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Estimated prevalence of Wolfram syndrome (WS) is 1/770,000 worldwide.

2 types of WS may be distinguished: type 1 (WS1) and type 2 (WS2). WS1 has onset in the first decade, with DM (91% of cases) and OA (87%) manifestations. Patients present a progressive reduction of visual acuity and loss of color vision. 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 some degree of deafness (slowly progressive high frequency). The full phenotype spectrum 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 manifestations (depression). Life-threatening complications, including central apnea (due to bulbar dysfunction) are frequent and may lead to recurrent aspiration pneumonia. Other reported symptoms are gastrointestinal disorders (bowel dysmotility, gastroparesis, and bowel incontinence), hypogonadism, and delay/disruption of sexual development. Patients with WS2 present early OA, DM, D, and decreased lifespan, but no DI.

2 causative genes have been identified: WFS1 (4p16.1) and CISD2 (4q24). WFS1 encodes Wolframin, a protein localized to the endoplasmic reticulum (ER) with roles in calcium homeostasis and unfolded protein response. Mutations in WFS1 are responsible for the majority of the WS phenotypes and account for WS1. CISD2 encodes the ERIS protein, located dynamically between the ER and mitochondria outer membrane, with roles in glucose homeostasis regulation, insulin sensitivity for calcium homeostasis and autophagy. Mutations in CISD2 account for WS2.

The clinical criteria for WS diagnosis are juvenile-onset DM and OA, family history of WS or DM and D. MRI 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, Mohr-Tranebjaerg syndrome, and Autosomal dominant optic atrophy plus syndrome. Other possible differential diagnoses are X-linked Carcot-Marie-Tooth disease type 5, Friedreich ataxia, Thiamine-responsive megaloblastic anemia, Bardet-Biedl and Alstrom syndromes. An autosomal dominant disorder, referred to as Wolfram-like syndrome, with DM occurring in adulthood, a juvenile onset of OA, and/or associated hearing impairment has also been described.

In families with characterized causative mutations, molecular carrier detection and preimplantation or prenatal diagnosis can be performed.

Transmission is autosomal recessive. Genetic counseling may be offered to at-risk couples carrying mutation either in WFS1 or CISD2 genes. Carrier testing may be possible when the variant associated to WFS1 poses heterozygous individuals 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.