Wolfram syndrome

Wolfram syndrome, also called DIDMOAD (Diabetes Insipidus,

Diabetes Mellitus, Optic Atrophy, and Deafness), is a rare genetic disorder,
causing diabetes mellitus, optic atrophy, and deafness as well as various
other possible disorders.
It was first described in four siblings in 1938 by Dr. Don J. Wolfram, M.D.[1]
[2]
The disease affects the brain (especially the brain stem) and central
nervous system.

[edit] Causes
It is thought to be caused by both a malfunction of the mitochondria and of
myelination, the latter in effect similar to multiple sclerosis. It may have
autosomal recessive or dominant or mitochondrial inheritance depending on
the genes involved.
Three genetic forms have been described: Wolfram Syndrome 1 (WFS1)[3] ,
Wolfram Syndrome 2 (WFS2)[4] and a possible mitochondrial syndrome[5] .

[edit] WFS1
The WFS1 or wolframin gene[6] provides instructions for making the
wolframin protein. The WFS1 gene is active in cells throughout the body,
with strong activity in the heart, brain, lungs, inner ear, and pancreas. The
pancreas provides enzymes that help digest food, and it also produces the
hormone insulin. Insulin controls how much glucose (a type of sugar) is
passed from the blood into cells for conversion to energy.
Within cells, wolframin is located in a structure called the endoplasmic
reticulum. Among its many activities, the endoplasmic reticulum folds and
modifies newly formed proteins so they have the correct 3-dimensional
shape to function properly. The endoplasmic reticulum also helps transport
proteins, fats, and other materials to specific sites within the cell or to the
cell surface. The function of wolframin is unknown. Based on its location in
the endoplasmic reticulum, however, it may play a role in protein folding or
cellular transport. In the pancreas, wolframin may help fold a protein
precursor of insulin (called proinsulin) into the mature hormone that controls

blood glucose levels. Research findings also suggest that wolframin may
help maintain the correct cellular level of charged calcium atoms (calcium
ions) by controlling how much is stored in the endoplasmic reticulum. In the
inner ear, wolframin may help maintain the proper levels of calcium ions or
other charged particles that are essential for hearing.
More than 30 WFS1 mutations have been identified in individuals with a
form of nonsyndromic deafness (hearing loss without related signs and
symptoms affecting other parts of the body) called DFNA6. Individuals with
DFNA6 deafness cannot hear low tones (low-frequency sounds), such as a
tuba or the "m" in moon. DFNA6 hearing loss is unlike most forms of
nonsyndromic deafness that affect high tones (high-frequency sounds), such
as birds chirping, or all frequencies of sound. Most WFS1 mutations replace
one of the protein building blocks (amino acids) used to make wolframin
with an incorrect amino acid. One mutation deletes an amino acid from
wolframin. WFS1 mutations probably alter the 3-dimensional shape of
wolframin, which could affect its function. Because the function of
wolframin is unknown, however, it is unclear how WFS1 mutations cause
hearing loss. Some researchers suggest that altered wolframin disturbs the
balance of charged particles in the inner ear, which interferes with the
hearing process. other disorders - caused by mutations in the WFS1 gene
Mutations in the WFS1 gene cause Wolfram syndrome, which is also known
by the acronym DIDMOAD. This syndrome is characterised by childhoodonset diabetes mellitus (DM), which results from the improper control of
glucose due to the lack of insulin; a gradual loss of vision caused by optic
atrophy (OA), in which the nerve that connects the eye to the brain wastes
away; and deafness (D). This syndrome can sometimes cause diabetes
insipidus (DI), a condition in which the kidneys cannot conserve water.
Other complications that affect the bladder and nervous system may also
occur.
Researchers have identified more than 100 WFS1 mutations that cause
Wolfram syndrome. Some mutations delete or insert DNA from the WFS1
gene. As a result, little or no wolframin is present in cells. Other mutations
replace one of the protein building blocks (amino acids) used to make
wolframin with an incorrect amino acid. These mutations appear to reduce
wolframin activity dramatically. Researchers suggest that the loss of
wolframin disrupts the production of insulin, which leads to poor glucose

control and diabetes mellitus. It is unclear how WFS1 mutations lead to

other features of Wolfram syndrome.

[edit] Treatment
There is no known treatment.

[edit] Prognosis
Life expectancy of people suffering from this syndrome is about 30 years.

