WOLFRAM SYNDROME (DIDMOAD)
Researched and Written by Joy Koenig, M.D., M.S.
Board Certified in Preventive Medicine
© 1999 All Rights Reserved
This page is lovingly dedicated to
Megan O'Donnell
(October 27, 1986 - March 28, 2004)
SUMMARY
Wolfram Syndrome is a rare and complex genetic disorder, sometimes referred to as DIDMOAD (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, and Deafness). It is classified as a progressive neurodegenerative disease. This means the disorder primarily affects the body's nervous system and that the nervous system gradually declines in its ability to work correctly. Wolfram syndrome derives its name from the physician who first reported in four siblings the combination of juvenile-onset diabetes mellitus and optic atrophy. Since then (1938), over 170 people with Wolfram syndrome have been reported in the published medical literature.
How do I know if my child has Wolfram Syndrome?
A presumptive diagnosis of Wolfram syndrome is made if your child has both juvenile-onset diabetes and optic atrophy. Currently, aside from genetic analysis, there is no definitive medical test for Wolfram Syndrome. Genetic studies usually can confirm the diagnosis, and may help elucidate the clinical path the disorder may take in your child's particular case, since there two different documented genetic routes of transmission - autosomal recessive and mitochondrial (see genetics, below).
The combination of juvenile-onset diabetes and optic atrophy can also be related to causes other than Wolfram syndrome, such as congenital rubella syndrome, Leber's hereditary optic neuropathy, and thiamine-responsive anemia syndrome. These (and other) diseases need to be ruled-out before a diagnosis of Wolfram syndrome can be made definitively.
Although not common, there have been people who were symptom-free until adolescence and early adulthood. Therefore, it is suggested that siblings of those with Wolfram Syndrome be screened for the disorder through genetic testing, especially those under the age of 15 years. The delay more commonly happens if the disease has been acquired through maternal mitochondrial inheritance.
OVERVIEW (research abstracts)
Dr. Timothy Barrett (The Children's Hospital, Birmingham, UK) and Dr. Brendan T. Kinsley (Joslin Diabetes Center, Harvard, Boston) have conducted active case-finding studies on Wolfram syndrome, and have described the natural history of this disorder. The syndrome is progressive and degenerative. It has a variable presentation, and the 'natural history' descriptions that follow are based on group data. Currently, the exact path an individual with Wolfram syndrome will take cannot be predicted. Some people are spared various complications; however, the disorder is always progressive and degenerative and results in death before age 50, usually before age 35.
Dr. Tim Barrett, et al describe the natural history of Wolfram syndrome as follows, based on a study conducted in the UK: "This study shows that most Wolfram syndrome patients present with non-immune, insulin-deficient diabetes mellitus followed by optic atrophy in the first decade, cranial 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. Death occurs prematurely, often from respiratory failure associated with brain stem atrophy. The diagnosis of Wolfram syndrome implies devastating consequences for the physical, educational, and emotional outlook of these patients."
Dr. Brendan Kinsley, et al, describe the natural history of Wolfram syndrome similarly, based on a study conducted in the US: "Diabetes was diagnosed at 1-26 years of age (mean 8.2 years; median 6.5 years) It was the first manifestation of Wolfram syndrome in 84% of the patients...The mean age of diagnosis [for optic atrophy] was 13.1 years; (median 12.6; range 6-30 years). In seven patients optic atrophy was diagnosed before diabetes...The average age of diagnosis for hearing loss was 14.6 years (median 15 years; range 1-29 years). Partial or complete diabetes insipidus was present in [51% of studied cases] with a mean age at diagnosis of 15.5 years (median 14.8 years; range 4-41 years)...Dilated neurogenic bladders were reported for [54% of studied patients] with a mean age of onset of 17.4 years (median 15.2 years; range 7-41 years)...The mean age of death was 28 years (median 28.0 years; range 14.75 - 43.5 years)."
