WS and Urological Manifestations

Structural and functional urinary tract abnormalities are commonly seen in patients with Wolfram syndrome and significantly affect quality of life. Yearly assessment of renal function, measurement of postvoid residual urine volume by ultrasound, a renal ultrasound, and urodynamic testing are recommended. A large atonic bladder, a low-capacity, high-pressure bladder with sphincteric dyssynergia, and hydroureteronephrosis are common manifestations. Both bladder dysfunction and upper urinary tract dilatation are primary manifestations although these symptoms may be partially affected by diabetes mellitus and diabetes insipidus. The treatment options for bladder dysfunction include anticholinergic drugs and clean intermittent catheterization. Electrical stimulation and physiotherapy have been effective in some patients.

Recurrent urinary tract infection (UTI) is one of the most common clinical challenges in patients with Wolfram syndrome. The bladder dysfunction caused by the central and peripheral neurologic dysfunction is thought to be the underlying cause of UTI. Urine culture is recommended for Wolfram patients with fever or other symptoms, such as headache. Inflammatory conditions associated with UTI may cause headache and other symptoms.

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WS and Neurological Disorders

About 60 percent of people with Wolfram syndrome develop a neurological or psychiatric disorder, most commonly problems with balance and coordination (ataxia), typically beginning in early adulthood. Other neurological problems experienced by people with Wolfram syndrome include irregular breathing caused by the brain’s inability to control breathing (central apnea), loss of the sense of smell, loss of the gag reflex, muscle spasms (myoclonus), seizures, reduced sensation in the lower extremities (peripheral neuropathy), and intellectual impairment. Psychiatric disorders associated with Wolfram syndrome include psychosis, episodes of severe depression, and impulsive and aggressive behavior.

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Wolfram Syndrome and Diabetes Insipidus

In diabetes insipidus, the pituitary gland, which is located at the base of the brain, does not function normally. This abnormality disrupts the release of a hormone called vasopressin, which helps control the body’s water balance and urine production. Approximately 70 percent of people with Wolfram syndrome have diabetes insipidus.

 

 

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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]

 

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