Wolfram syndrome is the constellation of juvenile onset diabetes mellitus and optic atrophy, known as DIDMOAD (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, and Deafness)

Manaviat, Masoud Reza

Mohammadi, Seyed Mohammad

Rashidi, Maryam

English

PubMed

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BioMed CentralCases Journal
ssOpen AcceCase Report
Wolfram Syndrome presenting with optic atrophy and diabetes 
mellitus: two case reports
Masoud Reza Manaviat, Maryam Rashidi* and 
Seyed Mohammad Mohammadi
Address: Yazd Diabetes Research Center, Shahid Sadoughi University of Medical Science, Jomhouri Boulevard, Yazd, 89179-45556, Iran
Email: Masoud Reza Manaviat - mr_manaviat@yahoo.com; Maryam Rashidi* - mary.rashidi@gmail.com; 
Seyed Mohammad Mohammadi - m_mohammadi@ssu.ac.ir
* Corresponding author    
Abstract
Wolfram syndrome is the constellation of juvenile onset diabetes mellitus and optic atrophy,
known as DIDMOAD (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, and Deafness).
Patients demonstrate diabetes mellitus followed by optic atrophy in the first decade, diabetes
insipidus and sensorineural deafness in the second decade, dilated renal outflow tracts early in the
third decade, and multiple neurological abnormalities early in the fourth decade.
This study reports two siblings with late diagnosed wolfram syndrome with diabetes insipidus,
diabetes mellitus, optic atrophy, deafness and severe urological abnormalities.
In conclusion, cases having early onset insulin-dependent diabetes mellitus and optic atrophy
together need to be evaluated with respect to Wolfram.
Background
For the first time in 1938, wolfram described four siblings
with diabetes mellitus and optic atrophy [1]. The main
features of wolfram syndrome are diabetes mellitus, dia-
betes insipidus, sensorineural deafness and optic atrophy
[2,3]. It is a progressive neurodegenerative disorder in
which patients present with nonautoimmune and non-
HLA linked diabetes mellitus associated with optic atro-
phy in the first decade; diabetes insipidus and sen-
sorineural deafness in the second decade; renal tract
abnormalities early in the third decade; and multiple neu-
rological abnormalities, like cerebellar ataxia, myoclonus,
and psychiatric illness early in the fourth decade [4]. Wolf-
ram patients usually die from central respiratory failure as
a result of brain stem atrophy in their third or fourth dec-
ade [4]. The clinical phenotype of wolfram shows similar-
ity with mitochondrial disorders, such as maternally
inherited diabetes and deafness, mitochondrial encepha-
lopathy, mitochondrial myopathy, lactic acidosis and
stroke-like episodes, or Leber's hereditary optic neuropa-
thy and some studies have concentrated on mitochondrial
pathology in Wolfram. Mitochondrial disturbances at the
biochemical, morphological, and molecular level have
been explained in patients with wolfram, but this has not
been a strong finding [5-7].
This study reports two siblings with wolfram and
described the course of disease in them to draw the atten-
tion of health professionals to think of this syndrome in
patients with IDDM and optic atrophy.
Published: 19 December 2009
Cases Journal 2009, 2:9355 doi:10.1186/1757-1626-2-9355
Received: 7 July 2009
Accepted: 19 December 2009
This article is available from: http://www.casesjournal.com/content/2/1/9355
© 2009 Manaviat et al; licensee BioMed Central Ltd. 
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), 
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Page 1 of 3
(page number not for citation purposes)
Cases Journal 2009, 2:9355 http://www.casesjournal.com/content/2/1/9355Case presentation
Case report 1
First case is an Iranian 20-year old female patient admitted
to ophthalmology clinic complaining decreased visual
acuity. She has suffered progressive visual deterioration
since 8 years ago. On fundoscopic examination, bilateral
optic atrophy was recognized, and there was no evidence
of diabetic retinopathy. Her visual acuity reduced to 20/
80 on both sides. Her visual fields demonstrated general-
ized constriction. IDDM was diagnosed at the age 6, for
which she is receiving insulin with rather poor control of
her blood sugar. She has a history of nocturia and high
urine output (12 liter per day) for 6 years and after that
she has had incontinency and since 2 years ago she has
had voiding difficulty and has used self intermittent cath-
eterization four times a day. Renal sonography showed
pelvicalyceal dilatation in both kidneys equal to hydrone-
phrose grade IV with dilation in proximal of urethra and
bladder enlargement secondary to high urine output. Ure-
thral pressure profile shows atonic bladder. Accordingly
wolfram was suspected by ophthalmologist and referred
her to an endocrinologist. Diabetes insipidus was diag-
nosed by dehydration test and after starting Minirin drop,
urine output decreased and voiding difficulty improved.
There was decreased audible acuity by the age of 16 and
audiometry showed bilateral high frequency sen-
sorineural hearing loss.
Renal function, hepatic function, thyroid function and
other blood test were normal.
Urea: 30 mg/dL, Creatinine: 1 mg/dL, Creatinine clear-
ance = 85 ml/min, Calcium: 10.7 mg/dL, Phosphorus: 4.8
mg/dL, Sodium: 135 mg/dL, Potassium: 4.6 mg/dL,
Alanine transaminase (ALT): 40 IU/L, Aspartate transami-
nase (AST):40 IU/L, Alkaline Phosphatase: 315 U/L, Total
Bilirubin: 0.8 mg/dL, Direct Bilirubin: 0.1 mg/dL, T4: 8.4
ng/dL, T3: 120 ng/dL, TSH: 2.5 mU/L, FT4: 1.1 ng/dL.
There was a family history of similar conditions among
her brother and one of her cousins. Also she has a 20-year
