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Wolfram syndrome: a clinical and molecular genetic analysis
  1. Philipp Eller,
  2. Bernhard Föger,
  3. Roland Gander,
  4. Teresa Sauper,
  5. Monika Lechleitner,
  6. Gerd Finkenstedt,
  7. Josef R Patsch
  1. Department of Medicine, Anichstrasse 35, A-6020 Innsbruck, Austria
  1. Dr Föger, bernhard.foeger{at}

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Editor—Wolfram syndrome (OMIM 222300) is a progressive neurodegenerative disorder characterised by the association of juvenile, non-autoimmune, insulin dependent diabetes mellitus and optic atrophy. The physician D J Wolfram, who reported four cases in 1938, is credited with the first description.1 With the identification of other clinical features, Wolfram syndrome was also referred to as DIDMOAD syndrome (diabetesinsipidus, diabetes mellitus,optic atrophy and deafness). The initial manifestation of Wolfram syndrome is typically, but not invariably, insulin deficient diabetes mellitus at a median age of 6 years, followed by optic atrophy at 11 years.2 In the second decade, many patients develop central diabetes insipidus and sensorineural deafness. Additional, but less frequent neurological and endocrinological abnormalities are atonic bladder, ataxia, myoclonus, peripheral neuropathy, hypogonadism, and a relatively high incidence of depression and psychotic behaviour.3-5 Death occurs between 25 and 49 years (median 30 years).

The prevalence of Wolfram syndrome was estimated at 1/100 000 in a North American population and 1/770 000 in the United Kingdom.2 6 Family studies indicate autosomal recessive inheritance.

Genetic linkage analysis has localised Wolfram syndrome to the short arm of chromosome 4 (4p16),7 8 and the primary genetic defect of the syndrome was attributed to theWFS1 gene, which consists of eight exons encoding a 890 amino acid polypeptide with an apparent molecular weight of 100 kDa.9 10 Hydrophobicity analysis suggested a transmembrane protein comprising three structural domains: a hydrophilic amino terminus separated from a hydrophilic carboxy-terminal tail by a hydrophobic region containing nine predicted transmembrane segments. Homologous genes in Mus musculus, Rattus norvegicus, andDrosophila melanogaster have been described (GenBank AF084482/AJ011971, AF136378; FlyBase FBgn0039003).

The majority of patients with Wolfram syndrome carry loss of function mutations …

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