By definition, all people with Wolfram syndrome have both optic atrophy and juvenile-onset diabetes. A significant number (70-75%) also develop diabetes insipidus, and roughly two-thirds develop some degree of auditory nerve deafness. Neurodegenerative complications of the urinary tract are present in about two-thirds of those with this disorder, and at least 60% have neurological symptoms such as ataxia (unbalanced walking) and startle myoclonus (an increased reaction to strong stimuli such as loud noises). Over half of the people with Wolfram syndrome have episodes of severe depression, psychosis, or organic brain syndrome, as well as impulsive verbal and physical aggression. In about 25% of people, the symptoms are severe enough to require hospital admission. In addition, those who carry the gene but don't have the disorder (certain blood relatives) are at a 25-50 fold risk of developing serious psychiatric illnesses. A considerable number of people (25%) have problems with their digestive systems, including recurring constipation or diarrhea, probably secondary to involvement of the nerves regulating intestinal motility.
In summary, the majority of children who develop diabetes mellitus and optic atrophy will eventually develop the other complications [diabetes insipidus and deafness] of this progressive degenerative disorder of the central and peripheral nervous systems, and will most likely die before age 40 years.
SYMPTOMS
(in order of usual appearance)
AGE 0 - 9 YEARS
Diabetes Mellitus (DM)
Diabetes mellitus (sugar diabetes) together with the presence of optic atrophy (see below), are the hallmark traits of Wolfram syndrome, and a person with these two traits is presumptively considered to have Wolfram syndrome until proven otherwise. The median age of DM diagnosis is 6 years, and it is the most common presenting symptom for people with Wolfram syndrome. Almost 85% of people develop and are diagnosed with DM before any other symptom of Wolfram syndrome is identified.
The cause and clinical path of DM in Wolfram syndrome is significantly different from 'classic' childhood diabetes. It is not auto-immune in nature, though it is caused by a deficiency of insulin. Although the underlying cause of insufficient insulin in Wolfram syndrome is still unknown, it is believed to be of a central nervous system nature (hypothalamic centers controlling glucose balance), since every other symptom of Wolfram syndrome has a neurologic basis.
Of significant importance is that the common diabetic complications of proliferative retinopathy (a vision disorder involving the retina) and glomerulosclerosis (a kidney abnormality) are remarkably absent in people with Wolfram syndrome as compared to people with other forms of juvenile-onset diabetes. Although tight blood sugar level control is critical in preventing and delaying the above complications in people with classic Type I diabetes, there is no evidence that it slows or alters the progression of Wolfram syndrome manifestations. Death from diabetes-related symptoms and complications is rare, but possible, among people with Wolfram syndrome.
Some studies have found higher frequencies of DM (typically adult-onset DM) in blood relatives of people with Wolfram syndrome, suggesting that just carrying the gene for Wolfram syndrome may increase the risk of this type of diabetes.
Optic Atrophy (OA)
The deterioration of the nerve carrying signals from the retina to the brain is termed optic atrophy (atrophy of the optic nerve). Clinically, OA presents as decreased visual acuity and diminished color vision, and is a hallmark trait of Wolfram syndrome. The median age of diagnosis for OA is about 12 years. On average, it takes about seven years for a person diagnosed with Wolfram syndrome to develop sufficient deterioration in vision to be categorized as 'legally blind'.
It is unusual for total blindness to develop in people with Wolfram syndrome, and most retain some ability, at least in one eye, for light/dark discrimination. Although some people with Wolfram syndrome will have clinical evidence of diabetic retinopathy in addition to optic atrophy, the contribution to decreased vision attributable to diabetic retinopathy as opposed to neurodegeneration, is so small as to be negligible. The only treatment currently available for OA is supportive not corrective.
AGE 10 - 19 YEARS
Diabetes Insipidus (DI)
Diabetes insipidus (water diabetes) is the third most common aspect of Wolfram syndrome. Roughly three-quarters of people with Wolfram syndrome develop DI, usually within ten years of their diagnosis of Wolfram syndrome (median age 15 years). The DI of Wolfram syndrome is caused by a deficiency of the hormone (vasopressin) responsible for instructing the kidney to re-absorb water during urine production. Since the hormone is not present in effective amounts, the kidneys eliminate much more water than is healthy - sometimes to the point of being life-endangering.
Symptoms of DI are similar to symptoms of poorly controlled diabetes mellitus; therefore, it is not uncommon for the diagnosis of DI to be delayed in people who have Wolfram syndrome. Symptoms include excessive thirst, frequent and copious urine output, and a frequent need to awake during the night to urinate, or involuntary bedwetting (nocturia and enuresis). Urine in people with untreated DI is very dilute; therefore, it usually looks like water (clear) instead of urine (yellow), and is often missing the characteristic odor of urine.
