Wolfram Syndrome Frequently Asked Questions

What is Diabetes Insipidus?

Diabetes insipidus is one of the common symptoms in patients with Wolfram syndrome. It is defined as the passage of large volumes of dilute urine. It has the two major forms, and patients with Wolfram have the central diabetes insipidus.

  1. Central (neurogenic, pituitary, or neurohypophyseal): characterized by decreased secretion of antidiuretic hormone called vasopressin.
  2. Nephrogenic: characterized by decreased ability to concentrate urine because of resistance to vasopressin action in the kidney.

What is the link between Wolfram syndrome and type 1 diabetes?

Both Wolfram syndrome and type 1 diabetes are characterized by juvenile-onset diabetes. We need to note that some patients with Wolfram syndrome and type 1 diabetes develop diabetes in adulthood. Both in Wolfram syndrome and type 1 diabetes, beta cells in the pancreas that produce insulin are destroyed. In type 1 diabetes, the etiology of beta cell death is autoimmunity. What is autoimmunity?

Our immune system protects us from invading organisms that can cause illness. In healthy states, our immune system does not attack our own cells. In type 1 diabetes, our immune system attacks our own pancreatic beta cells and destroys them. I call this “unintentional suicide.” What we don’t know is how autoimmunity is induced. Accumulating evidence suggest that endoplasmic reticulum dysfunction creates “neoantigen” in our beta cells, leading to autoimmunity. Neoantigen means abnormal cell products that can be mistakenly recognized as invading organisms.

Because the root cause of Wolfram syndrome is endoplasmic reticulum dysfunction, it is possible that a novel drug or an intervention for Wolfram syndrome can be beneficial for patients with type 1 diabetes. This is still a theory.

Diabetes and Optic Atrophy

I often get the following question, “Is there any relationship between diabetes and optic nerve atrophy?” This question implies a few different things. So here is my answer.

1. Type 1 Diabetes

I believe that there is no direct relationship between type 1 diabetes and optic atrophy. Type 1 diabetes is an autoimmune disease. Our immune cells attack antigens highly expressed in pancreatic β cells in type 1 diabetes. These autoimmune cells usually do not attack optic nerve although patients with type 1 diabetes are susceptible to other autoimmune diseases. As I mentioned in my previous blog, patients with type 1 diabetes may develop retinopathy if there blood sugar levels are not properly controlled.

2. Wolfram syndrome

In Wolfram syndrome, there is probably a direct relationship between diabetes and optic nerve atrophy. Both pancreatic β cells and optic nerve are susceptible to endoplasmic reticulum dysfunction. So β cell death and death of retinal ganglion cells have the same etiology, i.e. ER dysfunction.

3. Do all patients with Wolfram syndrome have diabetes and optic nerve atrophy?

The answer is, “No.” In most cases, diabetes is the first manifestation of Wolfram syndrome, followed by optic atrophy. However, there are some patients who develop optic atrophy first and don’t develop diabetes for a long period of time. I know one patient with Wolfram whose diabetes was diagnosed at 40 years old. I don’t know why, but it seems like these patients tend to have milder symptoms. I am very interested in carefully studying these patients because I may be able to find a way to delay the progression of Wolfram through these patients. This effort is underway.