Wolfram Syndrome

Inheritance:

Autosomal recessive

Prevalence:

Heterozygotes estimated at ~1%

Wolfram syndrome prevalence estimated at ~ 1 in 100,000 in North America

Locus:

WFS1 gene at 4p16.1

WFS2 at 4q22-q24

mitochondrial form has been suggested

Defining characteristics:

Diabetes mellitus (median age of onset 6 years; may occur childhood-adulthood)

Bilateral optic atrophy (median age of onset 11 years; may occur childhood-adulthood)

Back to the top

Other frequent characteristics:

Diabetes insipidus (onset in second decade)

Sensorineural deafness (onset in second decade)

Back to the top

Less frequent characteristics:

Atonic bladder

Ataxia

Myoclonus

Peripheral neuropathy

Hypogonadism

Back to the top

Natural History:

Death generally occurs between 25 and 49 years; median 30 years

Back to the top

Psychiatric characteristics:

• In homozygotes:
  
  Increased risk for depression, psychosis, aggression, dementia
  

  Swift, Sadler, and Swift (1990): 60% had psychiatric symptoms noted in their medical record; 25% had severe symptoms requiring hospitalization or resulting in suicide attempts

• In heterozygotes:
  
  Increased risk for depression, suicide attempts, and anxiety disorders
  

  Swift, Perkins, Chase, Sadler and Swift (1991):
  Increased rate of psychiatric hospitalizations, suicides, self-reported “mental illness” and self-reported “chronic nervous trouble.” Risk estimated at eightfold increased risk.
  
  Swift, Polymerpoulos, Torres, and Swift (1998):
  In relatives of individuals with Wolfram syndrome, the percent who were heterozygous made up a greater proportion of psychiatrically hospitalized relatives than expected by chance; the authors estimate carriers were 26 times more likely to require psychiatric hospitalizations than non-carriers.

  A small number of studies looking at rates of mutations in the Wolfram syndrome locus in individuals with affective disorders, schizophrenia, and individuals who committed suicide did not find significant evidence of mutations.

Back to the top

References:

Crawford, J., Zielinski, M.A., Fisher, L.J., Sutherland, G.R. Goldney, R.D. Is there a relationship between Wolfram syndrome carrier status and suicide? Am J Med Genet (Neuropsychiatric Genetics) 114: 343-346 (2002).

Eller, P. et al. Wolfram syndrome: a clinical and molecular genetic analysis. J Med Genet 38 (2001).

Furlong R.A., et al. A rare coding variant within the wolfram gene in bipolar and unipolar affective disorder cases. Neuroscience Letters 277: 123-126 (1999).

Middle, F., et al. Bipolar disorder and variation at a common polymorphism (A1832G) within exon 8 of the Wolfram gene. Am J Med Genet 96: 154-157 (2000).

Swift, R.G., et al. Psychiatric disorders in 36 families with Wolfram syndrome. Am J Psychiatry 148: 775-779 (1991).

Swift, R.G., Sadler, D.B., Swift, M. Psychiatric findings in Wolfram syndrome homozygotes. Lancet 336: 667-669 (1990).

Back to the top