The Symptoms of Wolfram Syndrome: "DIDMOAD"

Wolfram Syndrome (also known by its acronym, DIDMOAD*) is not an
easy condition to diagnose. Most patients have it for years before the
accurate diagnosis of Wolfram Syndrome (hereafter referred to as WS) is
confirmed.
In non medical terms here are some of the complaints that you might have or
see in your child

Type 1 Diabetes, usually starting between ages 5 and 15.

Unusually frequent urination in large volumes, combined with
constant thirst. Bedwetting starts again long after successful night
training.
Visual impairment, starting with wearing glasses, but rapidly
increasing. You find yourself holding books of all kinds very close to
your face.
Color blindness. Socks never match the outfit. The lawn has many
patches of missed grass, after cutting. Color blindness in girls is very
rare, except with WS patients.
Slow reacting iris in the eye. Even in bright light the pupils will never
go pinpoint. This may not be obvious from a distance in people with
brown eyes. This may be the first observable symptom in some cases.
High frequency hearing loss or tonal deafness becomes evident.
It is easy to become emotionally agitated or upset.

The challenge with these symptoms is that they are initially fairly mild. Any
one of them is not unreasonable to overlook or treat as an individual
anomaly.
If you find yourself or a family member with more than two of these
symptoms please consult your family doctor immediately and refer them to
the web links referenced here. (print them off and take them in, might be the
easiest way to insure that the doctor will at least take the time to look at
them.)
This is a rare disease, don't expect your physician to be well aware of its
symptoms or solutions. You may be well advised to get a second opinion
from an endocrinologist if your family doctor is not certain that you don't
have WS and you feel that the symptoms above describe you or your child.
While the initial symptoms of WS at the outset may not seem all that
terrible, the secondary complications which are discussed in greater detail in
the medical articles linked above certainly justify serious concern. WS is a
progressive degenerative disease.
* DIDMOAD stands for Diabetes Insipidus, Diabetes Meletis, Optical
Atrophy, Deafness, thus the acronym. Some patients with WS will never
display all four of its classic symptoms.

National Organization for Rare Disorders, Inc.

Wolfram Syndrome
Important
It is possible that the main title of the report Wolfram Syndrome is not the
name you expected. Please check the synonyms listing to find the alternate
name(s) and disorder subdivision(s) covered by this report.
Synonyms
Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy and Deafness
DIDMOAD
Disorder Subdivisions
None
General Discussion
Wolfram syndrome is the inherited association of childhood-onset diabetes
mellitus and progressive-onset optic atrophy. All people affected by Wolfram
syndrome have juvenile-onset diabetes mellitus and degeneration of the
optic nerve (optic atrophy). In addition, about 70 to 75% of those affected
develop diabetes insipidus and about two-thirds develop auditory nerve
deafness. Another name for the syndrome is DIDMOAD, which refers to
diabetes insipidus, diabetes mellitus, optic atrophy, and deafness.
For a Complete Report
This is an abstract of a report from the National Organization for Rare
Disorders, Inc. (NORD). A copy of the complete report can be obtained
for a small fee by visiting the NORD website. The complete report contains
additional information including symptoms, causes, affected population,
related disorders, standard and investigational treatments (if available), and
references from medical literature. For a full-text version of this topic, see
http://www.rarediseases.org/search/rdblist.html

The information provided in this report is not intended for diagnostic

purposes. It is provided for informational purposes only. NORD
recommends that affected individuals seek the advice or counsel of their
own personal physicians.
It is possible that the title of this topic is not the name you selected. Please
check the Synonyms listing to find the alternate name(s) and Disorder
Subdivision(s) covered by this report.
This disease entry is based upon medical information available through the
date at the end of the topic. Since NORD's resources are limited, it is not
possible to keep every entry in the Rare Disease Database completely
current and accurate. Please check with the agencies listed in the Resources
section for the most current information about this disorder.
For additional information and assistance about rare disorders, please
contact the National Organization for Rare Disorders at P.O. Box 1968,
Danbury, CT 06813-1968; phone (203) 744-0100; web site
www.rarediseases.org or email orphan@rarediseases.org
Last Updated: 5/28/2008
Copyright 1990, 1994, 1998, 2005 National Organization for Rare
Disorders, Inc.

