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High Prevalence of a Monogenic Cause in Han Chinese Diagnosed With Type 1 Diabetes, Partly Driven by Nonsyndromic Recessive WFS1 Mutations

Publication: American Diabetes Association | Publication Date: January 2020

Authors: Meihang Li, Sihua Wang, Kuanfeng Xu, Yang Chen, Qi Fu, Yong Gu, Yun Shi, Mei Zhang, Min Sun, Heng Chen, Xiuqun Han, Yangxi Li, Zhoukai Tang, Lejing Cai, Zhiqiang Li, Yongyong Shi, Tao Yang and Constantin Polychronakos

Abstract

It is estimated that ∼1% of European ancestry patients clinically diagnosed with type 1 diabetes (T1D) actually have monogenic forms of the disease. Because of the much lower incidence of true T1D in East Asians, we hypothesized that the percentage would be much higher. Read more

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Clinical and genetic analysis of two wolfram syndrome families with high occurrence of wolfram syndrome and diabetes type II: a case report

Publication: BMC Medical Genetics | Publication Date: January 14, 2020

Authors: Maryam Sobhani, Mohammad Amin Tabatabaiefar, Soudeh Ghafouri-Fard, Asadollah Rajab, Asal Hojjat, Abdol-Mohammad Kajbafzadeh & Mohammad Reza Noori-Daloii

Abstract

Conclusions: The mutational and phenotypic spectrum of WS is broadened by our report of novel WFS1 mutation. Our results reveal the value of molecular analysis of WFS1 in the improvement of clinical diagnostics for WS. Read more

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The Laboratory of Molecular & Cellular Signaling and its mission in Wolfram Syndrome research

The Laboratory of Molecular & Cellular Signaling (LMCS; https://gbiomed.kuleuven.be/english/research/50000618/50753344), co-directed by Prof. Jan B. Parys & Prof. Geert Bultynck, is part of the Department of Cellular and Molecular Medicine at KU Leuven. The research team studies intracellular Ca2+ signals and Ca2+-controlled processes such as cell death and cellular bio-energetics in human cells. Furthermore, the team aspires to elucidate how these Ca2+ signals contribute to human health and to disease when such signals are disturbed. Hence, by targeting the function of intracellular Ca2+-transport system, we hope to develop novel strategies to tackle such disease states or reduce disease burden. The lab has focused on diseases associated with suppressed Ca2+ signaling, such as cancer, as well as with excessive Ca2+ signaling, such as acute pancreatitis. For its research activities, the lab collaborates with several teams at KU Leuven, in Belgium and around the globe. To foster research collaboration among its partners and to serve as a Ca2+-signaling hub for other researchers, the lab has established a research community “Ca2+ signaling in health, disease & therapy” supported by the Research Foundation – Flanders (CaSign; www.casign.org).

Very recently and thanks to a recently established research alliance with Dr. Kaasik (Tartu University, Estonia) supported by CELSA (Central Europe Leuven Strategic Alliance), LMCS has included Wolfram Syndrome within its strategic ambitions for future research programs. The team aims to develop novel strategies to tackle Wolfram syndrome by targeting the Ca2+-signaling machinery and restoring Ca2+ homeostasis in cells. In cell systems that serve as a model for Wolfram Syndrome, the team will explore the role of anti-apoptotic Bcl-2 proteins in Ca2+-signaling dysregulation, since these proteins are key modulators of intracellular Ca2+-release channels perturbed in Wolfram Syndrome Type 1 and Type 2. Next, the team will exploit recently obtained insights in the interplay between Bcl-2-protein function and Ca2+ signaling to develop novel strategies to fight Ca2+-driven disease outcomes in Wolfram syndrome. In the (long-term) future with the help of several local partners at KU Leuven & its international network of collaborators (to whom we are very grateful), LMCS strives to translate their findings towards patient-derived cell models, such as fibroblasts and neuronal, eye, brain cell types differentiated from stem cells and to develop strategies to apply such tools in the eye or the brain. The team hopes to develop these research endeavors with the critical support from national funding agencies but also from foundations such as Eye Hope and SNOW Foundation.

Who is who in Wolfram research @ LMCS, KU Leuven

Geert Bultynck is a Professor & Principle Investigator at the Laboratory of Molecular & Cellular Signaling, Department of Cellular & Molecular Medicine, KU Leuven. His research focuses on exploring & exploiting intra- and intercellular Ca2+ signaling in health, disease & therapy. He teaches Cell Physiology and Human Physiology. He will direct & supervise the research on Wolfram syndrome. When Geert is not doing research/teaching, you can find him on the badminton pitch, the stands of his favorite soccer team, at the hobbies of his 2 children or travelling with his wife & children.

