Lower Urinary Tract Dysfunction and Associated Pons Volume in Patients with Wolfram Syndrome

Rove, Kyle O.; Vricella, Gino J.; Hershey, Tamara; Thu, Muang H.; Lugar, Heather M.; Vetter, Joel; Marshall, Bess A.; Austin, Paul F.

doi:10.1016/j.juro.2018.06.002

Cited by 18 publications

(16 citation statements)

References 31 publications

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“…respiration, urination) known to be affected in Wolfram syndrome. In fact, in a cross-sectional, correlational analysis, we found that ventral pons volume correlated with the degree of urinary dysfunction 30 . In addition, gait and balance, which are associated with the cerebellum, are known to be abnormal in Wolfram syndrome, even at the early stages of the disease process 7,8 .…”

Section: Discussionmentioning

confidence: 75%

Evidence for altered neurodevelopment and neurodegeneration in Wolfram syndrome using longitudinal morphometry

Lugar

Koller

Rutlin

et al. 2019

Sci Rep

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Wolfram syndrome is a rare disease caused by mutations in the WFS1 gene leading to symptoms in early to mid-childhood. Brain structural abnormalities are present even in young children, but it is not known when these abnormalities arise. Such information is critical in determining optimal outcome measures for clinical trials and in understanding the aberrant neurobiological processes in Wolfram syndrome. Using voxel-wise and regional longitudinal analyses, we compared brain volumes in Wolfram patients (n = 29; ages 5–25 at baseline; mean follow-up = 3.6 years), to age and sex-equivalent controls (n = 52; ages 6–26 at baseline; mean follow-up = 2.0 years). Between groups, white and gray matter volumes were affected differentially during development. Controls had uniformly increasing volume in white matter, whereas the Wolfram group had stable (optic radiations) or decreasing (brainstem, ventral pons) white matter volumes. In gray matter, controls had stable (thalamus, cerebellar cortex) or decreasing volumes (cortex), whereas the Wolfram group had decreased volume in thalamus and cerebellar cortex. These patterns suggest that there may be early, stalled white matter development in Wolfram syndrome, with additional degenerative processes in both white and gray matter. Ideally, animal models could be used to identify the underlying mechanisms and develop specific interventions.

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Section: Discussionmentioning

confidence: 75%

Evidence for altered neurodevelopment and neurodegeneration in Wolfram syndrome using longitudinal morphometry

Lugar

Koller

Rutlin

et al. 2019

Sci Rep

Self Cite

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“…La progresión normal como lo revela el estudio de este paciente indica que la mayoría desarrollará casi todas las complicaciones de la enfermedad (15), conviene mencionar además que las complicaciones neurológicas suelen aparecer alrededor de la cuarta década de la vida y son las que confieren mal pronóstico porque acortan la esperanza de vida (16); por tanto el tratamiento se basa en tratar las afecciones, pues no existen medidas curativas (5). La principal limitación del establecimiento del diagnóstico es la falta de análisis genético, que no se realiza en Ecuador.…”

Section: Discussionunclassified

Síndrome de Wolfram en uno de cuatro hermanos: caso reporte

Chávez

Cedeño

Amador

et al. 2019

ree

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El síndrome de Wolfram es una patología degenerativa, neuroendocrina, cuya sospecha diagnostica se debe plantear ante un sujeto joven con diabetes mellitus (DM) y atrofia óptica (1) que deberá ser confirmado con el estudio genético (2). Se conoce como síndrome de DIDMOAD debido a que asocia DM, diabetes insípida, atrofia óptica y sordera (3); se ha sugerido la denominación DIDMOADUA por la alta frecuencia de trastornos urológicos; además suelen existir manifestaciones a nivel neurológico, psiquiátrico y gonadal (4). El pronóstico es malo, no existiendo tratamiento curativo identificado hasta el momento, el promedio de vida es de 30 años y las manifestaciones neurológicas especialmente la atrofia del tronco cerebral constituyen la causa de muerte (5). Presentamos el caso de un paciente que reúne criterios clínicos diagnósticos definitivos de síndrome de Wolfram, con el objetivo de describir una patología que es rara, y por ende concientizar en su detección temprana, para que el paciente alcance una mejor calidad de vida.