Wolfram Syndrome
V Viswanathan*, S Medempudi**, M Kadiri**
Abstract
Wolfram syndrome is a rare neurodegenerative and genetic disorder,
which should be suspected in patients with young onset non-immune
insulin dependent diabetes mellitus and optic atrophy. Patients are
most likely to develop diabetes insipidus, deafness, urinary tract, and
neurological abnormalities. 60% of the people with Wolfram
syndrome die at age 35, usually due to central respiratory center
failure following brain stem atrophy. Though there is no treatment to
reverse the underlying mechanism of neurodegeneration, early
diagnosis and adequate hormonal replacement could improve quality
of life and survival.
INTRODUCTION
First described in 1938 by Wolfram and Wagener, Wolfram syndrome (WFS)
is a rare, complex, hereditary, neurodegenerative and genetic disorder. It
manifests as a combination of young onset non-immune insulin dependent
diabetes mellitus and progressive optic atrophy1 in all patients with added
diabetes insipidus and sensory neural deafness in 70% of the patients, where
it is referred to as DIDMOAD (Diabetes Insipidus, Diabetes Mellitus, Optic
Atrophy, Deafness)
Wolfram syndrome may also include urinary tract, 2 neurological,3
reproductive and psychiatric4 abnormalities, limited joint mobility,5
cardiovascular6 and gastrointestinal autonomic neuropathy, as well as some
types of endocrine dysfunction.7 Cases of upper gastro intestinal bleeds and
heart malformations have also been reported in Wolfram syndrome.
The prevalence estimate is 1 in 100,000 to 1 in 700,0008 based on an
observation of the prevalence of optic atrophy and diabetes mellitus.

Parental consanguinity has been noted and an estimated 1 in 350 people

carry the genes of WFS.
Genetics and Mechanism of disease
There are two documented genetic routes of inheritance of Wolfram
syndrome, either autosomal recessive (A.R.) or mitochondrial (Mt). The
mutant genes responsible for Wolfram syndrome include WFS1 gene in
chromosome 4P16.1 (A.R.), WFS2 gene in chromosome 4Q22-Q24 (A.R.),
and mitochondrial genes.
WFS1 gene mutations is the most common cause of Wolfram syndrome. It
is inherited as an autosomal recessive trait, which means, for a patient to
manifest a disease he has to receive the defective genes from both his
parents. Carriers do not develop WFS, but are at increased risk of
developing serious psychiatric illness or adult onset diabetes mellitus.
Usually the mutant gene is on the short arm of 4th chromosome 4P16.1
(WFS1gene)9 that normally encode for the structural properties and function
of mitochondria, and also provide instruction for making an endoglycoside
H sensitive protein called Wolframin.
Wolframin is a transmembrane protein (also found in endoplasmic
reticulum) located throughout the body and has strong activity in heart,
brain, pancreas, liver, kidney, skeletal muscle and inner ear.
There are more than 100 mutations identified so far, that could cause
Wolfram syndrome. Some mutations delete or insert DNA from WFS gene.
As a result no or little Wolframin is present in cells. Other mutations replace
amino acids that make Wolframin, with incorrect amino acid. As a result the
Wolframin activity is reduced dramatically. Alterations of 3 dimensional
shape of the protein due to mutations could be the probable cause of
decreased activity.
Researchers suggest that the loss of Wolframin that is essential for neuron
survival leads to neurodegeneration and its features in CNS. Apart from
neurodegeneration it also disrupts production of insulin from proinsulin and
there by leads to poor glucose control and diabetes mellitus. It is also

evidenced that altered Wolframin disturbs the balance of calcium ions in the
inner ear, which interferes with hearing process.
WFS2 gene mutations are seen in Jordanian consanguineous families.
These patients differ from classical WFS by absent or decreased incidence of
diabetes insipidus and increased incidence of peptic ulcer disease. In
mitochondrial variant of WFS the mitochondrial genes themselves are
defective10 and features of DIDMOAD are comparatively late in onset.
Inheritance is exclusively from mother to child.
CASE DETAILS
Patient S is a 14-year-old male child born to a 2 nd degree consanguineous
marriage and was a product of an uncomplicated pregnancy. He was
diagnosed with diabetes mellitus at the age of 7 years for which he has been
receiving insulin, but his glycemic control has rather been poor.
He has presented with polyuria, polydipsia, bedwetting, visual
impairment, hearing loss, and quick emotional upset/agitation. His height
was 139 cm and weight was 30.4 kg. He is currently showing normal
development of secondary sexual characteristics denoting onset of puberty.
No limited joint mobility, no obvious cardiovascular, gastrointestinal,
endocrine dysfunction. No regular physical activity, intermittently consumes
pastries and sweets. His scholastic performance was average.
Work Up
Patient underwent detailed laboratory evaluation that included complete
blood count, urea/creatinine, lipid profile, liver function tests, serum
electrolytes, serum osmolality, urine osmolality, C- peptide, and GAD anti
bodies. We measured the volume of a 24 hr collection of urine and
performed a water deprivation test for about 6 hrs. Spot urine studies (spot
sodium ISE) were also done.
The radiological evaluation included MRI axial study of brain, which was
done in flair and T2W sequence. T2W coronal images and T1W sagittal
images were also obtained. Additional T2W sagittal screening of the entire
spinal cord was done. Echocardiogram, chest X-ray, ultra sonography of the