old brother who is normal.
Case report 2
First case has a 14-year old brother, who acquired IDDM
at the same age as his sister, and has had a similar course
of disease. He was diagnosed with IDDM at the age of 6
years and has been receiving insulin since then. He has
had nocturia, polyuria and voiding difficulty for 3 years
and has used self intermittent catheterization too. His vis-
ual acuity reduced to 20/120 on both sides. On fundo-
scopic examination, he has bilateral optic atrophy
without diabetic retinopathy (Figure 1, and Figure 2).
Renal sonography showed pelvicalyceal dilatation in both
kidneys equal to hydronephrose grade III with dilation in
proximal of urethra and bladder enlargement. Urethral
pressure profile shows atonic bladder. Subsequently wolf-
ram was diagnosed for him and Minirin started. Audio-
gram was normal. Renal and hepatic function, thyroid
function and other blood tests were normal.
Discussion
Wolfram is a neurodegenerative disease, which incidence
is estimated at one in every 770,000 live births [8]. Early-
onset IDDM and optic atrophy are believed to be the ini-
tial and basic features of the syndrome [9]. Patients usu-
ally demonstrate diabetes mellitus associated by optic
atrophy in the first decade, sensorineural deafness and
diabetes incipidus in the second decade, dilated renal out-
flow tracts early in the third decade, and several neurolog-
ical abnormalities early in the fourth decade [10]. The
prevalence, severity and age of onset of the various mani-
festations of this syndrome are not constant in other stud-
ies [11]. In our cases diabetes insipidus, optic atrophy and
dilated renal outflow tracts were appeared in second dec-
ade.
Photographic image of the patient right eye showing optic atr phy without diabetic retinopathyFigure 1
Photographic image of the patient right eye showing 
optic atrophy without diabetic retinopathy.
Photographic image of the patient left eye showing optic atr phy without diabetic retinopathyFigure 2
Photographic image of the patient left eye showing 
optic atrophy without diabetic retinopathy.Page 2 of 3
(page number not for citation purposes)
Cases Journal 2009, 2:9355 http://www.casesjournal.com/content/2/1/9355Patients with wolfram demonstrate progressive ophthal-
mologic symptoms that usually occur after diabetes melli-
tus. Besides optic atrophy, constriction of visual fields and
decline visual acuity and color vision are the other oph-
thalmological findings in wolfram syndrome [9,12]; how-
ever, diabetic retinopathy is rarely observed [10]. Only
five cases with Wolfram have been reported without optic
atrophy [10]. In our cases, visual acuity of both eyes was
20/80 and 20/120 respectively. Fundus examination
revealed optic atrophy, but no sign of diabetic retinopathy
was seen. Also, concentric narrowing was present in the
field of vision in both cases.
A wide range of urological abnormalities have been
observed in Wolfram, including various degrees of upper
urinary tract dilatation and bladder dysfunction. An
atonic bladder with a large capacity has been mostly
reported. Cremers et al. [13] and Barret et al. [4] reported
urological abnormalities in 13 and 58% of their patients,
respectively, which was seen in our cases as well.
Sensorineural hearing loss or an abnormal audiogram was
observed in 39-62% of patients [4,13]. Audiometry
showed bilateral high frequency sensorineural hearing
loss in one of our cases, but in second case was not seen.
Wolfram is considered to have an autosomal recessive
mode of inheritance. Finding from different studies sug-
gest that wolfram is contributed by alternations in genes
located on chromosome 4 or alternatively, in the mito-
chondrial DNA [10]. Since the initial recognition of the
WFS 1 gene by Inoue et al. [14], different research has
determined more than 50 distinct mutations of this gene.
Accordingly, it is postulated that wolfram is genetically
heterogenic [10]. We did not perform genetic analyses in
our cases; however, our cases' mother, father, and one sib-
ling underwent systemic and ophthalmological examina-
tion. There were no manifestations of wolfram in their
examinations, but our cases had a cousin with these symp-
toms that was died from renal disorder.
Conclusion
In summary, IDDM and optic atrophy are the first and
essential features of Wolfram followed by development of
deafness, diabetes insipidus and urinary tract abnormali-
ties. Generally cases having IDDM and optic atrophy
together need to be evaluated with respect to Wolfram.
Cases with Wolfram should be followed all their lives. In
these cases, rehabilitation to a normal social life is possi-
ble with good follow-up and treatment. The disorder
should be kept in mind particularly in our part of the
world, where consanguinity is prevalent.
Consent
Written informed consent was obtained from the patients
for publication of this case report and accompanying
images. A copy of the written consent is available for
review by the Editor-in-Chief of this journal.
Competing interests
The authors declare that they have no competing interests.
Authors' contributions
MRM carried out ophthalmologic examination and
revised the manuscript. MR helped with data collection
and drafted the manuscript. SMM participated in the
management of the patients. All authors read and
approved the final manuscript.
Acknowledgements
This study was supported by Yazd diabetes Research Center of Shahid 
Sadoughi University of Medical Sciences.
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Wolfram Syndrome presenting with optic atrophy and diabetes mellitus: two case reports

