Wolfram syndrome (WS) also known as DIDMOAD, is a neurodegenerative disorder characterized by type I diabetes mellitus (DM), diabetes insipidus (DI), sensorineural deafness (D), bilateral optical atrophy (OA) and neurological signs. Other related problems are urinary tract atony, ataxia, peripheral neuropathy, psychiatric disorders and/or seizures. 2 types of WS may be distinguished: type 1 and type 2 (WS1 and WS2).
The prevalence is estimated to be 1/770,000 in UK.
Onset of WS1 lies in the first decade and it is characterized with DM (91% of cases), OA (87%). Patients present a progressive reduction of visual acuity and loss of color vision (leading to vision of 6/60 or less in the better eye over an average of 8 years). Less frequent ocular abnormalities include abnormal papillary light reflexes, nystagmus, cataracts, pigmentary maculopathy, retinopathy (pigmentary or diabetic) and glaucoma. 50% of patients also develop DI and present some degree of deafness (slowly progressive high frequency). The full DIDMOAD phenotype is observed in 65% of cases. Additional features may include urinary tract abnormalities (hydroureter, urinary incontinence, recurrent infections), neurological involvement (ataxia, myoclonus, epilepsy, hyposmia and cognitive disability) and psychiatric disorders (depression). Life-threatening complications, including central apnea (due to bulbar dysfunction) are frequent and may lead to recurrent aspiration pneumonia. Gastrointestinal disorders (bowel dysmotility, gastroparesis, and bowel incontinence) and bilateral cataracts can also be present. Hypogonadism and delay/disruption of sexual development have also been reported. Patients with WS2 present early OA, DM, D, decreased lifespan, but no DI. It has been described in 3 consanguineous families of Jordanian descent. An autosomal dominant disorder, referred to as Wolfram-like syndrome (see this term), with DM occurring in adulthood, a juvenile onset of OA, and/or associated hearing impairment has also been described.
2 causative genes have been identified: WFS1 (4p16.1) which codes for Wolframin, a protein localized to the endoplasmic reticulum (ER) and which plays a role in calcium homeostasis and unfolded protein response. Mutations in WFS1 are responsible for the majority of the WS phenotypes and account for WS1. CISD2 (4q24), located to ER and mitochondria, is thought to help maintaining mitochondrial functioning. Mutations in CISD2 account for WS2.
The clinical criterion for WS diagnosis is juvenile-onset DM and OA, family history of WS or DM and D. Magnetic resonance imaging scans show generalized brain atrophy, especially in the cerebellum, medulla, and pons; absence of signal from the posterior pituitary; and reduced signal from the optic nerve. Diagnosis is confirmed by genetic screening.
Differential diagnosis includes mitochondrial disorders such as maternally-inherited diabetes and deafness; Leber hereditary optic neuropathy; thiamine-responsive megaloblastic anemia syndrome; autosomal dominant optic atrophy plus syndrome and Mohr-Tranebjaerg syndrome (see these terms).
In families in which the causative mutations have been characterized, molecular carrier detection and prenatal diagnosis can be performed.
Transmission is autosomal recessive. Genetic counseling may be offered to at-risk couples. WFS1 heterozygous individuals are at risk of developing low frequency D and DM.
Management is supportive and includes an annual screening for DM, vision, D, urodynamic testing, nephropathy and daily insulin injections and a controlled diet to treat DM. Treatment of DI, apnea and urinary disorders (i.e. prophylactic antibiotherapy for urinary infections) is needed. 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.
Last update: September 2014
- Dr Miguel LOPEZ DE HEREDIA
- Dr Virginia NUNES MARTÍNEZ