abdomen, Doppler studies of lower limb vessels, nerve conduction velocity

tests, complete ophthalmic and ENT evaluation was done.
RESULTS
The biochemical and hematological results were within normal limits
except raised HbA1C (14.8%), increased serum osmolality (301 mosm/kg)
and decreased urine osmolality (177 mosm/kg) values by osmometer. Spot
sodium ISE =39 meq/l. There has been decrease in fasting and stimulated Cpeptide levels. GAD antibodies were negative. Serum Na+ was 145. His
calcium and renal function test was normal. Water deprivation test was in
favor of central DI.
On ophthalmic examination his best-corrected visual acuity was 6/24 in
both eyes. IOP was 16mmhg in both eyes. Fundus examination with indirect
ophthalmoscopy showed pale disc in both eyes indicative of optic atrophy.
Audiogram revealed moderate to severe sloping showing sensory neural loss
in both ears. Psychosocial consultation unveiled components of anxiety as
well as depression.

Radiologically MRI brain/spinal cord showed no significant abnormalities

except for absent posterior pituitary signal. USG abdomen revealed

thickened bladder wall. Post-voidal residual volume was 85 ml and features

are suggestive of diabetic cystopathy.
DISCUSSION
Patient reported here have, at the age of 13yrs, all the four cardinal
features of Wolfram syndrome. Patient developed DM at age 7yrs, before
any other symptom of Wolfram syndrome is identified. The mean age of DM
diagnosis reported earlier in kinsley studies is 8.2yrs (range 1-26). He had
negative GAD anti bodies and decreased fasting and stimulated C peptide
levels which show its non-immune insulin dependent nature. Non-immune
IDDM in these patients could result from hypothalamic degeneration
although pancreatic beta islet cell loss is part of a specific defect of
neuroectodermal amine precursor uptake decarboxylation derived cells in
the pancreas and in the supraoptic and paraventricular nuclei.11
Optic atrophy, which is a hallmark trait of Wolfram syndrome, was
diagnosed at the age of 9 years. Mean age in Kinsleys study being 13.1yrs
(range 6-30). Patient here was only able to differentiate between light &
darkness and he is legally blind. There has been no evidence of diabetic
retinopathy. Total blindness is unusual in Wolfram syndrome and it takes
7yrs for the significant deterioration in vision to be categorized as legally
blind. The cause for blindness is severe axonal loss and demyelination of
optic nerves, chiasm and tracks.
Polys, nocturia, enuresis, very dilute clear odorless urine with
biochemically raised serum osmolality, decreased urine osmolality and water
deprivation test all confirmed the presence of diabetes insipidus at the age
13yrs. The mean age onset according to kinsley studies is 15.5yrs (range 441). Diabetes insipidus of Wolfram syndrome is caused by degeneration and
atrophy of hypothalamus with loss of vasopressin secreting neurons in the
supraoptic and paraventricular nuclei12 leading to the deficiency in
vasopressin that is responsible for concentration of urine. Hence patients
passes very dilute clear odorless excessive amounts of urine. However in our
patient the symptom due to Diabetes insipidus are not very severe and hence
been advised to monitor serum sodium every 2 months and a desmopressin
spray has to be considered if sodium increases or symptoms worsen.