Tim Vervliet is a postdoctoral researcher at the Laboratory of Molecular & Cellular Signaling. Tim is supported by a fellowship from the Research Foundation – Flanders (FWO). His research focuses on the role of ryanodine receptor Ca2+ channels in cell function & disease, including neurodegenerative diseases. He teaches a work session on Ion Channels. He will perform research on Wolfram syndrome, but also supervise and train new students arriving in the lab. When Tim is not doing research, he is renovating his house, taking care of the vegetable garden or going out with his friends.

Rita La Rovere is a part-time technical expert at the Laboratory of Molecular & Cellular Signaling and helps out several PhD students & postdocs with their projects. Rita will provide technical support to the research on Wolfram syndrome. When Rita is not in the lab, you can find her most of the time at home, focusing on her daughters’ activities and the family needs. She also likes Italian cooking and spends time outside with her family.

Jens Loncke currently is a last year student in the Master of Biochemistry & Biotechnology. Jens will join the Laboratory of Molecular & Cellular Signaling in September 2019 for a 4-years PhD project aiming to study Ca2+ signaling and Bcl-2-protein function in Wolfram syndrome. We are grateful and excited that the Eye Hope Foundation recently decided to support Jens’ PhD project (1 year PhD salary). Further support for Jens and his project is sought from external sources, including the SNOW Foundation. When Jens is not studying/doing research, he enjoys listening to music at concerts or playing music himself. As an outdoors person, he enjoys hiking and practicing sports in open air.

Marth Briers currently is 3rd year Bachelor student in the Master of Pharmaceutical Sciences. Marth will join the Laboratory of Molecular & Cellular Signaling during the summer of 2019. To support her stay in the lab, she applied for a student internship grant from the Biochemical Society – UK. Marth will work on the biochemical link between CISD2 and Bcl-2 in Ca2+-signaling control. When Mart is not studying, you can find her on the tennis court, on the playground as a scouts guide or enjoying a drink with friends.

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Amarantus Bioscience

MANF Therapeutics is developing mesencephalic astrocyte-derived neurotrophic factor (MANF) as a therapeutic protein for the treatment of certain protein-misfolding and neurological disorders. MANF is currently in pre-clinical development as a disease modifying treatment for Parkinson’s disease and Wolfram’s Syndrome. In Wolfram’s, many of the key disease etiologies, including vision loss, hearing loss, diabetes and neurodegeneration have protein misfolding as a key molecular signature that MANF could potentially address. The lead application for MANF in Wolfram’s is for the treatment of vision loss. MANF has demonstrated safety and efficacy in animals for the treatment of retinal degeneration, including the increased protection and function of rods, cones and retinal ganglion cells in the retina. Leading scientists in the Wolfram’s community believe MANF could be the first disease-modifying treatment developed for the disease. MANF Therapeutics is in the process of raising capital to support preparations for clinical trials, and thereafter the initiation of human clinical trials in Wolfram’s Syndrome and Parkinson’s. Once the capital is raised, it will take approximately 12-18 months to start clinical development.

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Washington University 2019 Wolfram Research Clinic Update

Washington-University-School-of-MedicineWASHINGTON UNIVERSITY’S

2019 WOLFRAM RESEARCH CLINIC UPDATE

Wait no more – the 2019 WU Wolfram Research Clinic planning is underway! We’re sure many of you have lots of questions and hopefully some of them will be answered here. If not, you can always contact Samantha directly. Her contact information is below.

Due to the number of participants enrolled in the clinic and an effort to make the clinic days more manageable, we will be dividing the clinic into two sessions. The official dates for the clinic are as follows:

Group 1
 Arrival: Tuesday, 7/9/19

Clinic: Wednesday, 7/10/19 – Friday, 7/12/19

Group 2
 Arrival: Sunday, 7/14/19

Clinic: Monday, 7/15/19 – Wednesday, 7/17/19

Scientific Session (TBD) Saturday, 7/13/19

Family Dinner TBD

We are still working out the details of the Scientific Session and the Family Dinner(s) and we will share that information with you as soon as it is finalized. Until then, these are the clinic dates. It is important at this time that you let Samantha know if you have a preference to attend as part of Group 1 or Group 2. Please keep in mind that another person or family cannot communicate your preference for you. Samantha must hear from you directly as to which session you’d like to attend. If you do not have a preference, that works too. You will then be assigned to a group once all preferences are in. The deadline for reserving your slot in a particular group is Jan. 31, 2019. That being said, it is important to get your preference in as soon as possible as we are trying to split the groups evenly which means that your preferred group could reach capacity prior to you stating your preference.

