Wolfram Syndrome Symptoms

How do the Symptoms of Wolfram Syndrome Develop?

The symptoms of WS are caused by dysfunctional wolframin protein. In WS the endoplasmic reticulum (ER), a protein maker and powerhouse for the cell, is not able to do its job well because it lacks functional wolframin protein. Wolframin helps fold other proteins properly and maintain proper calcium levels in the ER. Without properly functioning wolframin, misfolded proteins accumulate, calcium leaks into the body of the cell, and ultimately the cell dies. The cells most affected in WS are insulin producing beta cells and neurons.

Of great interest in WS is the realization that there appear to be 3 levels at which cells are affected. At level 1 cells are still functional. At level 2 cells are dormant and thus still alive, though not functioning properly. At level 3 cells have gone through apoptosis and have died. The cells existing at level 2 have the potential to be revived and thus function restored and protected in patients with Wolfram syndrome.

In normal cells, pathways that involve wolframin protein are activated to rescue the cell when ER stress occurs. In Wolfram syndrome wolframin is unable to help rescue the cell, and apoptosis (cell death) ultimately occurs.

Normal Ocular Cells

Mitochondria provide energy and are abundant in cells that require large amounts of energy to function. The protein produced from the CISD2 gene is found in the outer membrane of the mitochondria to help mitochondria function normally.

Mutated Ocular Cells

Mutated WFS1 alters regulation of calcium balance in cells. Because one effect is altered folding proinsulin, diabetes occurs in these patients. Due to altered ER calcium homoeostasis in retinal ganglion cells connected to the optic nerve, progressive optic atrophy ensues. There are a variety of systemic features including hearing loss, diabetes insipidus, anemia, seizures, ataxia and even respiratory failure secondary to brain stem atrophy.

Endocrine System

Insulin Shortage, Diabetes Melitus

The hallmark features of the disease are high blood sugar levels resulting from a shortage of the hormone insulin, which resembles diabetes mellitus. Diabetes mellitus is typically the first symptom of WS, usually it is diagnosed at age 6. Nearly everyone who has WS and has developed diabetes mellitus has to undergo insulin replacement therapy.

Most of those affected with WS develop insulin-dependent diabetes mellitus before the age of 16, (about 87% of patients do). The Carbohydrates that humans consume are normally processed by the digestive system into glucose that later circulates into the blood as an energy source for bodily functions. A hormone produced by the Pancreas, (insulin), allows muscle and fat cells to take up glucose. In diabetes mellitus, the pancreas doesn’t produce enough insulin which results in the cells not being able to take up enough glucose and the patients blood sugar gets too high. As a result, the patient will need daily injections of insulin to control the blood sugar. Further symptoms of diabetes mellitus include frequent urination, excessive thirst, increased appetite, weight loss, and blurred vision.

Pituitary Gland Dysfunction (Diabetes Insipidus) and Reduced Testosterone:

42% of WS patients develop Diabetes Insipidus. Diabetes Insipidus doesn’t have much in common with Diabetes except for symptoms of excessive thirst and urination. This causes excretion of large quantities of watery urine. Patients tend to drink a lot of water to compensate. Other symptoms of Diabetes Insipidus include dehydration, weakness, dry mouth, and if water levels are not replaced, constipation.

In Diabetes Insipidus, the pituitary gland doesn’t function normally. This abnormality disrupts the release of vasopressin hormone which regulates the body’s water balance and urine production. Pituitary gland dysfunction can also cause hypogonadism in males which causes a lack of testosterone that leads to growth and sexual development abnormalities. People with WS type 2 do not develop diabetes insipidus.

Ulcers & Bleeding:

Individuals with WS type 2 may develop stomach or intestinal ulcers and excessive bleeding after an injury. These two tendencies combined typically lead to abnormal bleeding in the gastrointestinal bleeding.