Symptomatic sensory neural hearing loss to both high frequency followed

by low frequency sounds developed at the age 13 yrs and is confirmed with
audiogram. Mean age of onset in Kinsley studies being 14.6 yrs (range 1
29). Deafness in these patients is neurological affecting auditory nerve and
its central pathways, degenerative atrophy of the vestibulocochlear nuclei
and inferior colliculi13 leading to decreased perception of sounds rather than
deficit in transmitting the sound to the nerve.
Urinary tract abnormalities are expected in about 66% of persons with
Wolfram syndrome and are as well present in our patient with symptoms of
frequent urination, incontinence and recurrent infection of the bladder. Postvoidal residual volume by ultrasound imaging is 85 ml and there is
thickened bladder wall. The symptoms are caused by bladder nerve
dysfunction and a loss of nerve tissue in the bladder and the ureters. The
nervous centers in the brain that control urination may also play a role.
As age advances impaired sexual development, central nervous system
complication such as nystagmus, ataxia, startle myoclonus, seizure
disorders, mental health disorders and digestive problems are likely to
appear and are not identified till now in our patient and hence to be screened
periodically.
The median age of death in these patients according to Kinsley is 28 yrs
and 60% of the people with Wolfram syndrome die at age 35. Death can be
caused by central respiratory center failure following brain stem atrophy,
complications related to urinary tract atony, bulbar dysfunction (aspirations)
and in some cases suicide secondary to depression.
There has been no treatment to reverse the under lying mechanism of
neuro degeneration in persons with WFS and all cases reported till now have
progressed to one or more of the above discussed life-threatening
complications and premature death.
CONCLUSION
Though a rare disorder Wolfram syndrome is to be suspected in any
individual presenting with IDDM and OA within first 3 decades of life.
Genetic studies offer the best opportunity to confirm diagnosis and

multidisciplinary assessment is vital to manage many facets of this

condition. Early adequate treatment avoids serious complications such as
hyperglycemic, hyperosmolar, hypernatremic coma, and can improve the
quality of life and survival.
In addition, these patients have wide variety of social, emotional and
psychological needs. Blind school, computers with software for blind,
listening to books on tape could accommodate the visually disabled and help
build self-esteem, confidence as well as maximizing school performance.
Skills and attitudes that build self-confidence, autonomy and self-control
should be focused upon and parents and relatives should help them to reach
their goals. No matter how short and challenging life should be worthwhile.
REFERENCES
1.

Wolfram DJ. Diabetes mellitus and simple optic atrophy among

siblings: report of four cases. Mayo Clin Proc 1938; 9:715-8.

2.

Tekgul S, Oge O, Simsek E, Yordam N, Kendi S. Urological

manifestations of the Wolfram syndrome: observations in 14 patients. J
Urol 1999;161:616-7.

3.

Grosse Aldenhovel HB, Gallenkamp U, Sulemana CA. Juvenile onset

diabetes mellitus, central diabetes insipidus and optic atrophy (Wolfram
syndrome)neurological findings and prognostic implications.
Neuropediatrics 1991;22:103-6.

4.

Swift RG, Perkins DO, Chase CL, Sadler DB, Swift M. Psychiatric
disorders in 36 families with Wolfram syndrome. Am J Psychiat
1991;148:775-9.

5.

Seshiah V, Sanjeevi CB, Venkataraman S, Rao KV. Wolfram syndrome

with limited joint motility. J Assoc Physicians India 1987;35:528-9.

6.

Medlej R, Wasson J, Baz P, Azar S, Salti I, Loiselet J, Permutt A,

Halaby G. Diabetes Mellitus and Optic Atrophy: A Study of Wolfram
Syndrome in the Lebanese Population. J Clin Endocrinol Metab 89:
1656-61.

7.

Kinsley BT, Dumont RH, Swift M, Swift RJ. Morbidity and mortality
in the Wolfram syndrome. Diabetes Care 1995;18:1566-70.

8.

Barret TG, Bundey SE. Wolfram (DIDMOAD) syndrome. Med Genet

1997;34:838-41.

9.

Inoue H, Tanizawa Y, Wasson J, et al. A gene encoding a

transmembrane protein is mutated in patients with diabetes mellitus and
optic atrophy (Wolfram syndrome). Nat Genet 1998;20:143-8.

10. Bundey S, Poulton K, Whitwell H, Curtis E, Brown IAR, Fielder AR

Mitochondrial abnormalities in the DIDMOAD syndrome. J Inherit
Metab Dis 1992;15:315-9.
11. Galluzzi P, Filosomi G, Vallone IM, et al. MRI of Wolfram syndrome
(DIDMOAD). Neuroradiology 1999;41:729-31.
12. Thompson CJ, Charlton J, Walford S, et al. Vasopressin secretion in
DIDMOAD (Wolfram) syndrome. QJ Med 1989;71:333-45.
13.
Gregorios JB. Wolfram's syndrome with schizophrenia and cerebral
hypoventilation. A neuropathological study. J Neuropathol Exp Neurol
1989;48:308 (abstract).

