Wolfram Syndrome: Diagnosis, Management, and Treatment

 Wolfram Syndrome: Diagnosis, Management, and Treatment

 

Wolfram syndrome is an autosomal recessive genetic dis-order characterized by juvenile-onset diabetes mellitus,diabetes insipidus, optic nerve atrophy, hearing loss, andneurodegeneration. It was first reported in 1938 by Wol-fram and Wagener who found four of eight siblings withjuvenile diabetes mellitus and optic nerve atrophy [1].Wolfram syndrome is considered a rare disease and esti-mated to afflict about 1 in 160,000–770,000 [2, 3]. In1995, Barrett, Bundey, and Macleod described detailedclinical features of 45 patients with Wolfram syndromeand determined the best available diagnostic criteria forthe disease [3]. According to the draft International Clas-sification of Diseases (ICD-11), Wolfram Syndrome iscategorized as a rare specified diabetes mellitus (subcate-gory 5A16.1, Wolfram Syndrome). The prognosis of thissyndrome is currently poor as most patients die prema-turely with severe neurological disabilities such as bulbardysfunction and organic brain syndrome, with the medianage at death being 30 years (range, 25–49 years), usuallyfrom respiratory failure as a result of brain stem atrophy[3, 4]. Although there are currently no effective treatmentsthat can delay, halt, or reverse the progression of Wolframsyndrome, the use of careful clinical monitoring and sup-portive care can relieve the debilitating symptoms. In thisarticle, we provide recommendations for diagnosis andclinical management and introduce potential new treat-ments for Wolfram syndrome.

Diagnosis of Wolfram 

SyndromeClinical 

DiagnosisIt is important for physicians to provide an accurate andprompt diagnosis of Wolfram syndrome, which allows us toprovide patients with support and education and initiate ap-propriate interventions. Suspicion of the diagnosis of Wolframsyndrome is usually based on history and clinical manifesta-tions. Most commonly, the observation of optic nerve atrophyafter the diagnosis of diabetes mellitus under the age of 16triggers the suspicion. Increasing evidence indicates that Wol-fram syndrome is a spectrum disorder. Diabetes insipidus,sensorineural deafness, neurological signs including ataxia,autonomic neuropathy, and epilepsy, and neurogenic bladderin combination with diabetes mellitus or optic nerve atrophycould be a sign of Wolfram syndrome. The differential diag-noses include mitochondrial disorders, mutant WFS1 gene-induced deafness, autosomal dominant optic nerve atrophy,Friedreich ataxia, Bardet–Biedl syndrome, and Alstr msyndrome.

Power of Wolfram SyndromeIncreasing

 evidence indicates that ER stress and ER dys-function play important roles in the pathogenesis of com-mon diseases, such as type 1 and type 2 diabetes, as wellas multiple neurodegenerative diseases [46]. Its monogen-ic etiology makes Wolfram syndrome more amenable torevealing the mechanisms of ER stress-mediated celldeath than other common conditions in which multiplefactors typically interact to produce the disease manifes-tations. Thus, Wolfram syndrome represents an ideal mod-el to shed new light on the underlying causes ofβcelldeath in diabetes, neurodegeneration, and retinal celldeathmediatedbyERdysfunction.We believe in the strong power of Wolfram syndrometo understand the pathogenesis and develop novel thera-peutic modalities for more prevalent diseases. Our studyon Wolfram may lead to a breakthrough for treatments ofnot only Wolfram syndrome but also common diseases,such as type 1 diabetes, type 2 diabetes, and neurodegen-eration, in which ER dysfunction is involved

Wolfram syndrome affects different organs and systems inthe body. Thus, multidisciplinary care by physicians andhealthcare professionals from a range of disciplines is re-quired. Based on our experience, a strong patient-doctorpartnership can facilitate the communication betweenphysicians in different specialties. Patient organizationshave played an important role to encourage physiciansfrom different specialties, clinics, hospitals, and evencountries to work together. The strong partnershipbetween physicians, researchers, and patient organizationsis also important to conduct successful clinical trials

References

Papers of particular interest, published recently, have beenhighlighted as:•Of importance••Of major importance1.  Wolfram DJ, Wagener HP. Diabetes mellitus and simple optic atro-phy among siblings: report of four cases. Mayo Clin Proc. 1938;1:715–8.2.  Kinsley BT, Swift M, Dumont RH, et al. Morbidity and mortality inthe Wolfram syndrome. Diabetes Care. 1995;18(12):1566–70.3.  Barrett TG, Bundey SE, Macleod AF. Neurodegeneration and dia-betes: UK nationwide study of Wolfram (DIDMOAD) syndrome.Lancet. 1995;346(8988):1458–63.4.  Barrett TG, Bundey SE. Wolfram (DIDMOAD) syndrome. J MedGenet. 1997;34(10):838–41.5.  Hershey T, Lugar HM, Shimony JS, et al. Early brain vulnerabilityin wolfram syndrome. PLoS One. 2012;7(7):e40604. doi:10.1371/journal.pone.0040604.6.  Zmyslowska A, Malkowski B, Fendler W, et al. Central nervoussystem PET-CT imaging reveals regional impairments in pediatricpatients with Wolfram syndrome. PLoS One. 2014;9(12):e115605.doi:  10.1371/journal.pone.0115605.7.  Swift RG, Sadler DB, Swift M. Psychiatric findings in Wolframsyndrome homozygotes. Lancet. 1990;336(8716):667–9.8.  Swift RG, Perkins DO, Chase CL, et al. Psychiatric disorders in 36families with Wolfram syndrome. Am J Psychiatry. 1991;148(6):775–9.9.  Inoue H, Tanizawa Y, Wasson J, et al. A gene encoding a trans-membrane protein is mutated in patients with diabetes mellitus andoptic atrophy (Wolfram syndrome). Nat Genet. 1998;20(2):143–8.10.  Hansen L, Eiberg H, Barrett T, et al. Mutation analysis of the WFS1gene in seven Danish Wolfram syndrome families; four new muta-tions identified. Eur J Hum Genet. 2005;13(12):1275–84. doi:10.1038/sj.ejhg.5201491.11.  Bespalova IN, Van Camp G, Bom SJ, et al. Mutations in theWolfram syndrome 1 gene (WFS1) are a common cause of lowfrequency sensorineural hearing loss. Hum Mol Genet.2001;10(22):2501–8.12.  Lesperance MM, Hall 3rd JW, San Agustin TB, et al. Mutations inthe Wolfram syndrome type 1 gene (WFS1) define a clinical entityof dominant low-frequency sensorineural hearing loss. ArchOtolaryngol Head Neck Surg. 2003;129(4):411–20. doi:10.1001/archotol.129.4.411.13.  Bonnycastle LL, Chines PS, Hara T, et al. Autosomal dominantdiabetes arising from a wo