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Disease Profile

Wolfram syndrome

Prevalence
Prevalence estimates on Rare Medical Network websites are calculated based on data available from numerous sources, including US and European government statistics, the NIH, Orphanet, and published epidemiologic studies. Rare disease population data is recognized to be highly variable, and based on a wide variety of source data and methodologies, so the prevalence data on this site should be assumed to be estimated and cannot be considered to be absolutely correct.
1-9 / 1 000 000

331 - 2,979

US Estimated

1-9 / 1 000 000

514 - 4,622

Europe Estimated

Age of onset

Childhood

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ICD-10

E34.8

Inheritance

Autosomal dominant A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease

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Autosomal recessive Pathogenic variants in both copies of each gene of the chromosome are needed to cause an autosomal recessive disease and observe the mutant phenotype

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X-linked
dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

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X-linked
recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder

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Mitochondrial or multigenic Mitochondrial genetic disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria and inadequate production of energy.

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Multigenic or multifactor Inheritance involving many factors, of which at least one is genetic but none is of overwhelming importance, as in the causation of a disease by multiple genetic and environmental factors.

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Not applicable

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Other names (AKA)

WFS; Diabetes insipidus and mellitus with optic atrophy and deafness; DIDMOAD;

Categories

Congenital and Genetic Diseases; Ear, Nose, and Throat Diseases; Endocrine Diseases;

Summary

Wolfram syndrome, which is also known by the acronym DIDMOAD, is an inherited condition characterized by diabetes insipidus (DI), childhood-onset diabetes mellitus (DM), a gradual loss of vision caused by optic atrophy (OA), and deafness (D).[1] Other symptoms may include bladder and bowel dysfunction, problems with the parts of the inner ear and brain that help control balance and eye movements (vestibular deficits), temperature regulation problems, decreased balance, uncoordinated (ataxic) gait and olfactory deficits. Also, psychiatric symptoms such as anxiety and depression have also been noted in some cases.[2][3] There are two types of Wolfram syndrome (type 1 and type 2) which are primarily differentiated by their genetic cause. Type 1 is caused by changes (mutations) in the WFS1 gene, while type 2 is caused by mutations in the CISD2 gene. Both forms are inherited in an autosomal recessive manner.[2][4] However, some cases of Wolfram syndrome type 1 have an autosomal dominant inheritance and are more severe.[5] Diagnosis is suspected in cases of childhood-onset diabetes mellitus and optic atrophy, and this visual impairment is not due to the diabetes.[6] Treatment is symptomatic and supportive.[2]

Symptoms

The two types of Wolfram syndrome (type 1 and type 2) have many overlapping features. Wolfram syndrome type 1, which is also known by the acronym DIDMOAD, is characterized by diabetes insipidus (DI), childhood-onset diabetes mellitus (DM), gradual loss of vision due to optic atrophy (OA), and deafness (D).[1] About 65% of affected people will develop all four of these symptoms, while others will only have some of the associated health problems.[7]

Other signs and symptoms of Wolfram syndrome type 1 may include:[7][1][8]

  • Urinary tract abnormalities
  • Ataxia (problems with coordination and balance)
  • Loss of sense of smell
  • Loss of gag reflex
  • Myoclonus (muscle spasms)
  • Decreased sensation in some parts of the body (peripheral neuropathy)
  • Seizures
  • Depression
  • Impulsive and/or aggressive behavior
  • Psychosis
  • Gastrointestinal problems
  • Intellectual disability
  • Irregular breathing due to lack of brain's inability to control breathing (central apnea) and central respiratory failure
  • Hypogonadism in males (reduced amounts of the sex hormone testosterone)

In addition to the signs and symptoms found in Wolfram syndrome type 1, people with Wolfram syndrome type 2 may also have stomach and/or intestinal ulcers; and a tendency to bleed excessively after injuries.[1]

This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.

Medical Terms Other Names
Learn More:
HPO ID
80%-99% of people have these symptoms
Diabetes insipidus
0000873
Polydipsia
Extreme thirst
0001959
30%-79% of people have these symptoms
Abnormality of mesentery morphology
0100016
Ataxia
0001251
Dysarthria
Difficulty articulating speech
0001260
Dysuria
Painful or difficult urination
0100518
Feeding difficulties in infancy
0008872
Nephropathy
0000112
Nystagmus
Involuntary, rapid, rhythmic eye movements
0000639
Recurrent urinary tract infections
Frequent urinary tract infections
Repeated bladder infections
Repeated urinary tract infections
Urinary tract infections
Urinary tract infections, recurrent

[ more ]