 

Need Help? For questions or requests regarding the Wolfram Syndrome Research Clinic please contact the WFS Research Clinic Coord., Samantha Ranck, MSW at 314.362.6514 or rancks@npg.wustl.edu

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Neuropsychiatric features of Wolfram Syndrome and other genetic disorders

As discussed in a previous newsletter, we have learned

that anxiety and depression symptoms are fairly common

in people with Wolfram Syndrome. These symptoms are

also very common in people without Wolfram Syndrome,

and may be influenced by genes, life stress, and other

factors.

In preliminary examination of our data, I have also noticed

some trends indicating that psychiatric symptoms and

certain types of neurological signs/symptoms might be

related.  I plan to further analyze the data to confirm

whether this is true. I would also like to take a closer look

at the brain imaging findings to investigate whether

specific difference in brain structure or function may be

related to specific psychiatric and/or neurological

symptoms.

I also hope to do some investigation comparing the types

of symptoms seen in Wolfram Syndrome to those

reported in other genetic disorders that affect the

functioning of ryanodine receptor calcium channels

(RYRs), which release calcium from the endoplasmic

reticulum (ER) within cells. In Wolfram Syndrome, too

much calcium is released through these channels. Studying

disorders with similar disease mechanisms could help us

understand what produces the symptoms of both

Wolfram Syndrome and other related other disorders. It is

possible that diseases with similar mechanisms may

respond to similar types of treatment.

By Angela M. Reiersen, MD, MPE

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RESEARCH UPDATE-Tamara Hershey, PhD

 Washington-University-Wolfram-Study-groupWashington-University-School-of-MedicineWashington University School of Medicine

Dear Wolfram Community:

I am very pleased to announce that we have received

notification from the NIH that our Wolfram natural

history study has been OFFICIALLY FUNDED! This means

that we can start having our Wolfram Research Clinics

again, probably starting next summer and continuing for

5 more years! Samantha, Dr. Marshall and I will begin

planning for the research clinic and will keep you all informed as things move along.

We are excited to continue working with Dr. Bess

Marshall as our caring and dedicated Medical Director!

We will also continue to collaborate with Dr. Fumi Urano

by collecting samples for his lab and coordinating with

the Dantrolene trial. In addition, Dr. Tim Barrett in

Birmingham, UK will share MRIs from his clinical trial, so

that we can learn about individual differences in

neurological progression. Finally, Dr. Gordon Xu, at Mt

Sinai in New York, is helping us measure the optic nerve

with MRI. We are excited to work with all of the

incredible scientists and clinicians on our team.

Thank you for your support and patience during this

time of being in limbo. Please know that we never

stopped caring and we never stopped working on

understanding Wolfram syndrome and its effect on the

brain and its functions. We have high hopes that the

information we gain from this study will have a positive

and lasting impact on all people affected by Wolfram

syndrome! Please call me or Samantha with any questions

about the research clinic.

Sincerely,

Tamara Hershey, PhD

Professor

Scientific Director and Principal Investigator

WU Wolfram Research Clinic

tammy@wustl.edu; 314-362-5593

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Update from the Institute of Neurosciences, Montpellier

Our team’s goal is to discover, test and develop treatments in order to prevent or limit visual impairment and to improve the autonomy and the quality of life of patients. Our efforts focus on a very severe form of syndromic Inherited Optic Neuropathy: Wolfram Syndrome (WS). WS is characterized by a rapid degeneration of retinal ganglion cells (RGC) resulting to severe visual impairment before the age of 20 years. To date, there is no treatment to stop the progression of the disease.

The analysis of biological samples from patients with the recessive WS revealed that the WFS1 protein is absent, or less stable, compared to the normal protein. This reduced quantity of WFS1 suggests that the re- expression of WFS1 through gene augmentation therapy could restore the protein function and thus possibly protect the cells from degeneration.

It is important to say that the eye is a perfect model for applying gene therapy approach. It is small, transparent, allowing for very precise visual monitoring. It is also a closed organ, relatively isolated from the rest of the body. RGC are easily accessed by the ocular surgeon who targets them through intravitreal injection, a current routine procedure used to inject medications in various retinal pathologies. In this regard, gene complementation for Wolfram patients is an ideal therapeutic approach to treat visual impairment. Consequently, micro-injection of a vector expressing the human WFS1 cDNA, directly in the vitreous close to the retinal ganglion cell layer should allow to prevent RGC dysfunction and degeneration.

