Selective cognitive and psychiatric manifestations in Wolfram Syndrome

Allison N. Bischoff, Angela M. Reiersen, Anna Buttlaire, Amal Al-Lozi, Tasha Doty, Bess A. Marshall, Tamara Hershey, P. Austin, G. Earhart, S. Eisenstein, J. Hoekel, L. Tychsen, T. Hullar, R. Karzon, L. Manwaring, A. R. Paciorkowski, Y. Pepino De Gruev, K. Pickett, J. Shimony, A. ViehoeverN. H. White, F. Urano, S. Ranck, B. Beato, E. Bihun, J. M. Koller, H. M. Lugar, J. Rutlin, K. Semenkovich

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32 Scopus citations


Background: Wolfram Syndrome (WFS) is known to involve diabetes mellitus, diabetes insipidus, optic nerve atrophy, vision loss, hearing impairment, motor abnormalities, and neurodegeneration, but has been less clearly linked to cognitive, sleep, and psychiatric abnormalities. We sought to determine whether these abnormalities are present in children, adolescents, and young adults with WFS compared to age- and gender-matched individuals with and without type 1 diabetes using standardized measures. Methods: Individuals with genetically-confirmed WFS (n = 19, ages 7-27) were compared to age- and gender- equivalent groups of individuals with type 1 diabetes (T1DM; n = 25), and non-diabetic healthy controls (HC: n = 25). Cognitive performance across multiple domains (verbal intelligence, spatial reasoning, memory, attention, smell identification) was assessed using standardized tests. Standardized self- and parent-report questionnaires on psychiatric symptoms and sleep disturbances were acquired from all groups and an unstructured psychiatric interview was performed within only the WFS group. Results: The three groups were similar demographically (age, gender, ethnicity, parental IQ). WFS and T1DM had similar duration of diabetes but T1DM had higher HbA1C levels than WFS and as expected both groups had higher levels than HC. The WFS group was impaired on smell identification and reported sleep quality, but was not impaired in any other cognitive or self-reported psychiatric domain. In fact, the WFS group performed better than the other two groups on selected memory and attention tasks. However, based upon a clinical evaluation of only WFS patients, we found that psychiatric and behavioral problems were present and consisted primarily of anxiety and hypersomnolence. Conclusions: This study found that cognitive performance and psychological health were relatively preserved WFS patients, while smell and sleep abnormalities manifested in many of the WFS patients. These findings contradict past case and retrospective reports indicating significant cognitive and psychiatric impairment in WFS. While many of these patients were diagnosed with anxiety and hypersomnolence, self-reported measures of psychiatric symptoms indicated that the symptoms were not of grave concern to the patients. It may be that cognitive and psychiatric issues become more prominent later in life and/or in later stages of the disease, but this requires standardized assessment and larger samples to determine. In the relatively early stages of WFS, smell and sleep-related symptoms may be useful biomarkers of disease and should be monitored longitudinally to determine if they are good markers of progression as well.

Original languageEnglish
Article number66
JournalOrphanet Journal of Rare Diseases
Issue number1
StatePublished - May 30 2015


  • Behavior
  • Cognition
  • Development
  • Diabetes mellitus
  • Psychiatry
  • Wolfram syndrome


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