Treatment of DI is relatively uncomplicated. Most people obtain complete relief of symptoms through the use of vasopressin intranasal spray or tablets. Poorly controlled DI can contribute to the seriousness of urinary tract problems (below).
Urinary Tract Abnormalities
People with Wolfram syndrome often develop urinary tract problems. The median age of onset in Kinsley's study was 15 years, and in Barrett's study 20 years. Symptoms include frequent urination, incontinence, and recurrent infections of the bladder and/or kidneys. Serious kidney damage can develop, and renal failure is not an uncommon cause of death in people with Wolfram syndrome.
The symptoms are caused by dysfunction of the nerves that lead to the bladder and a loss of nerve tissue in the bladder and the ureters (the tubes that lead from the kidneys to the bladder). The nervous centers in the brain that control urination may also play a role. The bladder can become functionally obstructed (versus anatomically), with residual urine left in the bladder after urinating, requiring intermittent self-catheterization or indwelling catheter (a device used to by-pass the bladder's functional impairment) to manage incontinence and prevent back flow of urine into the kidneys.
Kidney disease develops in approximately one-third of people. Prophylaxis with antibiotics to prevent recurrent bladder infections and/or kidney infection is often warranted. There have been some deaths associated with blood infections that developed secondary to kidney infections.
Deafness
Symptomatic deafness develops in about two-thirds of people with Wolfram syndrome, and about 25% of these people require hearing aids. The hearing loss is almost always selective for high frequencies, rather than global, though there can be low frequency loss as well. The median age for the development of deafness is 15-16 years.
As with all traits of Wolfram syndrome, the physiological mechanism of deafness is neurological, affecting the auditory nerve and possibly the central auditory pathways. Deafness is caused by a lack of perception of sound, rather than a deficit in transmitting the sound to the nerve. The technical term for the type of deafness associated with Wolfram syndrome is 'sensorineural'. Deafness may have been under-diagnosed in the early reported cases, since the deafness associate with this syndrome is typically selective and not severe, unlike the blindness.
AGE 20 - 29 YEARS
Delayed or Impaired Sexual Development
It is common for males and females with Wolfram syndrome to have impaired and/or delayed sexual development. It is most likely related to dysfunction of the hypothalamus. In both males and females, the gonads (ovaries and testicles) can be under-developed. The onset of menstruation, when it occurs, is usually significantly delayed (commonly age 16 and as late as age 19). Just as with the auditory nerve, there are some who are spared reproductive involvement. A few women with Wolfram syndrome and sexual partners of men with Wolfram syndrome have had normal pregnancies with normal children.
Central Nervous System Complications
The most devastating and serious complications of Wolfram syndrome are those of the central nervous system. Death is most commonly a result of degeneration of the central nervous system.
The most common non-life-threatening abnormalities are disorders of the eyes such as nystagmus (abnormal eye movements) and changes in the pupils. Approximately one-third of people develop ataxia (unsteady gait and falls). Other neurological abnormalities include a loss of taste and smell. Startle myoclonus (an exaggerated response to things that 'startle' such as loud noises) is present in about 20% of people with Wolfram syndrome, and in rare instances can require confinement to a wheelchair. Seizure disorders are not uncommon (20%; median age 19 years), and may be caused by hypoglycemia (low blood sugar) or by the underlying neurodegeneration.
Life-threatening complications include central apnea (brief periods of respiratory arrest) and central respiratory failure resulting from degeneration of the brain stem, where the 'breathing center' is located. Bulbar dysfunction (the area of the brain controlling swallowing) can lead to death by causing repeated aspiration of food and stomach contents into the lungs.
Mental Health
People living with Wolfram syndrome often have serious psychiatric and psychological illness. Over half of the people with Wolfram syndrome have episodes of severe depression, psychosis, or organic brain syndrome, as well as impulsive verbal and physical aggression. In about 25% of people, the symptoms are severe enough to require admission to a psychiatric hospital. In some people with Wolfram syndrome, psychiatric illness such as depression (and suicide attempts) may be related to the struggles of living with a chronic debilitating disease. Researchers believe, however, that the psychiatric illnesses seen among people with Wolfram syndrome are directly related to physiologic changes that occur in the brain due to the syndrome.
