Dataset Information

Wolfram Syndrome 1: From Genetics to Therapy.

ABSTRACT: Wolfram syndrome 1 (WS1) is a rare neurodegenerative disease transmitted in an autosomal recessive mode. It is characterized by diabetes insipidus (DI), diabetes mellitus (DM), optic atrophy (OA), and sensorineural hearing loss (D) (DIDMOAD). The clinical picture may be complicated by other symptoms, such as urinary tract, endocrinological, psychiatric, and neurological abnormalities. WS1 is caused by mutations in the WFS1 gene located on chromosome 4p16 that encodes a transmembrane protein named wolframin. Many studies have shown that wolframin regulates some mechanisms of ER calcium homeostasis and therefore plays a role in cellular apoptosis. More than 200 mutations are responsible for WS1. However, abnormal phenotypes of WS with or without DM, inherited in an autosomal dominant mode and associated with one or more WFS1 mutations, have been found. Furthermore, recessive Wolfram-like disease without DM has been described. The prognosis of WS1 is poor, and the death occurs prematurely. Although there are no therapies that can slow or stop WS1, a careful clinical monitoring can help patients during the rapid progression of the disease, thus improving their quality of life. In this review, we describe natural history and etiology of WS1 and suggest criteria for a most pertinent approach to the diagnosis and clinical follow up. We also describe the hallmarks of new therapies for WS1.

SUBMITTER: Rigoli L

PROVIDER: S-EPMC8949990 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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Wolfram Syndrome 1: From Genetics to Therapy.

Rigoli Luciana L Caruso Valerio V Salzano Giuseppina G Lombardo Fortunato F

International journal of environmental research and public health 20220309 6

Wolfram syndrome 1 (WS1) is a rare neurodegenerative disease transmitted in an autosomal recessive mode. It is characterized by diabetes insipidus (DI), diabetes mellitus (DM), optic atrophy (OA), and sensorineural hearing loss (D) (DIDMOAD). The clinical picture may be complicated by other symptoms, such as urinary tract, endocrinological, psychiatric, and neurological abnormalities. WS1 is caused by mutations in the <i>WFS1</i> gene located on chromosome 4p16 that encodes a transmembrane prote ...[more]

PMID: 35328914

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Project description: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.

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Wolfram Syndrome 1: From Genetics to Therapy.

Publications

Wolfram Syndrome 1: From Genetics to Therapy.

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