WFS1 Wolfram Syndrome Spectrum Disorder
Lisbeth Tranebjærg, Timothy Barrett, Nanna Dahl Rendtorff
Abstract
Clinical characteristics WFS1 Wolfram syndrome spectrum disorder (WFS1-WSSD) is a progressive neurodegenerative disorder characterized by onset of diabetes mellitus (DM) and optic atrophy (OA) before age 16 years, and typically associated with other endocrine abnormalities, sensorineural hearing loss, and progressive neurologic abnormalities (cerebellar ataxia, peripheral neuropathy, dementia, psychiatric illness, and urinary tract atony). Although DM is mostly insulin-dependent, overall the course is milder (with lower prevalence of microvascular disease) than that seen in isolated DM. OA typically results in significantly reduced visual acuity in the first decade. Sensorineural hearing impairment ranges from congenital deafness to milder, sometimes progressive, hearing impairment. Diagnosis / testing The diagnosis of WFS1-WSSD is established in a proband with suggestive findings and biallelic pathogenic variants in WFS1 by molecular genetic testing. Management Treatment of manifestations: Recommendations (based on detailed clinical guidelines for Wolfram syndrome) include routine management by multidisciplinary specialists for the following: insulin-dependent DM; OA; hearing impairment; mobility and activities of daily living; dysarthria; dysphagia; endocrine disorders; developmental delay/intellectual disability; neurogenic bladder; and psychiatric/behavioral issues. Surveillance: Routine follow up evaluations to assess effectiveness of ongoing care and to identify new disease manifestations. Genetic counseling WFS1-WSSD is inherited in an autosomal recessive manner. If each parent is known to be heterozygous for a WFS1 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of being unaffected and not a carrier. Once the WFS1 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.