In this new grant, researchers hypothesize that ER stress-related dysfunction could inhibit production of myelin during neurodevelopment in WFS, as active and developing oligodendrocytes (cells that produce myelin in the brain) are more vulnerable to ER stress than mature ones. However, standard DTI methods conflate inflammatory processes (which can also be associated with ER stress) in the extra-axonal space with metrics of axonal and myelin integrity, leading to potentially confounded measurements. The research team proposea to collect novel, validated diffusion sequences on a new state of the art MRI scanner (Siemens Prisma) and apply cutting-edge analysis approaches to measure white matter integrity throughout the brain and in the optic nerve, improving the ability to draw conclusions about axonal and myelin integrity over time. Researchers will assess WFS patients annually at our WU Wolfram Research Clinic using these methods.

Findings from this work may indicate future targets for brain-specific intervention, identify outcome measures or high-risk subgroups for clinical trials targeting neurological symptoms. These data will also greatly expand our understanding of the cross-sectional and longitudinal phenotype of WFS1-mutation related disorders, rather than classically defined Wolfram Syndrome. Such knowledge will have a significant impact on patients and families by allowing physicians to provide more accurate prognoses. Finally, forms of ER stress-mediated apoptosis have been implicated in more common neurodegenerative, endocrine and neurodevelopmental diseases, which may benefit from the insights gained here.

• Wolfram Syndrome Patients
  Participant has confirmation of a WFS1 mutation OR Both of the following conditions: diabetes mellitus requiring insulin and optic nerve atrophy diagnosed by a physician. Both conditions diabetes mellitus and optic nerve atrophy had to be diagnosed at age younger than 18 years old
• Proxy Group
  Adult Biological parent(s), biological caregiver or non-biological caregiver of adult and minor participants in the any of the groups.

Wolfram Syndrome Group (WFS):

Inclusion Criteria:

• Participant has confirmation of a WFS1 mutation OR

• Both of the following conditions:

  • diabetes mellitus requiring insulin and
  • optic nerve atrophy diagnosed by a physician.
• Both conditions diabetes mellitus and optic nerve atrophy had to be diagnosed at age an younger than 18 years old

Exclusion Criteria:

• Participant is unaware of their diagnosis.
• Inability of patient or guardian to understand informed consent.
• Advanced disease that makes traveling too problematic and/or uncomfortable for the patient and/or guardian, such as use of ventilator or inability to walk.

Proxy Group: Adult Biological parent(s), biological caregiver or non-biological caregiver of adult and minor participants in the any of the four groups.

Inclusion criteria:

• Biological or non-biological parent/caregiver (proxy) of a participant.

Exclusion Criteria:

• Proxy is unaware of the participant's diagnosis (as it applies).