Wolfram Syndrome

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

1.  
 
 
 
 
                  
 
                  
                       
                       
            
                             
WOLFR
AAM SYNDR
  
ROME 

2. Case Report
INTRODUCTION
Wolfram syndrome also known as DIDMOAD
syndrome (diabetes - insipidus, diabetes mellitus, optic
atrophy, deafness), is an autosomal recessive,
neurodegene-rative disorder. The condition is very rare
with the prevalence of 1:770,000 of normal population,
1:150 of Juvenile IDDM and with a carrier frequency of
1:354 [1] . The patients with this syndrome also have other
clinical manifestations, like urinary tract abnormalities,
neuro-psychiatric manifestations, gastrointestinal
manifestations, hypogonadism etc., diabetes mellitus and
optic atrophy are the two essential criteria for diagnosis. In
this report, we present three patients with Wolfram
syndrome.
CASE REPORT
Clinical and laboratory findings are summarized in
Table 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 with
equal frequency in both sexes. It manifests as a
combination of juvenile onset non-immune insulin
dependent diabetes mellitus and progressive optic atrophy
in all patients with added diabetes insipidus and sensori
neural deafness in 70% of patients, where it is referred to as
DIDMOAD.
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, Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy and Deafness. We report three siblings with clinical features of Wolfram 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.

3. Apollo Medicine, Vol. 7, No. 1, March 2010 52
Case Report
The pathogenesis of the disorder although unknown, is
ascribed to mutation of a gene on chromosome 4p encoding
a transmembrane protein of undetermined function called
wolframin, located throughout the body and has strong
activity in heart, brain, pancreas, liver, kidney, skeletal
muscle and inner ear.
There are two documented genetic routes of
inheritance, either Autosomal Recessive (AR) or mito-
chondrial (mt). The mutant genes responsible for wolfram
syndrome include WFS1 gene in chromosome 4p16-1,
WFS2 gene in chromosome 4q22-24 and mitochondrial
genes. Carriers do not develop WFS, but are at increased
risk of developing serious psychiatric illness or adult onset
diabetes mellitus [2].
Patients present with Diabetes Mellitus(DM) followed
by Optic Atrophy in the first decade, Cranial Diabetes
Insipidus(DI) in second decade, dilated renal outflow tracts
in early third decade and multiple neurological abnor-
malities in early fourth decade [3]. The pathogenesis of
juvenile DM is due to selective loss of islet beta cells of
pancreas, which is non autoimmune [4]. Visual loss is
progressive and ends in total blindness which is due to
severe 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 sensori
sensori neural hearing sensori neural hearing neural hearing
loss of both ears loss of both ears loss of both ears.
4. EEG Normal Normal Epileptiform activity
5. ENMG Demyelinative Carpal tunnel Abnormal anterior
neuropathy of upper syndrome – right>left visual pathways
and lower limbs.
Abnormal anterior
visual pathways
6. USG Abdomen Dilated bladder, ureter Mild bladder wall Dilated bladder,
and renal calyces (boththickening ureter and renal
side) calyces (right > left)
Bladder wall - thick Bladder wall –
with trabeculations thick with
trabeculations
7. Upper GI Scopy Patulous LES _ Duodenitis
Antral gastritis
chiasma and tracts. Loss of vison may also occur due to diabetic retinopathy.
DI is caused by degeneration and atrophy of
hypothalamus with loss of vasopressin secreting neurons in the supra-optic and para ventricular nuclei leading to deficiency of vasopressin which causes symptoms [2].
Sensory neural hearing loss, usually for high frequency
sounds is due to degenerative atrophy of auditory nerve and its central pathway.
Other abnormalities found in WFS are dilated renal
outflow tracts, neurological manifestation like cerebella ataxia, nystagmus, seizures (myoclonic, petit mal, grand mal) and dementia, psychiatric-manifestations like depression and chronic fatigue, gastrointestinal dysmotility symptoms, short stature, primary hypogonadism [2], thiamine responsive anemia [5] etc.
Diabetic microvascular complications may occur at a
later stage [2]. Death occur prematurely usually in the fourth decade and is due to central respiratory failure. MRI brain of the patients show atrophy throughout the brain, markedly in the brain stem[2].

4. Case Report
53 Apollo Medicine, Vol. 7, No. 1, March 2010
REFERENCES
1. Barrett TG, Bunday SE, Macleod AF. Neurodegeneration
and 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 Paediatric
Endocrinology 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 forms
of diabetes , 488.
5. Borgna Pignatti C, Marradi P, Pinelli L, Monetti N, Patrini
C.Thiamine responsive anemia in DIDMOAD Syndrome.
J. Paediatrics 1989; 114(3): 405-410.

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