In addition, those who carry the gene but don't have the disorder (certain blood relatives) are at a 25-50 fold risk of developing serious psychiatric illnesses.
ALL AGES
Less Common Complications
People with Wolfram syndrome also seem to have more frequent problems with heart rhythm (sinus tachycardia (abnormally fast but regular rhythm), and irregularities in the rhythm of either the atria or ventricles of the heart).
Gastrointestinal problems such as frequent constipation and diarrhea are also more common than is seen in the general population (about 25% of people with Wolfram syndrome) and may be related to dysfunction of the nerves that control the motion of the digestive tract.
LONG TERM PROGNOSIS (Life Expectancy)
This disorder is characterized by progressive deterioration of the central and peripheral nervous systems. Dr. Barrett found the median age of death for people with this disorder to be 30 years (range 25 - 49 years); Dr. Kinsley reported the median age of death as 28 years, and that 60% of the people with Wolfram syndrome had died by the age 35. As reported in the literature, the youngest person to die with Wolfram syndrome was 14 years old, the oldest was 49 years old.
Death can be caused by central respiratory center failure, kidney failure, hypoglycemic (low blood sugar) reactions, complications related to aspiration (bulbar dysfunction), seizures, and in some cases, suicide secondary to depression, as well as other causes.
| Summary of Symptoms (in order of usual appearance) | |
AGES 0 - 9 YEARS | |
| Diabetes Mellitus (DM) | 100 % |
| Optic Atrophy (OA) | 100 % |
AGES 10 - 19 YEARS | |
| Diabetes Insipidus (DI) | ~ 70 % |
| Urinary Tract Abnormalities | ~ 66 % |
| Abnormal Sexual Development | < 50 % |
| Deafness | ~ 66 % |
AGES 20+ YEARS | |
| Central Nervous System Symptoms | < 60 % |
ALL AGES | |
| Mental Health Disorders | > 50 % |
| Heart Rhythm Disorders | < 10 % |
| Digestive System Symptoms | ~ 25 % |
GENETICS AND MECHANISM OF DISEASE
Wolfram syndrome is most commonly inherited in a pattern referred to as autosomal recessive. Recent medical research has found evidence that some cases of Wolfram syndrome are transmitted by maternal mitochondrial DNA transmission (see below) instead of autosomally. Autosomal refers to chromosome transmission, and specifically means that the genes (DNA) that encode for the disorder are on the regular chromosomes, not the chromosomes (X,Y) that determine a person's gender. This is evidenced by the fact that an equal number of men and women are affected by Wolfram syndrome.
Recessive means that the normal function of the gene is dominant, so a person has to receive the Wolfram genes from both parents in order to develop the disorder. If a person receives a set of Wolfram genes from one parent, and normal genes from the other parent, the individual will not have Wolfram syndrome, since the normal state dominates over the Wolfram state. However, those who carry one, but not two, sets of the genes that code for Wolfram syndrome may be at an increased risk for serious psychiatric illness and adult onset diabetes, and can pass the Wolfram set of genes on to their children. An estimated 1 in 350 people carry the genes for Wolfram syndrome.
Recently, the genes that control the characteristics of Wolfram syndrome have been mapped to the short 'arm' of the fourth chromosome (4p16.1). It is believed, though not yet proven, that the genes in this area of the fourth chromosome might encode for the structural properties and function of mitochondria, a cell component found in most cells.
Although the physiologic mechanism of this disorder is still under investigation, symptoms are currently believed to occur through defects in nuclear and mitochondrial DNA that code for cell processes controlled by mitochondria, a cellular component responsible for many cell functions. Mitochondria have their own DNA as well as being governed by nuclear DNA. In a small number of people, investigators have found a normal fourth chromosome, but abnormalities in the DNA of the mitochondria. In some people, most of the mitochondria have been affected, in other people only a small percentage of the mitochondria carry DNA defects. The severity of the disorder in these individuals appears to be directly correlated with the percentage of mitochondria that have disordered DNA. Mitochondrial inheritance is exclusively mother-to-child.
