What is Diabetes Mellitus?

Diabetes Mellitus is typically the first symptom of Wolfram syndrome, usually diagnosed around age 6. Nearly everyone with Wolfram syndrome who develops diabetes mellitus requires insulin replacement therapy. Diabetes mellitus prevents your body from properly using the energy from the food you eat. Diabetes occurs in one of the following situations:

  • The pancreas (an organ behind your stomach) produces little insulin or no insulin at all. Insulin is a naturally occurring hormone, produced by the beta cells of the pancreas, which helps the body use sugar for energy.

-Or-

  • The pancreas makes insulin, but the insulin made does not work as it should. This condition is called insulin resistance.
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Wolfram Facts

DID YOU KNOW?

A diagnosis of Wolfram syndrome is based on the presence of characteristic signs and symptoms. The identification of a change (mutation) in the WFS1 gene or CISD2 gene confirms the diagnosis.[2][8]

The following are the most important features that help with the diagnosis:[2]

  •  Juvenile-onset (age <16 years) diabetes mellitus
  •  Juvenile-onset optic atrophy (age <16 years)
  • Autosomal recessive inheritance
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Wolfram Syndrome Prognosis

The long-term outlook (prognosis) for people with Wolfram syndrome varies depending on the signs and symptoms present in each person. All the features that give Wolfram syndrome the acronym DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness) are observed in 65% of people, while others only have some of the associated health problems. Most affected people develop diabetes mellitus and optic atrophy before age 15 years. Hearing loss is present in 64% of affected people by age 20 years and up to 72% will eventually develop diabetes insipidus. Wolfram syndrome may also be associated with a variety of other symptoms that can affect almost every part of the body.[7][2]

Wolfram syndrome is often fatal by mid-adulthood (average lifespan 30 years).

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RESEARCH UPDATE – Tamara Hershey, PhD

Washington University School of Medicine

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

Dear Wolfram Community, 

Since the last newsletter, we have been very busy, both looking backwards to data from previous research clinics and looking forward to our 2019 research clinic. 

Looking backwards, we submitted two papers for review based on previous research clinic data. One paper is on sleep disturbances in Wolfram syndrome, where we show that there is a high rate of sleep apnea based on the sleep monitoring we did during the 2015 and 2016 clinics. The second paper is based on our longitudinal neuroimaging data, and suggests that Wolfram syndrome affects the development of specific regions and tissue types in the brain, and ultimately degenerates others. From these data, we recommend the best measures for tracking neurodegeneration over time in clinical trials. We hope that these findings will help with clinical trial planning, with the development of more brain-targeted interventions, and will inspire other groups to investigate specific hypotheses about the mechanisms underlying these changes. 

Looking forward, planning for next summer’s research clinic is underway! Samantha has been reserving rooms, Heather has reserved the MRI scanner and collaborators are blocking off their calendars. We our also testing our new MRI sequences to better measure changes in the optic nerve and in white matter across the brain. 

Finally, the Snow Foundation is leading an effort, with which we are helping with, to obtain grant funding from the NIH to support a research and clinical symposium for families during the clinic. Stay tuned for details! Time will pass quickly, and before we know it, we will be greeting some of you in summery St. Louis! 

Sincerely, 

Tamara Hershey, PhD 

Professor
Scientific Director and Principal Investigator WU Wolfram Research Clinic tammy@wustl.edu

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Wolfram Syndrome and Genes

DID YOU KNOW?

Wolfram syndrome is inherited in an autosomal recessive manner.[1] This means that to be affected, a person must have a mutation in both copies of the responsible gene in each cell. The parents of an affected person usually each carry one mutated copy of the gene and are referred to as carriers. Carriers typically do not show signs or symptoms of the condition. When two carriers of an autosomal recessive condition have children, each child has a 25% (1 in 4) risk to have the condition, a 50% (1 in 2) risk to be a carrier like each of the parents, and a 25% chance to not have the condition and not be a carrier.

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Birmingham England, Clinic Dates

WolframSyndromeSupportUKAdult Wolfram clinics are run from the Centre for Rare Diseases in the Heritage Building at The Queen Elizabeth Hospital, Birmingham and are taking place on the following days:

January 18th

March 29th

May 24th

July 19th

September 27th

November 29th

All dates are currently provisional

For more information please contact either Andrea Mitchell , or Tracy at WSUK.  

 

The dates for the Children’s Clinics run from Waterfall House, the Rare Disease Centre at Birmingham Children’s Hospital are:

7th & 8th January

4th & 5th March

3rd & 4th June

7th & 8th October

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Types of Wolfram syndrome

DID YOU KNOW?

The two types of Wolfram syndrome (type 1 and type 2) are primarily differentiated by their genetic cause.  Variations (mutations) in the WFS1 gene are responsible for about 90% of Wolfram syndrome type 1 cases. This gene encodes wolframin, a protein that is important for the proper functioning of the endoplasmic reticulum (the part of a cell that is involved in protein production, processing, and transport). Wolframin helps regulate the amount of calcium in cells, which is important for many different cellular functions. Mutations in WFS1 result in a defective form of wolframin that is unable to perform its normal role. This causes cells to trigger their own death (apoptosis). The death of cells in various organs and other parts of the body results in the signs and symptoms of Wolfram syndrome type 1.[1]

A specific mutation in the CISD2 gene causes Wolfram syndrome type 2. Although the exact function of this gene is not known, scientists suspect that it plays an important role in the mitochondria (the part of the cell where energy is produced). Mutations in CISD2 lead to the loss of mitochondria which decreases the amount of energy available to cells. Cells that do not have enough energy die. As in Wolfram syndrome type 1, the death of cells in different parts of the body results in the many health problems associated with Wolfram syndrome type 2.[1]

 

Donate today!

