DEFINITION
Wolfram syndrome, also called DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness), is a rare autosomal-recessive genetic disorder that causes childhood-onset diabetes mellitus, optic atrophy, and deafness as well as various other possible disorders.
It has now been established that Wolfram syndrome is caused by endoplasmic reticulum dysfunction
Wolfram Syndrome
Tissue distribution
EPIDEMIOLOGY
age, sex, seasonality, etc
SYMPTOMS
DIAGNOSIS
histopathology
radiology
NMR
laboratory tests
PATHOGENESIS
Diabetes
Wolfram syndrome and Diabetes pathogenesis - Results from Quertle® AI-based Biomedical Literature Platform
Early impairment of glucose tolerance and β-cell function in obese children. 2010
Diabetes present in Wolfram syndrome is a result of the selective β cell loss and failed insulin secretion which is probably associated with non-autoimmune pathogenesis.
Diabetes therapy
Differential diagnosis of type 1 diabetes: which genetic syndromes need to be considered? 2007
Wolfram syndrome
Wolfram syndrome [also known as diabetes insipidus, diabetes mellitus, optic atrophy, and deafness (DIDMOAD)] is an autosomal recessive syndrome in which the association of insulin‐dependent diabetes with progressive optic atrophy under 16 yr of age is diagnostic 14 (Fig. 2). Other features include bilateral progressive sensorineural deafness, cranial diabetes insipidus, autonomic nervous system dysfunction leading to neuropathic bladder, and other signs of neurodegeneration including cerebellar ataxia, myoclonic epilepsy, and brainstem atrophy. The complete phenotype is seen in about 75% of patients. The diabetes is non‐autoimmune and insulin deficient and presents at a median age of 6 yr. Patients usually require insulin treatment from diagnosis. The median age of death in Wolfram syndrome is 30 yr, and development of the full phenotype is seen with increasing age.
Figure 2
Natural history of Wolfram syndrome. D, deafness; DI, diabetes insipidus; DM, diabetes mellitus; Neuro, neurodegeneration; OA, optic atrophy; renal, neuropathic bladder.
The syndrome is caused by loss of function mutations in the Wolfram (WFS‐1) gene 15, encoding Wolframin, an endoplasmic reticulum (ER) membrane protein. Pancreatic β‐cells are some of the most susceptible cells to ER stress, and ER stress‐mediated apoptosis causes diabetes in Wolfram syndrome. Mutations are distributed throughout the entire gene, but with one loss of function mutation at the carboxy‐terminal end (c.2648‐2651delTCTT; F883fsX950) recurring in white European populations 16. Mutations in the WFS‐1 are present in 90% of patients. In general, patients with one or more inactivating mutations will have a severe phenotype, whereas homozygosity or compound heterozygosity for missense mutations is more likely to result in a mild phenotype 17. The most important part of management is in supporting the family with this devastating diagnosis and teaching the child low skills, while there is useful vision remaining.
Eye
Wolfram syndrome 1 (Wfs1) gene expression in the normal mouse visual system. 2008
The function of WFS1 (wolframin), the distribution of this protein in the mammalian visual system, and the pathogenesis of optic atrophy in Wolfram syndrome are unclear.
Cochlea
Expression pattern of wolframin, the WFS1 (Wolfram syndrome-1 gene) product, in common marmoset (Callithrix jacchus) cochlea. 2016
Elucidating the function of wolframin protein in the basal cells of primates would be essential for understanding the pathogenesis of hearing loss in patients with Wolfram syndrome, which may lead to the discovery of new therapeutics.
Micro-RNA Binding Site Polymorphisms in the WFS1 Gene Are Risk Factors of Diabetes Mellitus. 2015
Although the connection between loss of function mutations of the WFS1 gene and DIDMOAD-syndrome including diabetes mellitus underpins the significance of wolframin in the pathogenesis, exact role of WFS1 polymorphic variants in the development of type 1 and type 2 diabetes has not been discovered yet.
PATIENT RISK FACTORS
Vascular
Genetic
Acquired
Hormonal
Genetic
Acquired
TISSUE SPECIFIC RISK FACTORS
anatomical (due its structure)
vascular (due to the local circulation)
physiopathological (due to tissue function and activity)
COMPLICATIONS
THERAPY
