WOLFRAAM SYNDR

  

ROME 

Case Report

INTRODUCTION

Wolfram syndrome also known as DIDMOADsyndrome (diabetes - insipidus, diabetes mellitus, opticatrophy, deafness), is an autosomal recessive,neurodegene-rative disorder. The condition is very rarewith the prevalence of 1:770,000 of normal population,1:150 of Juvenile IDDM and with a carrier frequency of1:354 [1] . The patients with this syndrome also have otherclinical manifestations, like urinary tract abnormalities,neuro-psychiatric manifestations, gastrointestinalmanifestations, hypogonadism etc., diabetes mellitus andoptic atrophy are the two essential criteria for diagnosis. Inthis report, we present three patients with Wolframsyndrome.

CASE REPORT

Clinical and laboratory findings are summarized inTable 1 & 2. The parents and another sibling were normal.There was no consanguinity.

DISCUSSION

Wolfram syndrome (WFS) is a rare complex,hereditary neurodegenerative and genetic disorder withequal frequency in both sexes. It manifests as acombination of juvenile onset non-immune insulindependent diabetes mellitus and progressive optic atrophyin all patients with added diabetes insipidus and sensorineural deafness in 70% of patients, where it is referred to asDIDMOAD.

51 Apollo Medicine, Vol. 7, No. 1, March 2010

WOLFRAM SYNDROME

N VANI

Consultant Physician, Apollo Speciality Hospitals, Lake View Road, K K Nagar, Madurai 625 020, India.

Wolfram syndrome, otherwise known by an acronym DIDMOAD SYNDROME which comprises, DiabetesInsipidus, Diabetes Mellitus, Optic Atrophy and Deafness. We report three siblings with clinical features ofWolfram syndrome.

Key words: Diabetes mellitus, Diabetes insipidus, Optic atrophy, Deafness.

Table 1. Clinical manifestations

S. No. Clinical features Case 1 Case 2 Case 3

1. Age (in years) 29 26 24

2. Sex M F M

3. Diabetes mellitus- detected at the age (years) 5 2 7

4. Visual disturbances started at the age (years) 12 12 17- Optic atrophy + + +

5. Urinary symptoms- Polyuria + – +- Incontinence + – +

6. Hard of hearing started at the age (years) 25 22 -

7. Neurological symptoms- Convulsions + + +- Ataxia + – –

8. Memory disturbances + – –

9. Gastrointestinal symptoms- Reflux dyspepsia + – +

Note:• All three cases are on Insulin therapy; • Case – 3 is on Desmopressin.

Apollo Medicine, Vol. 7, No. 1, March 2010 52

Case Report

The pathogenesis of the disorder although unknown, isascribed to mutation of a gene on chromosome 4p encodinga transmembrane protein of undetermined function calledwolframin, located throughout the body and has strongactivity in heart, brain, pancreas, liver, kidney, skeletalmuscle and inner ear.

There are two documented genetic routes ofinheritance, either Autosomal Recessive (AR) or mito-chondrial (mt). The mutant genes responsible for wolframsyndrome include WFS1 gene in chromosome 4p16-1,WFS2 gene in chromosome 4q22-24 and mitochondrialgenes. Carriers do not develop WFS, but are at increasedrisk of developing serious psychiatric illness or adult onsetdiabetes mellitus [2].

Patients present with Diabetes Mellitus(DM) followedby Optic Atrophy in the first decade, Cranial DiabetesInsipidus(DI) in second decade, dilated renal outflow tractsin early third decade and multiple neurological abnor-malities in early fourth decade [3]. The pathogenesis ofjuvenile DM is due to selective loss of islet beta cells ofpancreas, which is non autoimmune [4]. Visual loss isprogressive and ends in total blindness which is due tosevere axonal loss and demyelination of optic nerves,

Table 2. Investigations

S. No. Test Case 1 Case 2 Case 3

1. Blood Sugar (mg/dL)- Fasting 404 234 346- Post prandial (2 hrs.) 475 328 470

2. Urine- Specific gravity 1.000 1.010 1.005- Osmolality (mosm/kg) 325 251 288- pH 6.0 6.0 6.5

3. Audiogram Moderately severe Moderate to profound Mild sensorisensori neural hearing sensori neural hearing neural hearingloss of both ears loss of both ears loss of both ears.

4. EEG Normal Normal Epileptiform activity

5. ENMG Demyelinative Carpal tunnel Abnormal anteriorneuropathy of upper syndrome – right>left visual pathwaysand lower limbs.Abnormal anteriorvisual pathways

6. USG Abdomen Dilated bladder, ureter Mild bladder wall Dilated bladder,and renal calyces (both thickening ureter and renalside) calyces (right > left)Bladder wall - thick Bladder wall –with trabeculations thick with

trabeculations

7. Upper GI Scopy Patulous LES _ DuodenitisAntral gastritis

chiasma and tracts. Loss of vison may also occur due todiabetic retinopathy.

DI is caused by degeneration and atrophy ofhypothalamus with loss of vasopressin secreting neurons inthe supra-optic and para ventricular nuclei leading todeficiency of vasopressin which causes symptoms [2].

Sensory neural hearing loss, usually for high frequencysounds is due to degenerative atrophy of auditory nerve andits central pathway.

Other abnormalities found in WFS are dilated renaloutflow tracts, neurological manifestation like cerebellaataxia, nystagmus, seizures (myoclonic, petit mal, grandmal) and dementia, psychiatric-manifestations likedepression and chronic fatigue, gastrointestinal dysmotilitysymptoms, short stature, primary hypogonadism [2],thiamine responsive anemia [5] etc.

Diabetic microvascular complications may occur at alater stage [2]. Death occur prematurely usually in thefourth decade and is due to central respiratory failure. MRIbrain of the patients show atrophy throughout the brain,markedly in the brain stem[2].

Case Report

53 Apollo Medicine, Vol. 7, No. 1, March 2010

REFERENCES

1. Barrett TG, Bunday SE, Macleod AF. Neurodegenerationand diabetes: UK nationwide study of (DIDMOAD)Syndrome. The Lancet, 1995; 346 (8988): 1458-1463.

2. Mohd Ashraf Ganie, Dilafroze Bhat. Current develop-ments in Wolfram syndrome. Journal of PaediatricEndocrinology and metabolism, 2009; 22(1): 3-10.

3. Barret TG, Bunday SE. Wolfram (DIDMOAD) Syndrome J.Medi Genet 1997; 34(10): 838-841.

4. Joslin’s Diabetes Mellitus, 14th Edition – secondary formsof diabetes , 488.

5. Borgna Pignatti C, Marradi P, Pinelli L, Monetti N, PatriniC.Thiamine responsive anemia in DIDMOAD Syndrome.J. Paediatrics 1989; 114(3): 405-410.

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