Genetic counseling and testing for all family members is important for several reasons, even if a couple does not desire more children.
- It is important for the child's care to know whether they have the autosomal version or the mitochondrial version of the disorder - prognosis and rate of progression are different;
- It is important to distinguish mitochondrial from autosomal transmission, to know which parent(s) and siblings are carriers of the gene in terms of their risk of serious psychiatric illness and adult onset diabetes, and to determine whether siblings may have a currently asymptomatic mild form of the disorder;
- Siblings and other blood relatives need to understand their reproductive as well as their personal risk if they are a carrier of the gene. If the disorder has been passed on through mitochondria in a particular family, then an unaffected sibling may have normal mitochondria and no risk of transmitting the disease, and no higher risk for mental illness or diabetes. If the disorder follows a classic autosomal recessive pattern in a family, then each sibling has a 50% chance of having the genes for the disorder and a 25% risk of having a child with Wolfram syndrome if they pair with another carrier.
CARE MANAGEMENT
Treatment consists of managing the complications of Wolfram syndrome as they occur, and preventing the secondary complications when possible. No individual person will follow the above described patterns exactly, and not everyone develops each of the manifestations before their death. For instance, in some people the auditory nerve is spared, in others the digestive system nerves. Other parts of the nervous system are universally affected, such as the optic nerve and the mechanism that regulates sugar metabolism. Therefore, although the specific path that each person takes will be different; the overall progression of the disease to premature death is not disputed. There have been no reported cases of people diagnosed with Wolfram syndrome that have not progressed to life-threatening complications and premature death, and there currently is no treatment for the underlying mechanism of neurodegeneration in Wolfram syndrome.
Once the diagnosis of Wolfram syndrome is established through genetic studies and ruling out other causes, care management focuses on screening for and treating the other predictable disorders of Wolfram syndrome.
Annual screening for diabetes insipidus using paired serum and urine osmolarity, annual vision and hearing assessments, and a baseline MRI are recommended by Dr. Tim Barrett. Monitoring for symptoms such as incontinence and bed-wetting as signs of diabetes insipidus and/or urinary tract dysfunction is also recommended. The use of oral antibiotics to prevent urinary tract infections caused by bladder malfunction, and watching for apnea (short periods of respiratory arrest) are important aspects to discuss with your health care provider.
The high prevalence of mental health problems may also warrant periodic screening for depression and other psychiatric symptoms. It may also be appropriate to educate pre-teens and teenagers about the probable delay or disruption of sexual development.
People living with Wolfram syndrome have a wide-variety of special social, emotional and psychological needs. Training in how to modify the home and school to accommodate the severe visual disability is critical in developing self-esteem and confidence, as well as maximizing school performance. Learning disabilities and mental retardation are not an integral part of Wolfram syndrome.
Most individuals with Wolfram syndrome live past childhood, but most do not live past the age of 35; therefore, quality of life is a strong issue. Decisions that affect quality of life should be made asking the question, "When we get to the end of the road, what will have made my child feel that life was worth living?" Often, we inadvertently ask this question, "What will make me feel that my child's life was worth living?" For most of us, simply having pleased our parents isn't sufficient for us to believe our life was worthwhile, especially if we see and move through the world differently than our parents (Myers Briggs personality types).
Focus on skills and attitudes that universally build self-worth, such as those that foster autonomy and self-control. Choose activities that fit your child's natural personality and values, whether that's going off by themselves to listen to books on tape, or meeting up with friends to listen to music. Some people value objective approaches, as well as accomplishments and competency with inanimate objects such as winning games and sports, school projects and building things. Others value subjective approaches as well as accomplishments and competency with animate objects - helping parents, friends and animals, being part of a team (win or lose) and building relationships.
Learn what your child values, and help your child reach those goals, and it's more likely that you will all end up believing, no matter how short and challenging, life was worthwhile.
(There is also a shorter version of this article on the Diabetes Insipidus web site)
wolfram syndrome, didmoad, genetic, neurodegenerative, disorder, disease, optic atrophy, deafness, diabetes insipidus, diabetes mellitus, blindess, sugar, water, diabetes, clinical, treatment, congenital
Design, Content and Images © Joy Koenig 1999 - 2008 All Rights Reserved. 
