Psychiatric Diagnoses and Medications in Wolfram Syndrome.

Background: Wolfram Syndrome is a rare genetic disorder usually resulting from pathogenic variation in the WFS1 gene, which leads to an exaggerated endoplasmic reticulum (ER) stress response. The disorder is typically characterized by diabetes insipidus, diabetes mellitus, optic nerve atrophy, hearing loss, and neurodegenerative features. Existing literature suggests it may also have psychiatric manifestations. Objective: To examine lifetime psychiatric diagnoses and medication history in Wolfram Syndrome. Method: Child, adolescent, and young adult Wolfram Syndrome participants (n=39) were assessed by a child & adolescent psychiatrist to determine best estimate DSM-5 lifetime psychiatric diagnoses as well as psychoactive medication history. In addition, the Child & Adolescent Symptom Inventory-5 (CASI-5) Parent Checklist was used to determine likely psychiatric diagnoses based on symptom counts in Wolfram Syndrome patients (n=33), type 1 diabetes (n=15), and healthy comparison (n=18) groups. Results: Study participants with Wolfram Syndrome had high lifetime rates of anxiety disorders (77%). Also, 31% had an obsessive-compulsive spectrum disorder, 33% had a mood disorder, 31% had a neurodevelopmental or disruptive behavior disorder, and 31% had a sleep-wake disorder. More than half of Wolfram Syndrome participants had taken at least one psychoactive medication, and one third had taken at least one selective serotonin reuptake inhibitor (SSRI). Some individuals reported poor response to sertraline but better response after switching to another SSRI (fluoxetine or citalopram). In general, people with Wolfram Syndrome often reported benefit from psychotherapy and/or commonly used psychoactive medications appropriate for their psychiatric diagnoses. Conclusions: Wolfram Syndrome may be associated with elevated risk for anxiety and obsessive-compulsive spectrum disorders, which seem generally responsive to usual treatments for these disorders.

Taste and smell function in Wolfram syndrome.

BACKGROUND: Wolfram syndrome is a rare genetic disease characterized by insulin-dependent diabetes, optic nerve atrophy, sensorineural hearing loss and neurodegeneration. Although olfactory dysfunction, a classical clinical marker of neurodegenerative processes, has been reported in Wolfram syndrome, its use as a clinical marker in Wolfram is limited due to data scarcity. In addition, it is unknown whether Wolfram syndrome affects the sense of taste. METHODS: Smell and taste perception were assessed in participants with Wolfram syndrome (n = 40) who were 15.1 ± 6.0 years of age (range: 5.1-28.7 years) and two sex- and age-matched control groups: one group with type 1 diabetes mellitus (T1D; n = 25) and a healthy control group (HC; n = 29). Smell sensitivity was assessed by measuring n-butanol detection thresholds and smell identification by using the University of Pennsylvania Smell Identification Test (UPSIT). Taste function was assessed using NIH Toolbox, which includes the assessment of sucrose (sweet) taste preference, and perceived intensity of sucrose, sodium chloride (salty), and quinine hydrochloride (bitter) both in the tip of the tongue (regional test) and the whole mouth. RESULTS: Smell sensitivity was not significantly different among groups; however, smell identification was impaired in Wolfram syndrome, as reflected by significantly lower UPSIT scores in Wolfram syndrome compared to HC and T1D (P < 0.001). Compared to participants in the control groups, participants with Wolfram syndrome had a blunted perception of sweetness and saltiness when taste stimuli were applied regionally (P < 0.05), but differences in perceived intensity were no longer significant among groups when taste stimuli were tasted with the whole mouth. Groups preferred similar sucrose concentrations. CONCLUSION: Wolfram syndrome was associated with olfactory dysfunction. However, the olfactory dysfunction was qualitative (related to smell identification) and not secondary to olfactory insensitivity or diabetes, suggesting is arising from dysfunction in central olfactory brain regions. In contrast to olfaction, and despite decreased perception of taste intensity in the anterior tongue, the sense of taste was overall well-conserved in individuals with Wolfram syndrome. Future longitudinal studies of taste and smell perception in Wolfram syndrome will be important to determine the use of the chemical senses as clinical markers of disease progression.

Evidence for altered neurodevelopment and neurodegeneration in Wolfram syndrome using longitudinal morphometry.

