Abstract
BackgroundWolfram 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.MethodsStandardized 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.ResultsForty 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.ConclusionsMost 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.
Highlights
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)
Accurate identification of the type and severity of SNHL in patients with WFS requires periodic audiologic assessment with a standardized test battery administered by qualified personnel from the onset of WFS diagnosis
SNHL is prevalent in WFS and preliminary results suggest that in addition to routine audiologic measures, the unaided Speech Intelligibility Index (SII) may be a useful measure for determining amplification candidacy
Summary
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). 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. The most frequently cited clinical manifestations include diabetes mellitus (DM), optic nerve atrophy (OA), diabetes insipidus (DI), sensorineural hearing loss (SNHL), neurological symptoms, renal tract abnormalities, psychiatric disorders and gonadal disorders [4, 5]. Review of 392 analyzable patient records from 49 references indicated that the first WFS symptoms identified were as follows: DM, 79.50%; SNHL, 6.35%; OA, 17.08%; neurological, psychiatric developmental defects, 8.96%; and DI 2.70%, urological or renal defects, 5.26% [8]
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