Uncovering a Milder Wolfram Syndrome Variant in Jewish Populations (Part 3)

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For context, Parts 1 and 2 of this series can be found here:

Part 1: https://wolframsyndrome.wustl.edu/uncovering-a-milder-wolfram-syndrome-variant-in-jewish-populations-part-1/

Part 2: https://wolframsyndrome.wustl.edu/uncovering-a-milder-wolfram-syndrome-variant-in-jewish-populations-part-2/

In Parts 1 and 2, I discussed our discovery of a milder form of Wolfram syndrome prevalent in Jewish populations, particularly among individuals of Ashkenazi descent. This variation is linked to a specific WFS1 gene variant: WFS1 c.1672C>T (p.Arg558Cys). Based on our research, the carrier frequency of this variant is approximately 2.5%, meaning that 1 in 40 Ashkenazi Jewish individuals are carriers. You can find further details in our study here: https://insight.jci.org/articles/view/156549/figure/1

While some may question this high frequency, our findings are consistent with data from other reputable genetic studies, including those conducted by the Broad Institute’s gnomAD project: https://gnomad.broadinstitute.org/variant/4-6301467-C-T?dataset=gnomad_r4

The Broad Institute, affiliated with MIT and Harvard, is recognized as one of the leading medical research institutions worldwide, further validating our conclusions.

Identifying Patients with This Variant

A key question is how to identify individuals affected by this variant. While the process is not straightforward, there are hints—particularly in their diabetes presentation. These individuals often exhibit signs of atypical diabetes. Let me explain what this means.

Diabetes typically falls into two major categories:

  • Type 1 Diabetes: An autoimmune condition leading to rapid insulin dependence.
  • Type 2 Diabetes: A metabolic condition, often linked to obesity and lifestyle factors, with a slower progression to insulin dependence.
    More on diabetes types

Patients with the Ashkenazi Jewish variant of Wolfram syndrome develop diabetes in a manner distinct from these categories. Here are the key characteristics:

  • Slow progression: Blood glucose levels rise gradually over time.
  • Leanness: These individuals tend to be lean, unlike many with type 2 diabetes.
  • Negative for type 1 markers: They do not test positive for autoimmune markers associated with type 1 diabetes.
  • Prediabetes stage: They may remain prediabetic for an extended period.
  • No typical risk factors: They lack common risk factors for type 2 diabetes, such as obesity, sedentary lifestyle, or dyslipidemia.
  • Atypical progression: Despite the absence of these risk factors, their glucose levels steadily increase.

In addition to atypical diabetes, another hallmark of this variant is vision problems, often emerging during late high school or early college years. These vision issues, not correctable with glasses, are another clue. However, it is important to note that not all patients with this variant exhibit these symptoms.

Screening and Future Directions

To effectively identify these patients, a dedicated screening program is essential. I have a comprehensive plan to develop such a program and am hopeful about implementing it in the coming years. This will not only improve diagnosis but also pave the way for therapeutic developments targeting the Ashkenazi Jewish variant of Wolfram syndrome.

I will share more about these plans and our progress in therapeutic development in my next blog. Thank you for your continued interest and attention.

Fumihiko (Fumi) URANO, MD, PhD

Samuel E. Schechter Professor of Medicine

Director, Wolfram Syndrome and Related Disorders Clinic and Research

Washington University Medical Center