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“…6,8,23 Urinary tract problems, including dilation of the urinary tracts, neurogenic bladder, and urinary incontinence, have been reported in 19% of patients with WS, but this figure is likely to represent an underestimate. 23,25 There is evidence that lower pontine volume on magnetic resonance imaging (MRI) is associated with more severe urinary tract dysfunction and lower quality of life in WS. 25 With greater access to genetic testing and the application of next-generation sequencing in clinical practice, there is increasing recognition of a subgroup of patients who harbor heterozygous dominant pathogenic variants in the WFS1 gene.…”

Section: Molecular Genetics and Clinical Features Of Wolfram Syndromementioning

confidence: 99%

“…23,25 There is evidence that lower pontine volume on magnetic resonance imaging (MRI) is associated with more severe urinary tract dysfunction and lower quality of life in WS. 25 With greater access to genetic testing and the application of next-generation sequencing in clinical practice, there is increasing recognition of a subgroup of patients who harbor heterozygous dominant pathogenic variants in the WFS1 gene. [17][18][19] These are more often missense pathogenic variants, compared to the loss-of-function variants and deletions identified in patients with recessive WFS1 mutations.…”

Section: Molecular Genetics and Clinical Features Of Wolfram Syndromementioning

confidence: 99%

Wolfram syndrome: new pathophysiological insights and therapeutic strategies

Mishra

Chen

Richa

et al. 2021

Therapeutic Advances in Rare Disease

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Wolfram Syndrome (WS) is an ultra-rare, progressive neurodegenerative disease characterized by early-onset diabetes mellitus and irreversible loss of vision, secondary to optic nerve degeneration. Visual loss in WS is an important cause of registrable blindness in children and young adults and the pathological hallmark is the preferential loss of retinal ganglion cells within the inner retina. In addition to optic atrophy, affected individuals frequently develop variable combinations of neurological, endocrinological, and psychiatric complications. The majority of patients carry recessive mutations in the WFS1 (4p16.1) gene that encodes for a multimeric transmembrane protein, wolframin, embedded within the endoplasmic reticulum (ER). An increasingly recognised subgroup of patients harbor dominant WFS1 mutations that usually cause a milder phenotype, which can be limited to optic atrophy. Wolframin is a ubiquitous protein with high levels of expression in retinal, neuronal, and muscle tissues. It is a multifunctional protein that regulates a host of cellular functions, in particular the dynamic interaction with mitochondria at mitochondria-associated membranes. Wolframin has been implicated in several crucial cellular signaling pathways, including insulin signaling, calcium homeostasis, and the regulation of apoptosis and the ER stress response. There is currently no cure for WS; management remains largely supportive. This review will cover the clinical, genetic, and pathophysiological features of WS, with a specific focus on disease models and the molecular pathways that could serve as potential therapeutic targets. The current landscape of therapeutic options will also be discussed in the context of the latest evidence, including the pipeline for repurposed drugs and gene therapy. Plain language summary Wolfram syndrome – disease mechanisms and treatment options Wolfram syndrome (WS) is an ultra-rare genetic disease that causes diabetes mellitus and progressive loss of vision from early childhood. Vision is affected in WS because of damage to a specialized type of cells in the retina, known as retinal ganglion cells (RGCs), which converge at the back of the eye to form the optic nerve. The optic nerve is the fast-conducting cable that transmits visual information from the eye to the vision processing centers within the brain. As RGCs are lost, the optic nerve degenerates and it becomes pale in appearance (optic atrophy). Although diabetes mellitus and optic atrophy are the main features of WS, some patients can develop more severe problems because the brain and other organs, such as the kidneys and the bladder, are also affected. The majority of patients with WS carry spelling mistakes (mutations) in the WFS1 gene, which is located on the short arm of chromosome 4 (4p16.1). This gene is highly expressed in the eye and in the brain, and it encodes for a protein located within a compartment of the cell known as the endoplasmic reticulum. For reasons that still remain unclear, WFS1 mutations preferentially affect RGCs, accounting for the prominent visual loss in this genetic disorder. There is currently no effective treatment to halt or slow disease progression and management remains supportive, including the provision of visual aids and occupational rehabilitation. Research into WS has been limited by its relative rarity and the inability to get access to eye and brain tissues from affected patients. However, major advances in our understanding of this disease have been made recently by making use of more accessible cells from patients, such as skin cells (fibroblasts), or animal models, such as mice and zebrafish. This review summarizes the mechanisms by which WFS1 mutations affect cells, impairing their function and eventually leading to their premature loss. The possible treatment strategies to block these pathways are also discussed, with a particular focus on drug repurposing (i.e., using drugs that are already approved for other diseases) and gene therapy (i.e., replacing or repairing the defective WFS1 gene).

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Lower Urinary Tract Dysfunction and Associated Pons Volume in Patients with Wolfram Syndrome

Abstract: A significant number of children, adolescents and young adults with Wolfram syndrome have objective evidence of lower urinary tract dysfunction. Decreased pons volume is associated with more abnormal urinary function and lower quality of life in patients with Wolfram syndrome.

Cited by 18 publications

References 31 publications

Evidence for altered neurodevelopment and neurodegeneration in Wolfram syndrome using longitudinal morphometry

Evidence for altered neurodevelopment and neurodegeneration in Wolfram syndrome using longitudinal morphometry

Síndrome de Wolfram en uno de cuatro hermanos: caso reporte

Wolfram syndrome: new pathophysiological insights and therapeutic strategies

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