Wolfram Syndrome 1

Clinical Characteristics
Ocular Features: 

Optic atrophy in association with diabetes mellitus is considered necessary to the diagnosis of Wolfram syndrome.  The optic atrophy is progressive over a period of years and can be the presenting symptom.  Its onset, however, is highly variable and may begin in infancy but almost always before the third decade of life.  The majority (77%) of patients are legally blind within a decade of onset.  The visual field may show paracentral scotomas and peripheral constriction.  Both VEPs and ERGs can be abnormal.  Diabetic retinopathy is uncommon and usually mild.

Two sibs with confirmed WFS1 have been reported with microspherophakia, congenital cataracts, and glaucoma in addition to optic atrophy .

Systemic Features: 

The clinical features of this disorder are many and highly variable.  Sensorineural hearing loss, diabetes insipidus, anemia, seizures, vasopressin deficiency, ataxia, and autonomic neuropathy are usually present. Respiratory failure secondary to brain stem atrophy may have fatal consequences by the age of 30 years.  A variety of mental disturbances including mental retardation, dementia, depression, and behavioral disorders have been reported.  The diabetes mellitus is insulin dependent with childhood onset.  Dilated ureters and neurogenic bladder are frequently seen, especially in older patients..


Wolfram syndrome 1 is an autosomal recessive disorder that can be caused by mutations in the WFS1 gene (4p16.1) encoding wolframin, a small protein important to maintenance of the endoplasmic reticulum.  However, a minority of individuals also have deletion mutations in mitochondrial DNA (598500).  Some evidence suggests that point mutations at 4p16.1 predispose deletions in mtDNA, and, if so, this recessive disorder may owe its appearance to combined mutations in both nuclear and mitochondrial DNA.  In addition, rare families with the Wolfram syndrome phenotype and mutations in the WFS1 gene show transmission patterns consistent with autosomal dominant inheritance.

Wolfram syndrome 2 (WFS2) (604928) results from mutations in CISD2 at 4q22-q24.

Treatment Options: 

No treatment is available for Wolfram syndrome but the administration of thiamin can correct the anemia.  Low vision aids may be helpful in early stages of disease.

Article Title: 


Wragg R, Dias RP, Barrett T, McCarthy L. Bladder dysfunction in Wolfram syndrome is highly prevalent and progresses to megacystis. J Pediatr Surg. 2017 Nov 14. pii: S0022-3468(17)30744-3. doi: 10.1016/j.jpedsurg.2017.11.025. [Epub ahead of print].

PubMedID: 29277467

Chac??n-Camacho O, Arce-Gonzalez R, Granillo-Alvarez M, Flores-Limas S, Ram??rez M, Zenteno JC. Expansion of the Clinical Ocular Spectrum of Wolfram Syndrome in a Family Carrying a Novel WFS1 Gene Deletion. Ophthalmic Genet. 2013 Feb 1. [Epub ahead of print].

PubMedID: 13373429

Cano A, Rouzier C, Monnot S, Chabrol B, Conrath J, Lecomte P, Delobel B, Boileau P, Valero R, Procaccio V, Paquis-Flucklinger V; French Group of Wolfram Syndrome, Vialettes B. Identification of novel mutations in WFS1 and genotype-phenotype correlation in Wolfram syndrome. Am J Med Genet A. 2007 Jul 15;143A(14):1605-12.

PubMedID: 17568405

Inoue H, Tanizawa Y, Wasson J, Behn P, Kalidas K, Bernal-Mizrachi E, Mueckler M, Marshall H, Donis-Keller H, Crock P, Rogers D, Mikuni M, Kumashiro H, Higashi K, Sobue G, Oka Y, Permutt MA. A gene encoding a transmembrane protein is mutated in patients with diabetes mellitus and optic atrophy (Wolfram syndrome). Nat Genet. 1998 Oct;20(2):143-8.

PubMedID: 9771706