Summary
Wolfram syndrome (WFS) is a rare neurodegenerative disorder characterized
by type I diabetes mellitus, diabetes insipidus, optical atrophy and
neurological signs. About 300 cases have been described, and prevalence is
estimated at 1/160 000. The minimum ascertainment criterion for WFS is the
association of juvenile onset type I diabetes mellitus (DM), without
antibodies and usually appearing during the first decade of life, with onset of
bilateral optic atrophy before the second decade. The optical atrophy only
affects the peripheral vision. About 70%-75% of patients also develop
diabetes insipidus, and about two-thirds present with some degree of
sensorineural deafness affecting the high frequencies. Other related
problems are urinary tract atony, ataxia, peripheral neuropathy, dementia,
psychiatric disorders and/or seizures. About 60% of homozygous WFS
patients have episodes of severe depression or psychosis, as well as
displaying compulsive verbal and physical aggression. About 25% of
patients present with digestive problems (recurrent constipation or diarrhea).
Kidney disease is present in about one-third of patients. Life-threatening

problems, including central apnea and central respiratory failure, are also
frequent. Bulbar dysfunction can lead to death due to recurrent aspiration
pneumonia. Cardiomyopathy and anemia can also be present. Delay or
disruption of sexual development has also been reported. WFS is transmitted
as an autosomal recessive trait. Two causative genes have been identified:
WFS1 (4p16.1), coding for Wolframin, which is localized to the
endoplasmic reticulum and plays a role in calcium homeostasis, and CISD2
encoding the CDGSH iron sulfur domain-containing protein 2. Mutations in
CISD2 have only been identified in three consanguineous families of
Jordanian descent and WFS1 mutations are responsible for the majority of
the WFS phenotypes. More than 150 different WFS1 mutations have been
described in different populations, most of them in exon 8. In families in
which mutations in WFS1 or CISD2 have been characterized, clinical
diagnosis and carrier identification can be performed. Heterozygous carriers
of WFS1 mutations are eight times more likely to be hospitalized for
psychiatric disorders than non-carriers. They are also at risk of developing
low frequency sensorineural hearing loss and diabetes mellitus. Molecular
prenatal diagnosis is available. Differential diagnosis includes autoimmune
type I diabetes and Leber optic atrophy or LHON (see this term). Treatment
is symptomatic. Care management is based on screening for and treating the
predictable disorders associated with the disease. Annual screening for
diabetes, vision and hearing loss, and a baseline MRI are recommended.
Daily insulin injections and a controlled diet are required to treat DM.
Management of diabetes insipidus, apnea and urinary disorders (i.e.
prophylactic antibiotherapy for urinary infections) is needed. As mental
health problems are highly prevalent in WFS patients, periodic screening for
depression and other psychiatric symptoms is necessary to provide patients
with specific medical, emotional and psychological intervention.
Progression of the disease to premature death is common, often by
respiratory failure. *Author: Dr V. Nunes Martinez (December 2007)*.

Wolfram Syndrome Presenting Marked Brain MR

Imaging Abnormalities with Few Neurologic
Abnormalities
Abstract
SUMMARY: Wolfram syndrome is a rare autosomal recessive disorder
featuring diabetes insipidus, diabetes mellitus, optic atrophy, and deafness;
DIDMOAD is a commonly accepted anonym for this disorder. We describe a
35-year-old man with Wolfram syndrome, who had marked atrophy of the
brain stem, middle cerebellar peduncle, and cerebellum. Despite these MR
imaging findings involving the pontocerebellar tract, the patient had no
neurologic abnormalities suggesting dysfunction of the brain stem or
cerebellum. Patients with Wolfram syndrome may have discrepancies
between neurologic and radiologic findings.

Introduction

In 1938, Wolfram and Wagener1 described a family in which 4 siblings

developed bilateral optic atrophy and diabetes mellitus, followed by
deafness, incontinence, and ataxia. The frequent association of diabetes
insipidus, diabetes mellitus, optic atrophy, and deafness led to the acronym
DIDMOAD, indicating 4 cardinal features.2 DIDMOAD, commonly known

as Wolfram syndrome, is a rare autosomal recessive disorder with

demonstrable clinical and genetic heterogeneity,24 and a gene for Wolfram
syndrome (WFS1) has been cloned and mapped to chromosome 4p.5 The
onset of Wolfram syndrome is usually juvenile, and most patients are referred
to pediatricians or endocrinologists. Therefore, despite the striking
neurologic and neuroradiologic features of Wolfram syndrome, the disorder
has made little impact on the neurologic and neuroradiologic literature. In
the present report, we describe a patient with Wolfram syndrome presenting
marked MR imaging abnormalities with few neurologic abnormalities.