Urogenital System:

Sixty to 90 percent of people with Wolfram syndrome have a urinary tract problem. Urinary tract problems in the ureters, which includes obstruction of the ducts between the Kidneys and Bladder, a large bladder that cannot empty normally due to abnormal nerve function (high-capacity atonal bladder), disrupted urination (bladder sphincter dyssynergia), and difficulty controlling the flow of urine (incontinence).

Urinary tract abnormalities are in 33% of patients, this is most often a problem with the bladder not emptying properly, so that the person needs to empty often. This symptom may be confused or complicated by diabetes insipidus, so both need to be checked if a person with Wolfram syndrome is having frequent urination.

Central Nervous System

Hearing Loss

Hearing loss in WS patients is caused by changes within the inner ear that cause sensorineural hearing loss (SNHL). Most WS patients will have slow progressive sensorineural hearing loss (SNHL) emerging in late childhood at a mean age of 8.3 years.

About 65 percent of WS patients have sensorineural deafness that can range in severity from deafness beginning at birth to mild hearing loss beginning in adolescence that worsens over time.

Overall hearing loss occurs in 48% of patients. The symptoms can occur at any time, and they can either be partial or complete. The hearing loss is due to loss of sound perception transmitted by sensorineural nerves. Symptoms include: loss of sound intensity or pitch, or loss of the ability to hear high tones.

Balance & Coordination Problems

About 60% of WS patients develop neurological or psychiatric disorders, most commonly problems with balance and coordination (also known as ataxia), typically beginning in early adulthood.

Imagining of the brain reveals that people with WS have smaller brainstem and cerebellum volumes which leads to differences in balance and coordination. These symptoms will increase over time.

Deficits within the inner ear, specifically vestibular deficits, cause balance and eye movement problems.

Irregular Breathing

Imagining of the brain reveals that people with WS have smaller brainstem and cerebellum volumes which affects breathing patterns as well.

Irregular breathing is caused by the brain’s inability to control breathing (which is also known as central apnea). Central apnea occurs because your brain doesn’t send proper signals to your muscles to control breathing.

Loss of Sense of Smell

Due to differences of patients brainstem and cerebellum volumes, a common symptom is the loss of sense of smell.

Balance, Irregular Breathing, Loss of Sense of Smell, Loss of Gag Reflex, and More

About 60% of WS patients develop a neurological or psychiatric disorder, most commonly problems with balance and coordination (Ataxia), irregular breathing caused by the brain’s inability to control breathing (central apnea), loss of sense of smell, loss of gag reflex, muscle spasms (myoclonus), seizures, intellectual impairments, and reduced sensation in lower extremities (peripheral neuropathy).

Muscles Spasms & Seizures

Differences in the nervous system and neural tissue cause both of these symptoms.
This can be associated with myoclonus, which are quick, involuntary muscle jerks.

Behavior Problems & Depression

Psychiatric disorders associated with WS include psychosis, episodes of severe depression, and impulsive and aggressive behavior. 26% of patients experience these symptoms. These symptoms are related to changes in the nervous system from WS itself or to the psychological and quality of life burden caused by the effects of the disease.

Vision Loss

Almost all of those affected with WS,(about 80% of patients), have primary optic atrophy (OA) and subsequent vision impairment before the age of 16. The optic nerve conducts visual information to the brain for processing. Loss of the nerve fibers (demyelination) results in color blindness and reduced vision beginning in childhood and progressing with age. The severity of progression depends on the patient.

Optic Atrophy appears around 11 years of age. The first signs of OA are loss of color vision and peripheral vision. Overtime, vision problems get worse, and people with OA are usually blind within approximately 8 years after signs of OA first begin.

Greater sleep disturbances

Wolfram patients have higher rates of OSA (Obstructive Sleep Apnea) in clinical studies.

Early Brain Vulnerability

Smaller intracranial volume with specific abnormalities in brainstem, cerebellum, and optic regions at earliest stage of clinical symptoms.

Lowered Participation in Daily Activities

Social and exercise related activities are most problematic.