Tracking Neurodegeneration in Early Wolfram Syndrome

Specific Aims: Wolfram syndrome (WFS) is a rare (1 in ~770,000) autosomal recessive genetic
disease characterized by early childhood onset insulin dependent diabetes, optic nerve
atrophy, vision and hearing loss, diabetes insipidus and neurodegeneration, resulting in
death in middle adulthood, typically due to brainstem atrophy-induced respiratory failure 3.
There are no interventions to slow or stop this devastating deterioration. However, much is
known about the mechanisms underlying these effects. The causative gene (WFS1) was identified
by the investigators group in 19984, and a number of loss-of-function mutations have been
described 4-6. Cell 7 and animal models 8 have determined that WFS1 encodes an endoplasmic
reticulum (ER) membrane-embedded protein called wolframin 9, and that mutant forms of the
WSF1 protein lead to disturbances of ER calcium homeostasis, driving ER stress-mediated
apoptosis 10-12. This process kills insulin producing pancreatic β-cells, leading to
diabetes. WFS1 is also expressed throughout the brain, and cell death via ER stress is
thought to underlie neurodegeneration in WFS 6,13, as well as being implicated in more common
neurodegenerative and endocrine (Type 1 and Type 2 diabetes) diseases 14. Work in animal
models of WFS is progressing rapidly towards the identification of viable interventions for
the ER stress related cell death12. Some neurological features of the disease may be feasible
to target and monitor in clinical trials, due to the fact that diabetes is already present
when a patient is diagnosed with WFS. Unfortunately, there is limited information on the
pattern of brain changes associated with WFS. Although clinical retrospective data suggest
that neurological features occur late (15-30 yrs of age; Fig 10) in the disease process15,16,
direct measurements (Preliminary Data) suggest that certain neurological abnormalities are
present at the earliest time point assessed, suggesting altered neurodevelopment, whereas
others follow a more neurodegenerative pattern. These distinctions are fundamentally new
insights into this disease and may shape treatment, biomarker selection and the investigators
understanding of the impact of ER stress on the developing brain. A better understanding of
the neurodegenerative and neurodevelopmental changes in early WFS is a necessary first step
towards being ready for future clinical trials. Thus, the primary goal of this proposal is to
determine the pattern of brain alterations in WFS over time. Only by understanding the
natural history of brain functional and structural changes in WFS will the investigator be
prepared to evaluate any benefits of novel treatments. The investigator will perform
cross-sectional and longitudinal assessments of youth with WFS, targeting sensitive neural
systems with quantified neuroimaging and relevant behavioral measures. In addition, the
investigator will validate a new WFS severity rating scale (WFS Unified Rating Scale or
WURS), which will have utility in future multi-site or treatment studies. Preliminary data
support the feasibility of this approach and its potential to generate important new
information about neurologic patterns in WFS. A better understanding of the trajectory of ER
stress-mediated brain changes in WFS may be relevant to other more common diseases. Specific
aims follow:

1. To determine the pattern of neurologic impairment in WFS and its association with
disease severity in a cross-sectional sample. The investigator hypothesizes that
specific brain measures will be altered earlier and will associate more closely with
overall disease severity than others in WFS. The investigator proposes that regional
white matter microstructural integrity in the cerebellum, optic nerve area, brain stem
volume, balance and possibly anxiety will distinguish individuals with early WFS from
controls and will correlate with severity on a standardized rating scale. To test this
hypothesis, the investigator will perform quantified neuroimaging, cognitive, motor,
psychiatric, visual and auditory evaluations on individuals with WFS, preferentially
recruiting those earlier in the disease process, (n=30; age 5 and older, within 10 years
of diabetes onset) and on matched healthy controls (n=30) and controls with Type 1
Diabetes Mellitus (T1DM; n=30).

2. To determine the longitudinal pattern of neurologic deterioration in WFS. The
investigator hypothesize that measures specified in Aim 1 will show detectable change,
and that the most sensitive measures will show change in the early Wolfram patients
compared to control groups. To test this hypothesis, WFS, T1DM and control participants
will be re-assessed annually for 3 years. Variables of interest identified in
cross-sectional analyses will be targeted and compared between groups and correlated
with change in disease severity as measured with the investigators standardized rating
scale.

3. To explore brain structure-function relationships within WFS. To determine if
neuroimaging measures identified in Aims 1 and 2 have functional correlates, the
investigator will explore how differences (cross-sectional data) or change (longitudinal
data) in neuroimaging variables correlate with differences or change in selected
functional measures. Such data would help build hypotheses about the neural
underpinnings of functional changes in WFS. For example, the investigator speculates
that the integrity of the brainstem and cerebellum will be related to gait and balance
and that optic nerve area will be related to visual acuity.

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 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.

T1DM Group:

Inclusion criteria:

- Age within the 0-28 yrs age range of WS participant

- Dx of T1 diabetes mellitus

Exclusion criteria:

- Participant is unaware of their diagnosis.

- Inability of patient or guardian to understand informed consent.

- Diagnosis of any major neurological or medical condition.

- Chronic disease other than T1DM, well-controlled asthma, or Hashimoto's thyroiditis.

- Other current serious medical illness

- Co-morbid psychiatric illness: such as mania, mental retardation, or psychoactive drug
dependence.

- Co-morbid neurological illness: stroke, seizure, major loss of consciousness, other
brain trauma/surgery, or head injuries (i.e. near drowning), encephalitis, or
hydrocephalus, blindness, deafness.

- Pre-maturity at birth >4 wks early (<36 wk term) w/ sequelae (e.g. on respirator at
NICU)

- Contraindication to MRI scan (e.g. claustrophobia, metal implants, foreign bodies)

- Orthodontic braces. Full and top braces will exclude.

Healthy Control (HC) Group:

Inclusion criteria:

• Age within the 0-28 yrs age range of WFFS participants

Exclusion criteria:

- Inability of patient or guardian to understand informed consent.

- Dx of T1 diabetes mellitus

- Diagnosis of any major neurological or medical condition.

- Chronic disease other than well-controlled asthma, or Hashimoto's thyroiditis.

- Other current serious medical illness

- Co-morbid psychiatric illness: such as mania, mental retardation, or psychoactive drug
dependence.

- Co-morbid neurological illness: stroke, seizure, major loss of consciousness, other
brain trauma/surgery, or head injuries (i.e. near drowning), encephalitis, or
hydrocephalus, blindness, deafness

- Pre-maturity at birth >4 wks early (<36 wk term) w/ sequelae (e.g. on respirator at
NICU)

- Contraindication to MRI scan (e.g. claustrophobia, metal implants, foreign bodies)

- Orthodontic braces. Full and top braces will exclude. Bottom braces are ok (but the
scan might not work out). Retainers are ok.

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).