Case Report
A 35-year-old man had diabetes insipidus, diabetes mellitus, and visual loss
due to optic atrophy since he was 3 years of age. He had been diagnosed
with Wolfram syndrome on the basis of the typical clinical features and
familial history of diabetes mellitus. The man was admitted to our hospital
because of consciousness disturbance in June 2005. Laboratory examinations
showed diabetic ketoacidosis. He was stuporous and opened his eyes only to
painful stimuli. After the patient recovered from diabetic ketoacidosis,
neurologic examinations revealed complete visual loss and mild sensory
hearing loss, but there were no findings suggesting abnormalities of the brain
stem or cerebellum, such as nystagmus, dysarthria, or cerebellar ataxia;
however brain MR imaging showed moderate atrophy of the brain stem and
middle cerebellar peduncle and mild atrophy of the cerebellum (Fig 1A, -B),
in addition to T2 elongation of peritrigonal white matter and absence of the
T1 hyperintensity normally recognized in the posterior pituitary lobe (Fig
1C, -D). There was atrophy of intraorbital and intracranial optic nerves and
tracts (Fig 1D, -E). The patient was treated by intensive insulin therapy and
discharged 3 weeks later. Diabetic mellitus was well controlled, and his
neurologic status showed no obvious deterioration in January 2006.

View larger version (69K):

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Fig 1. Axial T2-weighted MR images show atrophy of the brain

stem and middle cerebellar peduncles and areas of elevated
signal intensity in the pons (A and B). Cerebellar atrophy is
also recognized. Signal-intensity abnormalities in optic
radiation on both sides are also seen (C, arrowheads). A
sagittal T1-weighted MR image shows intracranial optic nerve
atrophy (D, arrows) and absence of T1-hyperinensity normally
recognized in the posterior pituitary lobe. A coronal T1weighted image shows atrophy of both intraorbital optic nerves
(E).

Discussion
Our patient had elevated signals in the pontine base and marked atrophy of
the brain stem, middle cerebellar peduncle, and cerebellum. These changes
involving the pontocerebellar tract resembled MR imaging findings in
multiple system atrophy (MSA) and some kind of familial spinocerebellar
degeneration (eg, spinocerebellar ataxia [SCA] 1, SCA2, Machado-Joseph
disease [MJD or SCA3], or dentatorubral-pallidoluysian atrophy [DRPLA]).
Neuroradiologically, MSA features pontocerebellar atrophy and pontine
signal-intensity changes widely known as "cross signs." It is difficult to
radiologically differentiate the present case from MSA, but the age at onset
of MSA is usually the 5th or 6th decade. The patients with SCA1 have brain
stem and cerebellar volume loss and mild supratentorial generalized volume
loss.6,7 Patients with SCA2 have more severe olivopontocerebellar atrophy
than patients with SCA1 and SCA3, and they also have supratentorial
atrophy.7,8 The patients with SCA3 and DRPLA have atrophy of the superior
cerebellar peduncle, in addition to pontocerebellar atrophy.7,911 In patients
with DRPLA, T2-weighted images usually show white matter
hyperintensities. In our patient, there was no atrophy of the superior
cerebellar peduncle, and white matter hyperintensities were more focal than
those in patients with DRPLA.
Although it is difficult to radiologically differentiate the present case from
the previously mentioned pontocerebellar disorders, our patient had no
neurologic abnormalities suggesting dysfunction of the brain stem or
cerebellum. Previous reports of Wolfram syndrome2,1214 showed nearly the

