Wolfram syndrome is an extremely rare neurodegenerative disorder characterized by diabetes mellitus, optic atrophy, deafness, and diabetes insipidus. Affected patients present with juvenile onset diabetes mellitus, and optic atrophy. A large number of these patients also develop diabetes insipidus, and/or sensorineural deafness. The optic atrophy is progressive, and most patients become blind by the age of 8-years. In addition, patients may also show neurological symptoms, such as ataxia and startle myoclonus, psychological complications, problems with digestion, and renal complications. The disorder is rare, with only about 170 people affected people having been reported till date.
The WFS1 gene has been implicated in the pathogenesis of Wolfram Syndrome. This gene, located on chromosome 4, codes for a protein known as wolframin. Although the exact function of this protein is not known, its localization within the endoplasmic reticulum seems to suggest that it may play a role in protein folding and post-translational modifications. A high level of expression of this gene is specially noticed in the pancreas, giving rise to the theory that wolframin may be involved in the folding of the pre-proinsulin molecule, thereby explaining defects in the gene leading to diabetes. In addition, several mutations within the WFS1 gene have been implicated in other forms of sensorineural deafness too. A probable explanation put forward is that the protein may help in maintaining the levels of calcium ions in the inner ear.
Hasan et al. (2000) described a Jordanian patient with Wolfram's Syndrome. The patient had one older sister who had earlier died of diabetes mellitus at the age of 11-years. His mother and all remaining eight siblings did not show any features of the condition.
Medlej et al. (2004) studied 37 patients with Wolfram Syndrome, belonging to 17 Lebanese families. Although they noted the detectuon of two putative mutations in the WFS1 gene in three of these families, further details were not availble.
Soliman et al. (1995) reported two Omani girls with DIDMOAD syndrome associated with early degeneration of the pituitary gland leading to isolated growth hormone deficiency. Both patients came from consanguinoeus families, and had close relatives who were similarly affected.
Salih and Tuvemo (1991) described two Sudanese families with two affected boys in one and an affected boy and girl in the other. Diabetes mellitus was the first manifestation (at 3 to 8 years), followed by deafness and visual failure. The disease ended fatally in one patient at the age of 20 years. In the other three, diabetes insipidus was confirmed using water deprivation tests for 8 hours. All three had severe bilateral hydronephrosis with dilated ureters and distended bladder without vesicoureteral reflux.
El-Shanti et al. (2000) and Ajlouni et al. (2002) described a Syrian family with two members affected with Wolfram syndorme. Genotyping identified that the condition in the Syrian family localized to the classical WFS1 locus.