0000010
Seizure
0001250
5%-29% of people have these symptoms
Abnormal autonomic nervous system physiology
0012332
Anemia
Low number of red blood cells or hemoglobin
0001903
Cardiomyopathy
Disease of the heart muscle
0001638
Central apnea
0002871
Cerebral cortical atrophy
Decrease in size of the outer layer of the brain due to loss of brain cells
0002120
Constipation
0002019
Delayed puberty
Delayed pubertal development
Delayed pubertal growth
Pubertal delay

[ more ]

0000823
Dementia
Dementia, progressive
Progressive dementia

[ more ]

0000726
Developmental regression
Loss of developmental milestones
Mental deterioration in childhood

[ more ]

0002376
Gastric ulcer
Stomach ulcer
0002592
Gastrointestinal hemorrhage
Gastrointestinal bleeding
0002239
Glaucoma
0000501
Hallucinations
Hallucination
Sensory hallucination

[ more ]

0000738
Intellectual disability
Mental deficiency
Mental retardation
Mental retardation, nonspecific
Mental-retardation

[ more ]

0001249
Joint stiffness
Stiff joint
Stiff joints

[ more ]

0001387
Malabsorption
Intestinal malabsorption
0002024
Male hypogonadism
Decreased function of male gonad
0000026
Myopathy
Muscle tissue disease
0003198
Ophthalmoplegia
Eye muscle paralysis
0000602
Peripheral neuropathy
0009830
Respiratory insufficiency
Respiratory impairment
0002093
Sleep disturbance
Difficulty sleeping
Trouble sleeping

[ more ]

0002360
Percent of people who have these symptoms is not available through HPO
Abnormal bleeding
Bleeding tendency
0001892
Abnormality of the skeletal system
Skeletal abnormalities
Skeletal anomalies

[ more ]

0000924
Autosomal recessive inheritance
0000007
Behavioral abnormality
Behavioral changes
Behavioral disorders
Behavioral disturbances
Behavioral problems
Behavioral/psychiatric abnormalities
Behavioural/Psychiatric abnormality
Psychiatric disorders
Psychiatric disturbances

[ more ]

0000708
Blindness
0000618
Cerebral atrophy
Degeneration of cerebrum
0002059
Decreased circulating antibody level
0004313
Depressivity
Depression
0000716
Diabetes mellitus
0000819
Dysphagia
Poor swallowing
Swallowing difficulties
Swallowing difficulty

[ more ]

0002015
Growth delay
Delayed growth
Growth deficiency
Growth failure
Growth retardation
Poor growth
Retarded growth

[ more ]

0001510
Hydronephrosis
0000126
Hydroureter
0000072
Hypothyroidism
Underactive thyroid
0000821
Impaired collagen-induced platelet aggregation
0008320
Limited mobility of proximal interphalangeal joint
Limited mobility of innermost hinge joint
0006217
Megaloblastic anemia
0001889
Mitochondrial inheritance
0001427
Neurogenic bladder
Lack of bladder control due to nervous system injury
0000011
Neutropenia
Low blood neutrophil count
Low neutrophil count

Cause

The two types of Wolfram syndrome (type 1 and type 2) are primarily differentiated by their genetic cause. Variations (mutations) in the WFS1 gene are responsible for about 90% of Wolfram syndrome type 1 cases. This gene encodes wolframin, a protein that is important for the proper functioning of the endoplasmic reticulum (the part of a cell that is involved in protein production, processing, and transport). Wolframin helps regulate the amount of calcium in cells, which is important for many different cellular functions. Mutations in WFS1 result in a defective form of wolframin that is unable to perform its normal role. This causes cells to trigger their own death (apoptosis). The death of cells in various organs and other parts of the body results in the signs and symptoms of Wolfram syndrome type 1.[1]

A specific mutation in the CISD2 gene causes Wolfram syndrome type 2. Although the exact function of this gene is not known, scientists suspect that it plays an important role in the mitochondria (the part of the cell where energy is produced). Mutations in CISD2 lead to the loss of mitochondria which decreases the amount of energy available to cells. Cells that do not have enough energy die. As in Wolfram syndrome type 1, the death of cells in different parts of the body results in the many health problems associated with Wolfram syndrome type 2.[1]

Mutations in mitochondrial DNA may also be a rare cause of Wolfram syndrome in some families.[9]

Diagnosis

A diagnosis of Wolfram syndrome is based on the presence of characteristic signs and symptoms. The identification of a change (mutation) in the WFS1 gene or CISD2 gene confirms the diagnosis.[2][8]

The following are the most important features that help with the diagnosis:[2]

  • Juvenile-onset (age <16 years) diabetes mellitus
  • Juvenile-onset optic atrophy (age <16 years)
  • Autosomal recessive inheritance

Carrier testing for at-risk relatives and prenatal testing are possible if the two disease-causing mutations in the family are known.[2] 

The Genetic Testing Registry (GTR) is a centralized online resource for information about genetic tests. It offers information on genetic testing for Wolfram syndrome type 1 and Wolfram syndrome type 2. The intended audience for the GTR is health care providers and researchers. Patients and consumers with specific questions about a genetic test should contact a health care provider or a genetics professional. 

