8th International Wolfram Symposium Presentation Prof Gil Leibowitz – President of the Israel Endocrine Society (IES), Hadassah Medical center, the Hebrew University, Jerusalem, Israel.
Pathophysiology and treatment of type 2 Wolfram syndrome.
Abstract: Type 2 Wolfram syndrome results from a missense mutation in the CISD2 gene, encoding NAF-1, which transfers Fe-S clusters from the mitochondria to cytosolic acceptor proteins. The carrier rate of CISD2 missense mutation among the Palestinian population in the Middle East is 1:40, suggesting a founder effect. Type1 and type 2 Wolfram syndrome have common and distinct clinical features, suggesting heterogeneity in disease phenotype and pathophysiology. NAF-1 deficiency leads to increased labile iron accumulation in the mitochondria with subsequent development of mitochondrial dysfunction and oxidative stress, resulting in neurodegeneration and diabetes. Treatment of NAF-1 deficient cells by iron chelation, N-acetylcysteine and GLP-1-RA reduced mitochondrial iron overload and alleviated oxidative stress and mitochondrial dysfunction. I will discuss the therapeutic implications of these findings.
Points noted:
- T2WS is not extremely rare in the Middle east region (compared to WFS1). This is very different from the situation reported elsewhere (e.g. in US – almost all patients have WFS1 mutations rather than CISD2 mutations).
- CISD2 gene mutation (Glutamate – Glutamine, 8 amino acid frameshift with abnormal splicing and stop sequence) generates a protein which is 25% of the size of the native protein that is rapidly degraded. Unrelated families can carry the same mutation.
- Combined GLP-1-RA (e.g. exenatide) and N-acetylcysteine generate increased effects, compared with single treatment (e.g. beta cell protection).
- Better understanding of T2WS has implications for more common forms of Diabetes Mellitus.
- Early intervention is likely to be needed.
- RCTs need broad international collaboration.
- Heterozygous mutations were not studied to date.
Characterization of Mouse Models for Optic Atrophy in Wolfram Syndrome -Urano Lab
Venu Gurram, William An, Shrini Bimal, Nila Palaniappan, Toko Campbell, Pooja Neerumalla, Devynn Hummel, Brianna Carman, Cris Brown, and Fumihiko Urano
8th International Wolfram Symposium Presentation Dra. Gema Esteban- Bueno, Dr. Juan R. Coca, Dr. Nicolas Fernández-Fernández, Leticia Fernandez Amores, Miguel Navarro Cabrero, Dra. Aida Berenguel-Hernández and Spanish Multidisciplinary Wolfram Syndrome Group. Spain.
Descriptive analysis of 68 patients with Wolfram syndrome with emphasis on sensorineural involvement and possible phenotype-genotype correlation.
Abstract: Our work consists in providing greater knowledge of what already exists in the Wolfram Syndrome phenotype with special attention to hearing loss, through a descriptive and longitudinal study of two sets of patients affected from Spain and Portugal. The first set (descriptive study) contain a registry with patients that have been appearing since 1999, and the second set collects data from multidisciplinary assessments that have been carried out in Spain since 2011 year after year (longitudinal study).
In turn, a brief study of the genotype-phenotype relationship of the hearing loss that exists in patients of Spain and Portugal with Wolfram Syndrome has been carried out, based on the genetic data collected by our team.
Point noted:
· Spanish and Portuguese families are evaluated through a multi-disciplinary team, who are in regular contact – to listen to families; accumulate experience and provide biopsychosocial support.
· Currently assessing 2 patient populations (second set is a sub-set of the first).
· No definitive pattern can be established for hearing loss or progression. Homozygous genetic changes are more severe.
· The team actively participates in the WS Global Awareness Day and plan more activities for 2023.
· The team are keen to collaborate with other groups / researchers to help drive change for families – valuable dataset.
· University of Birmingham group (through Dr Renuka Dias) has been assessing gonadal function – connecting with the team in Spain may be helpful.
8th International Wolfram Symposium Presentation Dr. Vania Broccoli – CNR – National Research Council Institute of Neuroscience, Milan. Italy.
New function of Wolframin in regulating the monocarboxylate transporter 1 (MCT1) in glial cells in brain and retina.
Abstract: A key pathological manifestation in Wolfram syndrome is the progressive optic atrophy which leads to relentless visual loss. Although some of the pathological mechanisms caused by wolframin mutations have been unraveled in the recent years, how they impinge on visual deficits it remains unclear. Through genomics and proteomics analyses on retinal tissues isolated from wolframin mutant mice, we identified a significant reduction of the monocarboxylate transport isoform 1 (MCT1) and its partner basigin that are highly enriched on retinal glia and myelin- forming oligodendrocytes in optic nerve together with wolframin. Loss of MCT1 causes a failure in lactate transfer from glial to neuronal cell bodies and axons leading to a chronic hypometabolic state that can cause retinal ganglion cell (RGC) degeneration. This metabolic dysfunction occurs months before the frank RGC degeneration suggesting an extended time-window for intervening with new therapeutic strategies focused on boosting retinal and optic nerve bioenergetics in WS1.
Points noted:
8th International Wolfram Symposium Presentation by Dr Malgorzata Zatyka – Institute of Cancer and Genomic Sciences, University of Birmingham, Edgbaston, Birmingham. UK
Depletion of WFS1 compromises mitochondrial function in hiPSC-derived neuronal models of Wolfram syndrome.
Abstract: Mitochondrial dysfunction involving mitochondria-associated ER membrane (MAM) dysregulation is implicated in the pathogenesis of late-onset neurodegenerative diseases, but understanding is limited for rare early-onset conditions. Loss of the MAM resident protein WFS1 causes Wolfram syndrome (WS), a rare early-onset neurodegenerative disease that has been linked to mitochondrial abnormalities. However, contradictory reports on mitochondrial functionality in non-human or nonclinical cell models and lack of data in disease- affected settings have precluded biomedical exploitation.
Here we demonstrated mitochondrial dysfunction in human induced pluripotent stem cell-derived neuronal cells of WS patients. VDAC1 was identified to interact with WFS1, whereas loss of this interaction in WS cells could compromise mitochondrial function. Genetic rescue by WFS1 restoration or pharmacological agents modulating mitochondrial function improved the viability and bioenergetics of WS neurons. Our data implicate a role of WFS1 in regulating mitochondrial functionality and highlight a therapeutic target for WS and related rare diseases with mitochondrial defects.
Points noted:
· Mitochondrial dysfunction and increased oxidative stress are seen in human induced PCS derived neuronal cells from WS patients.
· Not all typical biochemical mitochondrial markers were seen in WS patient derived cells.
· Treatment to rescue WSF1, rescued mitochondrial function and reduced cell death.
· WSF1 interacts with VDAC1 and may regulate VDAC1 function formation.
· Not yet assessed investigational compounds in this model to evaluate potential benefits.
Today ends the Deafblind Awareness Week. Deafblindness isn’t obvious and you can’t always tell by looking at someone. Try to be open and inclusive always. Hopefully we can make the world a more deafblind-friendly place. Support the Snow Foundation today in honor of those who struggle with vision and hearing loss. https://thesnowfoundation.org/donate/
About the Snow Foundation
The Snow Foundation is a collective voice for Wolfram syndrome patients, working towards a cure for Wolfram syndrome and developing novel therapies for diabetes, vision loss, hearing loss and neurodegeneration.
Rare Diseases…Common Problems
P.O. Box 50224 Clayton, MO 63105
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