Brain stem atrophy is a prominent feature that often results in death secondary to central apnea. Polysomnography, as well as overnight oximetry test, can be used as screening studies. Central apnea should be managed by a pulmonologist. Some patients may require tracheostomy.
Wolfram syndrome is characterized by progressive neurodegeneration. The most common problem is ataxia. Cerebellar ataxia should be assessed yearly or twice a year by neurologists. Dysarthria and swallowing disorders (dysphagia) are commonly seen. Swallowing treatment by a speech-language pathologist is beneficial for patients to prevent aspiration pneumonia. Surgical procedures, including esophageal dilation and esophagomyotomy, have been shown to be effective in some patients. Oral hygiene and dental care are important because dysphagia may lead to the impaired clearance of organisms and pathogenic colonization.
Sensorineural hearing loss is one of the common symptoms of Wolfram syndrome and observed in around 70 % of patients. The hearing loss affects the high frequencies first and progresses relatively slowly. Routine audiometry is recommended every year or every 2 years. Auditory brainstem response (ABR) audiometry should be performed at diagnosis to confirm the pathophysiology and examine the efficacy of any treatments. Management includes hearing aids and cochlear implant. Hearing manifestations in Wolfram syndrome should be carefully examined because dominant mutations in the WFS1 gene are a
common cause of low-frequency sensorineural hearing loss, which is different from Wolfram syndrome. These patients develop low-frequency sensorineural hearing loss but do not develop other symptoms seen in patients with Wolfram syndrome, such as diabetes mellitus and ataxia.
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.
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.
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.
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.
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
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).
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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