 

 

Treatment

Treatment of Wolfram syndrome is supportive and based on the signs and symptoms present in each person. For example, almost all affected people require insulin to treat diabetes mellitus. People with hearing loss may benefit from hearing aids or cochlear implantation.[2][7][8]

For more detailed information please visit the GeneReviews section regarding the treatment and management of Wolfram syndrome.

Organizations

Support and advocacy groups can help you connect with other patients and families, and they can provide valuable services. Many develop patient-centered information and are the driving force behind research for better treatments and possible cures. They can direct you to research, resources, and services. Many organizations also have experts who serve as medical advisors or provide lists of doctors/clinics. Visit the group’s website or contact them to learn about the services they offer. Inclusion on this list is not an endorsement by GARD.

Organizations Supporting this Disease

    Learn more

    These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

    Where to Start

    • MedlinePlus Genetics contains information on Wolfram syndrome. This website is maintained by the National Library of Medicine.
    • The National Organization for Rare Disorders (NORD) has a report for patients and families about this condition. NORD is a patient advocacy organization for individuals with rare diseases and the organizations that serve them.

      In-Depth Information

      • GeneReviews provides current, expert-authored, peer-reviewed, full-text articles describing the application of genetic testing to the diagnosis, management, and genetic counseling of patients with specific inherited conditions.
      • The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. Monarch’s tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. This initiative is a collaboration between several academic institutions across the world and is funded by the National Institutes of Health. Visit the website to explore the biology of this condition.
      • Online Mendelian Inheritance in Man (OMIM) is a catalog of human genes and genetic disorders. Each entry has a summary of related medical articles. It is meant for health care professionals and researchers. OMIM is maintained by Johns Hopkins University School of Medicine. 
        Wolfram Syndrome 1
        Wolfram Syndrome 2
        Wolfram Syndrome, Mitochondrial Form
      • Orphanet is a European reference portal for information on rare diseases and orphan drugs. Access to this database is free of charge.
      • PubMed is a searchable database of medical literature and lists journal articles that discuss Wolfram syndrome. Click on the link to view a sample search on this topic.

        References

        1. Wolfram syndrome. Genetics Home Reference. 2012; https://ghr.nlm.nih.gov/condition/wolfram-syndrome.
        2. Tranebjærg L, Barrett T & Rendtorff ND. WFS1-Related Disorders. Gene Review. 2013; https://www.ncbi.nlm.nih.gov/books/NBK4144/.
        3. Doty T, Foster ER, Marshall B, Ranck S & Hershey T. The effects of disease-related symptoms on daily function in Wolfram Syndrome. Translational Science of Rare Diseases. 2017; 2(1-2):89-100. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5677191/.
        4. Wolfram Syndrome 2. OMIM. September 2014; https://omim.org/entry/604928.
        5. Rigoli L, Bramanti P, Di Bella C & De Luca F. Genetic and clinical aspects of Wolfram syndrome 1, a severe neurodegenerative disease. Pediatr Res. May, 2018; 83(5):921-929. https://www.ncbi.nlm.nih.gov/pubmed/29774890.
        6. Bueno GE, Ruiz-Castañeda D, Martínez JR, Muñoz MR & Alascio PC. Natural history and clinical characteristics of 50 patients with Wolfram syndrome. Endocrine. May 4, 2018; https://www.ncbi.nlm.nih.gov/pubmed/29728875.
        7. Wolfram syndrome. Orphanet. September 2014; https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=3463.
        8. Wolfram Syndrome. NORD. 2017; https://www.rarediseases.org/rare-disease-information/rare-diseases/byID/850/viewFullReport.
        9. Wolfram Syndrome, Mitochondrial Form. OMIM. September 2013; https://www.omim.org/entry/598500?search=wolfram%20syndrome&;highlight=syndromic%20syndrome%20wolfram.
        10. de Heredia ML, Clèries R, Nunes V. Genotypic classification of patients with Wolfram syndrome: insights into the natural history of the disease and correlation with phenotype. Genet Med. 2013 Jul;15(7):497-506. July 2013; 15(7):497-506.

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