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Wolfram Association-Georgia

Matsatso Khachapuridze from Georgia is the founder of a non-governmental organization called “Wolfram Syndrome – Georgia”. “Wolfram Syndrome – Georgia” was founded on November 29th, 2017. Matsatso decided to establish this organization because she has Wolfram Syndrome (WS). In Georgia, WS is not on the list of rare genetic diseases and there is no statistical data for this disease. The only data that is available is in the “Diabetic Child Protection Association”, where there are 20 people with WS (official data).

Matsatso met with the chairman of the Committee on Health and Social Issues of the Parliament of Georgia. She was asked why she needed WS to be on the list of rare genetic diseases since people with WS already receive free medication for diabetes insipidus, diabetes mellitus, and desmopressin. She explained to the chairman that there are other things that are desperately needed for these patients due to the many manifestations of this disease. For example, hearing devices.

There are no medical institutions or special programs in Georgia where patients with WS could get a consultation to discuss all the aspects and issues of WS. Wolfram Syndrome-Georgia is hoping to change this. For more information please contact;

Wolfram Syndrome-Georgia

wolframgeorgia@gmail.com

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The Snow Foundation to Start a Patient Registry

The-Snow-Foundation-to-Start-Patient-RegistryTSF is leading the charge to find a cure for Wolfram Syndrome. A major step in this fight is to assemble an international patient registry that will help with the funding and drug development process. TSF’s patient registry will be used prospectively to quickly identify patients eligible for a clinical trial, or retrospectively to analyze the effectiveness of an intervention. A foundation patient registry will also help patients receive more accurate advice and improve care pathways, which can lead to improved care and life expectancy, even in the absence of a cure.

This registry may also serve as a way for patients and families to connect with each other, as emotional support is an important part of the healing and treatment process.  TSF will be contacting families shortly.

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Eye Problems in Wolfram Syndrome

Professor Patrick Yu-Wai-ManProfessor Patrick Yu-Wai-Man

Affiliations

  1. John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge
  2. MRC Mitochondrial Biology Unit, University of Cambridge
  3. Cambridge Eye Unit, Addenbrooke’s Hospital, Cambridge University Hospitals
  4. Moorfields Eye Hospital and UCL Institute of Ophthalmology, London

I am an eye doctor (ophthalmologist) with a particular interest in genetic eye diseases. I look after patients with Wolfram syndrome in my specialist clinic and I also lead a research group that is investigating ways of slowing or preventing loss of vision in patients affected with this relatively rare genetic disorder.

How is visual information sent from the eye to the brain?

visual info to brain

The eye is a very sensitive camera that converts an image from the outside world into an electrical signal. At the back of the eye is the optic nerve, which is similar to a high-speed “broadband cable” that allows this electrical signal to be sent quickly to the vision centres at the back of the brain to be decoded. The figure above illustrates how visual information gets from the eye to the brain via the connecting optic nerve.

What is optic atrophy?

The majority of patients with Wolfram syndrome will develop optic atrophy. Optic atrophy means that the optic nerve has been damaged and it looks pale in colour when the eye doctor looks at the back of the eye with the appropriate equipment. Because the optic nerve is damaged, less visual information is sent from the eye to the brain, and this also happens more slowly with transmission errors. As a result, patients with Wolfram syndrome start to struggle with their central vision and they find it increasingly difficult to read small print and make out people’s faces (as in the example shown below). Visual difficulties usually start in childhood and they tend to get progressively worse with time.

optic atrophy

What other eye problems can you get in Wolfram syndrome?

  1. Diabetes is very common in Wolfram syndrome, but fortunately diabetic eye complications tend to be rare. Nevertheless, patients with Wolfram syndrome need to take particular care that their blood sugar levels are well controlled to avoid further diabetic eye complications in addition to optic atrophy.
  2. A small group of patients with Wolfram syndrome can develop cataracts at a young age. If the eye doctor spots that a cataract is present and vision is getting worse because of it, the option of cataract surgery can be discussed.

What treatments can we offer at the moment?

  1. Unfortunately, there is currently no proven treatment to stop the damage to the optic nerve and loss of vision. There is a lot of research being carried out at the moment to look for drugs that can protect the optic nerve. Gene therapy is also being considered, but this strategy is still an early stage of development and so far, studies have only been carried out in mice.
  2. As there are no effective treatments yet for the optic atrophy in Wolfram syndrome, visual rehabilitation is very important and children, especially, must be provided with the right level of support at school.

How frequently should an eye check-up be carried out?

All patients with Wolfram syndrome should ideally have an annual check-up. Drops will usually be put in the eyes to dilate the pupils and make it easier to have a careful look at the back of the eye for any changes since the patient’s last visit.

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