Masoud Manaviat

Maryam Rashidi

Seyed Mohammadi

Crossref

AF: Neurodegeneration and diabetes: UK nationwide study of Wolfram (DIDMOAD) syndrome. Lancet

Andreani D: Wolfram's syndrome: a clinical, diagnostic, and interpretative contribution. Diabetes Care

Autosomal recessive Wolfram syndrome associated with an 8.5-kb mtDNA single deletion.

DM: Biochemical and molecular studies of mitochondrial function in diabetes insipidus, diabetes mellitus, optic atrophy, and deafness. Diabetes Care

Optic atrophy and nerve deafness in diabetes insipidus.

Permutt MA: A gene encoding a transmembrane protein is mutated in patients with diabetes mellitus and optic atrophy (Wolfram syndrome). Nat Genet

RG: Morbidity and mortality in the Wolfram syndrome. Diabetes Care

The mitochondrial genome in Wolfram syndrome.

Wagener HP: Diabetes mellitus and simple optic atrophy among siblings: report of four cases.

Wolfram syndrome: a mitochondrial-mediated disorder? Lancet

Wolfram Syndrome: Case Report and Review of the Literature. Compr Ther

Wolfram syndrome: report of four new cases and a review of literature. Diabetes Care

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Wolfram Syndrome presenting with optic atrophy and diabetes mellitus: two case reports

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