We have studied mice models of WS. Our results indicate that mice reproduced the optic atrophy of WS patients with loss of visual acuity starting at 1 month. We designed a therapeutic vector expressing human WFS1 that we microinjected into the vitreous of Wfs1 mutant mice. We showed that the animals injected with the therapeutic vector have a stabilization of their visual acuity between 3 and 6 months post-injection, a decrease of optic disc pallor and axonal damages. A parallel approach is applied on wild type animals using the same vector in order to assess the innocuousness of the treatment and the transgene expression and distribution. These promising results lead us to continue these therapeutic approach.

Our project consists in demonstrating the validity of the pre-clinical approach to treat Wolfram Syndrome by gene therapy. Obtaining this proof of concept will allow to transfer the protocol to patients assess the therapeutic benefits in the short and medium.

Dr. Cécile Delettre, PhD
cecile.delettre@inserm.fr
http://www.inmfrance.com/inm/en/

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Clinical Care Update

 Washington-University-Wolfram-Study-group Washington-University-School-of-MedicineWashington University School of Medicine

Clinical Care Update- Bess Marshall, MD

Dear Wolfram families,

As you now have heard from Samantha, I have determined that the Wolfram Research Clinic that was tentatively All of the Wolfram team is sad that we will not be able to see all of you in July. Please know that you are still a very high priority and that this bump will not derail the work at Washington University. We will not allow that to happen! You likely all saw the update from Dr. Barrett in the UK that his intervention trial is not yet underway as they also work through issues, but that it is making progress. Dr. Urano’s dantrolene study is moving along and he will be updating you on those results soon.
The Association du Syndrome de Wolfram meeting is coming up in June and Drs. Hershey and Urano and I will be going to hear updates from the other groups working on the syndrome alongside us, so we will update you in the next newsletter.

Some of the information you all have contributed by participating in the TRACK study was used to develop a paper led by Dr. Barrett’s group: Monogenic diabetes syndromes: Locus-specific databases for Alstrom, Wolfram, and Thiamine-responsive megaloblastic anemia. Human Mutation. 38(7):764-777, 2017 Jul.

This paper analyzes the specific gene changes in 309 people with WFS1 gene alterations in order to determine which changes are likely to cause a particular presentation in a person – for example, some genetic changes cause full-blown Wolfram Syndrome, which others cause diabetes mellitus without other features, others cause hearing loss without other features, etc. This will be very helpful information for patients at the time of diagnosis, getting their genetic testing results and wondering what to expect for their health.

As always, please get in touch if you need assistance with your health or with letters to insurance, etc.

All the best,

Bess Marshall, MD
Pediatric Endocrinologist
Medical Director, WU Wolfram Syndrome Research Clinic
Washington University School of Medicine
Email: Marshall@kids.wustl.edu

Need Help? For questions or requests regarding the Wolfram Syndrome Research Clinic please contact the WFS Research Clinic Coord., Samantha Ranck, MSW at 314.362.6514 or rancks@npg.wustl.edu 

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Washington University Research Clinic Update

 Washington-University-Wolfram-Study-group Washington-University-School-of-MedicineWashington University School of Medicine

Wolfram Research Clinic Update- Tamara Hershey, PhD

Dear Research Clinic Families,

As you now have heard from Samantha, I have determined that the Wolfram Research Clinic that was tentatively scheduled for July 2018 will not be able to happen. This was a very difficult decision, but ultimately, we felt it was the most ethical choice. Due to delays in NIH’s funding decision and its impact on our ability to prepare, we just could not provide the kind of experience you deserve and that the research demands. We felt that having a clinic under those circumstances would be a disservice to us all. Please know that we care deeply about you and this research and will start planning with enthusiasm once we get our funding notification. I’m assured by NIH that it will come soon, but there are many bureaucratic hurdles that they have to overcome due to their backlog. While we are very disappointed that the clinic will not happen as we had originally imagined for 2018, we already have several ideas of what we could do to make future clinics even better, such as Tasha’s work on the questionnaires, holding mini clinics throughout the year, and adding some testing of siblings without Wolfram Syndrome. We also continue to work towards analyzing and publishing the data that have already been collected, thus providing other researchers and clinicians with important information. We appreciate your understanding and apologize for the uncertainty that the funding situation has caused. We will keep you informed of any new information. Please feel free to contact me personally with any questions.

Sincerely,

Tamara Hershey, PhD
Professor, Psychiatry & Radiology Departments
Lab Chief, Neuroimaging Labs (NIL) @ MIR
Co-Director, Neuroscience PhD Program, DBBS
Washington University School of Medicine
Email: tammy@wustl.edu

Need Help? For questions or requests regarding the Wolfram Syndrome Research Clinic please contact the WFS Research Clinic Coord., Samantha Ranck, MSW at 314.362.6514 or rancks@npg.wustl.edu 

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