same MR imaging findings as those of our patient, but the previous patients
had some neurologic deficits secondary to brain stem and cerebellar
atrophy.2,13 For example, a patient described by Scolding et al2 had pendular
nystagmus in the primary position and gaze-evoked nystagmus as a
vestibulocerebellar dysfunction, and another patient had slurring dysarthria
and limb ataxia, which corresponded with pontocerebellar atrophy. A patient
reported by Pakdemirli et al13 had dysarthria, and her brain MR imaging
showed atrophy of the brain stem and cerebellum. In a pathologically
confirmed case of Wolfram syndrome in a patient described by Gens et al,15
the patient had slight dysarthria and gait unsteadiness caused by atrophy of
the pons and cerebellar white matter; however, some previous reports of
Wolfram syndrome did not contain sufficient description of the neurologic
conditions.12,14
In our patient, it is unclear why the neurologic deficits secondary to brain
stem and cerebellar atrophy were absent despite apparent MR imaging
abnormalities in that region. A previous neuropathologic report of Wolfram
syndrome15 showed moderate loss of neurons in pontine nuclei, inferior
olives, and dentate nuclei of the cerebellum, and cerebellar white matter that
was reduced in size without demyelination. Purkinje cells were reduced and
showed axonal ballooning, but the granular cell layer was normal. Similarly,
in our patient, the atrophy was more apparent in the brain stem and middle
cerebellar peduncle than in the cerebellar cortices. This relative preservation
of cerebellar cortical architecture might be one of the causes of the
neurologic normality of cerebellar function, which was mismatched with
brain stem and cerebellar atrophy on MR imaging. In the previous reports of
Wolfram syndrome,2,13 the patients had some neurologic deficits secondary to
brain stem and cerebellar atrophy, but these deficits were considered milder
than those in patients with multiple system atrophy.
Additionally, our patient had T2 elongation of peritrigonal white matter and
absence of T1 hypeintensity normally seen in the posterior pituitary lobe.
The former could reflect primary or secondary degeneration of optic
radiation, because past microscopic examinations showed atrophy of optic
nerves, chiasm, tracts, and optic radiations and neuronal loss in the lateral
geniculate nuclei and superior colliculi.15 The latter suggested loss of
vasopressin-containing neurons as a cause of diabetes insipidus.
In summary, in patients with Wolfram syndrome, there were marked brain
MR imaging abnormalities affecting the pontocerebellar tract, whereas there

were few neurologic abnormalities suggesting cerebellar dysfunction. These

patients may have discrepancies between neurologic and radiologic findings.

Acknowledgments
We thank Drs. Ichiro Tatsuno and Kenichi Sakurai in the Department of
Clinical Cell Biology, Graduate School of Medicine, Chiba University, for
their great contributions to diagnosis and treatment of the patients.

DIDMOAD (Wolfram Syndrome)

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Is diabetes insipidus in combination with smaller than normal optic nerves enough to point to
DIDMOAD? (5 Apr 2009)
A friend was diagnosed with type 1. His mother and aunt both died of Wolfram's syndrome. Even
though his father is not a carrier, could he have further complications? (24 Jan 2008)
My son has had hearing loss in both ears since birth. Last month, he was diagnosed with type 1
diabetes. Could he have DIDMOAD? (23 Mar 2006)
My brother has had type 1 for years. His doctor says he is going blind in one eye and needs liver
tests. I am in the U.S. How can I help him? (1 Feb 2006)
Has there been any research into a cure for Wolfram's syndrome? I have two cousins who have it.
Are their siblings at risk for it? (2 Jun 2004)
My daughter has type 1. She has a hearing loss and may have Wolfram's Syndrome. What is her
life expectancy? Will she get the optic atrophy? (14 Mar 2004)
My 17 year old daughter has DIDMOAD. What is her life expectancy? What can we do? How do I
know if I passed this to my youngest daughter? (8 Mar 2004)
An optical neurologist told me my family had Wolfram's Syndrome. Should I get tested, and, if so,
where would I go to get such a test? (11 Feb 2004)
My 9 year old daughter has just been diagnosed with Optic atrophy. Is this the same as
DIDMOAD? (30 Jan 2004)
Can you enlighten me more about DIDMOAD? (13 Feb 2003)

10.
11. My 22 month old daughter has been diagnosed with diabetes mellitus and diabetes insipidus. (18
Oct 2002)
If my daughter would decide to have children, would they inherit this condition? (28 Jul 2002)

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13. I realize that there are other circumstances that affect blood sugar levels, but the answer to three
questions will be of great benefit to me. (20 May 2002)

14. I have gastroparesis and have been unable to tolerate the medication (Reglan), but I have been
told there is no other medication presently available. (6 Jan 2002)

15. My dog seems to do fine for three or four days, but then she gets hypoglycemic, usually shortly
before her next meal. Is this because we are using Ultralente? (27 Nov 2001)

16. Is there a genetic screen for Wolfram Syndrome? (11 Nov 2000)

17. We would like to know answers to some questions about DIDMOAD. (7 Nov 2000)
18. My son, 11 years of age, was diagnosed with diabetes a year ago. He also has Optic Atrophy. (26
Mar 2000)

19. We have a son with neurogenic diabetes insipidus. Last year our youngest child was diagnosed
with a variant form of MSUD. (24 Dec 1998)

20. I have heard there is a diabetes that also brings deafness. (21 Nov 1998)
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