Wolfram Syndrome 2

Alternative Names

  • WFS2
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WHO-ICD-10 version:2010

Endocrine, nutritional and metabolic diseases

Diabetes mellitus

OMIM Number

604928

Mode of Inheritance

Autosomal recessive

Gene Map Locus

4q24

Description

WFS2 is the second gene locus found to be associated with Wolfram Syndrome. Patients affected with Wolfram Syndrome 2 present with the classical symptoms of diabetes mellitus, optic atrophy, and sensorineural hearing loss, but do not show any evidence of diabetes insipidus, the other main feature of classical Wolfram Syndrome. In addition, these patients also present with peptic ulcer disease, a significant bleeding tendency brought about by defective platelet aggregation and various neurological symptoms.

Molecular Genetics

The WFS2 locus is located on the long arm of chromosome 4. The classical locus for Wolfram Syndorme, WFS1, is positioned on the short arm of the same chromosome. The WFS2 locus contains the CISD2 (CDGSH Iron Sulfur Domain Protein 2) gene, mutations in which have been shown to directly cause Wolfram Syndrome.

Epidemiology in the Arab World

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Other Reports

Jordan

El-Shanti et al. (2000) and Ajlouni et al. (2002) studied three large, consanguineous Jordanian families with a phenotypic variant of Wolfram Syndrome. There were a total of 14 patients in these families, all of whom were born to consanguineous parents. None of the patients presented with diabetes insipidus. All, however, had optic atrophy and sensorineural hearing loss, and diabetes mellitus. In addition, all patients showed reduced platelet aggregation, and patients from two of the families had peptic ulcer disease. Al-Sheyyab et al. (2001) analyzed in detail the bleeding phenotype of these 13 Jordanian patients with WFS2. All patients underwent a coagulation screen, and the results were compared with a two sets of controls, one consisting of four of their healthy siblings, and the other comprised of seven individuals with type I diabetes mellitus only. All patients and control subjects studied were found to have normal coagulation parameters, except bleeding time, which was prolonged in 11 of the patients with Wolfram Syndrome, and one patient in each of the control groups. The bleeding time was significantly more prolonged in the patient group when compared to either of the control groups. Al-Sheyyab et al. (2001) hypothesized that the younger age of the two patients who did not have bleeding abnormality was responsible for the phenotype not being manifested; they were also not clear about the pathogenesis of this bleeding abnormality. While looking for linkage to the classical WFS1 locus, El-Shanti et al. (2000) and Ajlouni et al. (2002) found allelic heterozygosity in these families. This prompted the use of a genome-wide scan using a DNA pooling strategy to identify additional loci responsible for the disease condition in these families, which resulted in the identification of the WFS2 locus on chromosome 4q. Since the Neurokinin 3 Receptor gene mapped to the same region, El-Shanti et al. (2000) and Ajlouni et al. (2002) performed a mutation screening of this gene. However, they could find no mutations. Later, Amr et al. (2007) identified homozygous mutations in the CISD2 gene in these patients, which were responsible for the disease condition.

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