic atrophy, reminiscent of mitochondrial diseases. The role played by mitochondria remains elusive, with contradictory results on the occurrence of mitochondrial dysfunction. We evaluated 13 recessive WS patients by deep clinical phenotyping, including optical coherence tomography (OCT), serum lactic acid at rest and after standardized exercise, brain Magnetic Resonance Imaging, and brain and muscle Magnetic Resonance Spectroscopy (MRS). Finally, we investigated mitochondrial bioenergetics, network morphology, and calcium handling in patient-derived fibroblasts. Our results do not support a primary mitochondrial dysfunction in WS patients, as suggested by MRS studies, OCT pattern of retinal nerve fiber layer loss, and, in fibroblasts, by mitochondrial bioenergetics and network morphology results. However, we clearly found calcium mishandling between endoplasmic reticulum (ER) and mitochondria, which, under specific metabolic conditions of increased energy requirements and in selected tissue or cell types, may turn into a secondary mitochondrial dysfunction. Critically, we showed that Wolframin (WFS1) protein is enriched at mitochondrial-associated ER membranes and that in patient-derived fibroblasts WFS1 protein is completely absent. These findings support a loss-of-function pathogenic mechanism for missense mutations in WFS1, ultimately leading to defective calcium influx within mitochondria. Wolfram Syndrome (WS) is a rare genetic disorder also known as DIDMOAD, i.e. Diabetes Insipidus (DI), Diabetes Mellitus (DM), Optic Atrophy (OA) and Deafness 1. Additional neurological features include brainstem atrophy, cerebellar ataxia, peripheral neuropathy, cognitive deterioration and epilepsy 2. The onset of OA and DM, the minimal diagnostic criteria for WS, is typically within the second decade. The large majority of WS patients carry recessive mutations in the WFS1 gene encoding for the Wolframin (WFS1) protein 3. WFS1 is associated with the endoplasmic reticulum (ER) 4 and cellular and animal model studies involved Wolframin in the ER stress response, regulation of calcium homeostasis and Na/K ATPase function 5. Due to the clinical features resembling a mitochondrial disorder 6 and reports of mitochondrial DNA (mtDNA)

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Section: Discussionmentioning

confidence: 99%

Calcium mishandling in absence of primary mitochondrial dysfunction drives cellular pathology in Wolfram Syndrome

Morgia

Maresca

Amore

et al. 2020

Sci Rep

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“…In 18 WS1 children at relatively early stages, multiple ophthalmic markers, such as retinal nerve fiber layer thickness, have been identified. It would appear that these alterations correlate with the overall disease severity (62).…”

Section: Optic Atrophymentioning

confidence: 97%

“…It begins at an average age of 11 years (6 weeks to 19 years) with reduced visual acuity and loss of color vision. Other less-frequent ocular abnormalities reported are cataract (29.6-66.6%), abnormal papillary light reflexes, nystagmus, pigmentary maculopathy, and glaucoma (62). Pigmentary retinopathy has also been described in 30% of 15 Jordanian WS1 patients from four inbred families.…”

Section: Optic Atrophymentioning

confidence: 99%

Genetic and clinical aspects of Wolfram syndrome 1, a severe neurodegenerative disease

et al. 2018

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Wolfram syndrome 1 (WS1) is a rare autosomal recessive neurodegenerative disease characterized by diabetes insipidus, diabetes mellitus, optic atrophy, deafness, and other abnormalities. WS1 usually results in death before the age of 50 years. The pathogenesis of WS1 is ascribed to mutations of human WFS1 gene on chromosome 4p encoding a transmembrane protein called wolframin which has physiological functions in membrane trafficking, secretion, processing, and/or regulation of ER calcium homeostasis. Different types of WFS1 mutations have been identified, and some of these have been associated with a dominant, severe type of WS.

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“…Visual evoked potentials are useful to monitor the efficacy of potential treatments. Retinal thinning has been shown to be a reliable marker for the disease progression [ 16 , 17 ]. Magnification of images on smartphone and tablets, or by magnifying glasses, and voice systems are helpful.…”

Section: Clinical Managementmentioning

confidence: 99%

Wolfram Syndrome: Diagnosis, Management, and Treatment

2016

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Wolfram syndrome is a rare genetic disorder characterized by juvenile-onset diabetes mellitus, diabetes insipidus, optic nerve atrophy, hearing loss, and neurodegeneration. Although there are currently no effective treatments that can delay or reverse the progression of Wolfram syndrome, the use of careful clinical monitoring and supportive care can help relieve the suffering of patients and improve their quality of life. The prognosis of this syndrome is currently poor, and many patients die prematurely with severe neurological disabilities, raising the urgency for developing novel treatments for Wolfram syndrome. In this article, we describe natural history and etiology, provide recommendations for diagnosis and clinical management, and introduce new treatments for Wolfram syndrome.

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Ophthalmologic correlates of disease severity in children and adolescents with Wolfram syndrome

Cited by 47 publications

References 24 publications

Calcium mishandling in absence of primary mitochondrial dysfunction drives cellular pathology in Wolfram Syndrome

Calcium mishandling in absence of primary mitochondrial dysfunction drives cellular pathology in Wolfram Syndrome

Genetic and clinical aspects of Wolfram syndrome 1, a severe neurodegenerative disease

Wolfram Syndrome: Diagnosis, Management, and Treatment

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