Wolfram syndrome is a rare disease caused by mutations in the WFS1 gene leading to symptoms in early to mid-childhood. Brain structural abnormalities are present even in young children, but it is not known when these abnormalities arise. Such information is critical in determining optimal outcome measures for clinical trials and in understanding the aberrant neurobiological processes in Wolfram syndrome. Using voxel-wise and regional longitudinal analyses, we compared brain volumes in Wolfram patients (n = 29; ages 5-25 at baseline; mean follow-up = 3.6 years), to age and sex-equivalent controls (n = 52; ages 6-26 at baseline; mean follow-up = 2.0 years). Between groups, white and gray matter volumes were affected differentially during development. Controls had uniformly increasing volume in white matter, whereas the Wolfram group had stable (optic radiations) or decreasing (brainstem, ventral pons) white matter volumes. In gray matter, controls had stable (thalamus, cerebellar cortex) or decreasing volumes (cortex), whereas the Wolfram group had decreased volume in thalamus and cerebellar cortex. These patterns suggest that there may be early, stalled white matter development in Wolfram syndrome, with additional degenerative processes in both white and gray matter. Ideally, animal models could be used to identify the underlying mechanisms and develop specific interventions.

Longitudinal hearing loss in Wolfram syndrome.

BACKGROUND: Wolfram syndrome (WFS) is a rare autosomal recessive disease with clinical manifestations of diabetes mellitus (DM), diabetes insipidus (DI), optic nerve atrophy (OA) and sensorineural hearing loss (SNHL). Although SNHL is a key symptom of WFS, there is limited information on its natural history using standardized measures. Such information is important for clinical care and determining its use as an outcome measure in clinical trials. METHODS: Standardized audiologic measures, including pure-tone testing, tympanometry, speech perception, and the unaided Speech Intelligibility Index (SII) were assessed in patients with confirmed WFS annually. Mixed model analyses were used to examine main effects of age, time or interactions for pure tone average (PTA), high frequency average (HFA) and SII. RESULTS: Forty WFS patients were evaluated between 1 and 6 times. Mean age at initial enrollment was 13.5 years (SD = 5.6). Patients were classified as having normal hearing (n = 10), mild-to-severe (n = 24) or profound SNHL (n = 6). Mean age of diagnosis for SNHL was 8.3 years (SD = 5.1) with 75% prevalence. HFA worsened over time for both ears, and SII worsened over time in the worse ear, with greater decline in both measures in younger patients. Average estimated change over 1 year for all measures was in the subclinical range and power analyses suggest that 100 patients would be needed per group (treatment vs. placebo) to detect a 60% reduction in annual change of HFA over 3 years. If trials focused on just those patients with SNHL, power estimates suggest 55 patients per group would be sufficient. CONCLUSIONS: Most patients had a slow progressive SNHL emerging in late childhood. Change over time with standard audiologic tests (HFA, SII) was small and would not be detectable for at least 2 years in an individual. Relatively large sample sizes would be necessary to detect significant impact on hearing progression in a clinical trial. Hearing function should be monitored clinically in WFS to provide appropriate intervention. Because SNHL can occur very early in WFS, audiologists and otolaryngologists should be aware of and refer for later emerging symptoms.

Visual pathway function and structure in Wolfram syndrome: patient age, variation and progression.

BACKGROUND/AIMS: To report alterations in visual acuity and visual pathway structure over an interval of 1-3 years in a cohort of children, adolescents and young adults who have Wolfram syndrome (WFS) and to describe the range of disease severity evident in patients with WFS whose ages differed by as much as 20 years at first examination. METHODS: Annual, prospective ophthalmological examinations were performed in conjunction with retinal nerve fibre layer (RNFL) analysis. Diffusion tensor MRI-derived fractional anisotropy was used to assess the microstructural integrity of the optic radiations (OR FA). RESULTS: Mean age of the 23 patients with WFS in the study was 13.8 years (range 5-25 years). Mean log minimum angle resolution visual acuity was 0.66 (20/91). RNFL thickness was subnormal in even the youngest patients with WFS. Average RNFL thickness in patients with WFS was 57±8 µ or ~40% thinner than that measured in normal (94±10 µ) children and adolescents (P<0.01). Lower OR FA correlated with worse visual acuity (P=0.006). Subsequent examinations showed declines (P<0.05) in visual acuity, RNFL thickness and OR FA at follow-up intervals of 12-36 months. However, a wide range of disease severity was evident across ages: some of the youngest patients at their first examination had deficits more severe than the oldest patients. CONCLUSION: The genetic mutation of WFS causes damage to both pregeniculate and postgeniculate regions of the visual pathway. The damage is progressive. The decline in visual pathway structure is accompanied by declines of visual function. Disease severity differs widely in individual patients and cannot be predicted from their age.