Wolfram Syndrome

Overview

Wolfram syndrome is a rare genetic condition which affects several systems at the same time thus producing a classic set of symptoms. It is characterized by the occurrence of diabetes insipidus, juvenile-onset diabetes mellitus, optic atrophy (damage of optic nerve) and deafness along with neurological complications, hence known by its acronym DIDMOAD. No effective treatment is available to manage the cause of this condition and many patients die young most often from respiratory failure.

Cause

Wolfram syndrome results from mutations in the genes that encode production of endoplasmic reticulum (ER) which is a component of our body cells. ER performs several functions which include calcium storage, protein synthesis, cell signaling, normal cell death and few others as well. Endoplasmic reticulum is especially active in the pancreas where its abnormality leads to diabetes mellitus.

Signs and Symptoms

Important clinical features of Wolfram syndrome are following:

  • Diabetes Mellitus: High blood glucose level occurs. Important symptoms include frequent urination, thirst, hunger and weight loss, dryness and itching of the skin, and slow wound healing.
  • Diabetes Insipidus: Symptoms such as intense and frequent thirst, dehydration, dry skin and mouth, white tongue and large volume of urination which is often dilute.
  • Ocular Defects: Abnormally low vision and blindness occur due to degeneration of the optic nerve which is the primary connection between the eyes and brain. It’s equally possible that it can occur from diabetic retinopathy, a complication of diabetes mellitus that damage the retina.
  • Hearing Loss: Hearing function is lost, probably due to defective nerves that transfer the signals from ear to brain.
  • Infection: Chances of infection are high due to abnormal amount and function of the neutrophils, a component of blood that fights off bacteria and other microbes in the early stage of infection.
  • Widening of the Ureters: Ureters are structures that carry urine from kidneys to the bladder. Dilation of the ureters occur due to the excessive urine production and can damage the kidneys because of back-flow pressure.
  • Generalized Weakness: Malaise and fatigue is often present in this syndrome.
  • Heat Intolerance: Patients cannot tolerate high environmental temperature which is validated by extreme sweating and dehydration.
  • Neurological Symptoms: Loss of balance and coordination, seizures, diminished intellectual and cognitive function, and loss of smell sensation due to defective nerve function has been reported.
  • Psychiatric Symptoms: Depression, aggressive behavior and psychosis has been observed.

Diagnosis

Most often, Wolfram syndrome is not diagnosed. It is usually considered as juvenile-onset diabetes mellitus and treated for that. However, genetic screening should be performed whenever additional signs and symptoms are observed. Molecular genetic tests are available to check for mutations in the WFS1 and WFS2 genes.

Wolfram Syndrome Treatment

No effective treatment is available to cure the cause of Wolfram syndrome since it’s a genetic condition and will be present life-long. However, supportive and symptomatic treatment can reduce some of the complications of this condition.

  1. Insulin therapy to control diabetes mellitus and its associated complications.
  2. Vasopressin and other similar drugs to treat diabetes insipidus to conserve essential fluids.
  3. Hearing Aids and Cochlear Implants for patients with hearing loss.
  4. Spectacles for correcting low vision.

Other associated problems such as constipation, diarrhea, heat intolerance and difficulty in swallowing should be addressed as well. Regular evaluation is recommended for all bodily systems that are affected in this syndrome, particularly to assess renal function.

Genetic counseling is advised for patients who plan to have children.

New research is looking into the use of a drug called dantrolene which can reduce β-cell death in pancreas which produces insulin, and also prevent neurodegeneration.

Sources

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4705145/

https://ghr.nlm.nih.gov/condition/wolfram-syndrome

https://rarediseases.info.nih.gov/diseases/7898/wolfram-syndrome

https://www.omim.org/entry/222300