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.
El-Shanti et al. (2000) and Ajlouni et al. (2002) identified a new phenotypic and genotypic variant of Wolfram syndorme from a set of 16 affected patients belonging to four consanguineous families. Three of these families were Jordanian in origin, while one originated from Syria. Diabetes mellitus was found to be the first clinical manifestation in 87.5% of the patients, and the mean age of diagnosis was 10.8 years. Other clinical features noticed in the affected patients included optic atrophy, high frequency sensorineural hearing loss, diabetic retinopathy (in three individuals), neurological disease (in five out of 10 patients examined), and urinary tract dilatation (in nine of 15 patients tested). In the three Jordanian families, the condition was also characterized by the presence of peptic ulcer disease (PUD) in all 10 members who underwent GIT endoscopy, as well as defective platelet aggregation. Only one member of the Syrian family underwent GIT endoscopy, and was found to have no evidence of PUD. In addition, both members of the Syrian family had diabetes insipidus, a condition which was not found in any of the Jordanian patients. This discrepancy in the clinical features prompted Ajlouni et al. (2002) to look for a genotypic cause. Genotyping of the families identified that the condition in the Syrian family localized to the classical WFS1 locus, whereas in the remaining three families, the disease localized to a new locus, WFS2, on 4q22-q24.
Hasan et al. (2000) described a Jordanian patient with Wolfram's Syndrome. The 9-year-old boy born to consanguineous parents, first presented with polyuria, polydepsia, polyphagia, and weight loss. He was found to be hypoglycemic. He was also diagnosed with Type I Diabetes Mellitus, and was started on insulin therapy, which controlled his blood glucose levels. However, 2-years later, he presented with dysuria, fever, chills, and nocturia. Urine culture grew E. coli and abdomen US revealed dilated right pelvicalyceal system and a small left kidney. The right kidney was moderately dilated, while the left was non-functional. By 13-years of age, he developed severe chronic renal failure, needing hemodialysis twice weekly. He was also noticed to have a hearing loss, which was found to be bilateral high tone and sensorineural. Ophthlamic evaluation revealed bilateral optic atrophy, confirming the diagnosis of DIDMOAD. MRI cranium showed generalized brain atrophy and a pituitary gland small in size for age. 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. The father had died in a construction-related accident.
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. The first patient, who was a born of an uneventful pregnancy and delivery to consanguineous parents, was 22 months when she presented with severe pallor and failure to thrive. She had an elder sister who was deaf and diabetic, but died at the age of seven years after profound hypoglycemia following an excessive dose of insulin at home. Clinically, this patient was anemic with multiple bruises, bleeding gums, hematuria, petechia, hepatomegaly, and mild splenomegaly. She was found to have bilateral sensorineural deafness, confirmed by auditory evoked responses, as well as bilateral partial optic atrophy. She was again admitted at the age of 4.5 years with severe anemia, purpura and hyperglycemia with elevated glycated hemoglobin of 9.1%, as the parents discontinued thiamine for three months without medical advice. She responded to restarting thiamine and insulin. A diagnosis of partial neurogenic diabetes insipidus was made after improvement of plasma and urine osmolalities after a dose of intranasal antidiuretic (DDAVP). She was diagnosed with isolated growth hormone deficiency as she had delayed growth and height growth velocity of 3.2 cm/year. Her bone age was delayed; being 2.5 years when she was 4.3 years old, chronologically. CT scan of the brain revealed an empty sella. The second patient whose parents were first degree cousins was seven years when she presented with moderate developmental and growth delay with mild unsteady gait, tremor and nystagmus. She had an aunt who was diabetic and deaf, but her brothers were healthy. Clinically, she had nystagmus and bilateral optic atrophy and investigations revealed reduced growth hormone response to clonidine as well as reduced IGF-1 concentration. Other investigations were all normal and included renal and liver function tests, complete hemogram and renal ultrasound and intravenous pyelogram, but a delayed bone age of four years was found. Moderate bilateral high frequency hearing loss was detected by an audiogram, and CT scan of the brain revealed empty sella, hypoplastic cerebellum with large cisterna magna and small vermis and mild cerebral atrophy as shown by cortical sulci prominence and mild ventricular dilatation.
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.
[See: Jordan > El-Shanti et al., 2000; Ajlouni et al., 2002].