Summary

Wolfram syndrome (WFS) is a rare neurodegenerative disorder characterized by type I diabetes mellitus, diabetes insipidus, optical atrophy and neurological signs. About 300 cases have been described, and prevalence is estimated at 1/160,000. The minimum ascertainment criterion for WFS is the association of juvenile-onset type I diabetes mellitus (DM), without antibodies and usually appearing during the first decade of life, with onset of bilateral optic atrophy before the second decade. The optical atrophy only affects the peripheral vision. About 70%-75% of patients also develop diabetes insipidus, and about two-thirds present with some degree of sensorineural deafness affecting the high frequencies. Other related problems are urinary tract atony, ataxia, peripheral neuropathy, dementia, psychiatric disorders and/or seizures. About 60% of homozygous WFS patients have episodes of severe depression or psychosis, as well as displaying compulsive verbal and physical aggression. About 25% of patients present with digestive problems (recurrent constipation or diarrhea). Kidney disease is present in about one-third of patients. Life-threatening problems, including central apnea and central respiratory failure, are also frequent. Bulbar dysfunction can lead to death due to recurrent aspiration pneumonia. Cardiomyopathy and anemia can also be present. Delay or disruption of sexual development has also been reported. WFS is transmitted in an autosomal recessive manner. Two causative genes have been identified: WFS1 (4p16.1), coding for Wolframin, which is localized to the endoplasmic reticulum and plays a role in calcium homeostasis, and CISD2 encoding the CDGSH iron sulfur domain-containing protein 2. Mutations in CISD2 have only been identified in three consanguineous families of Jordanian descent and WFS1 mutations are responsible for the majority of the WFS phenotypes. More than 150 different WFS1 mutations have been described in different populations, most of them in exon 8. In families in which mutations in WFS1 or CISD2 have been characterized, clinical diagnosis and carrier identification can be performed. Heterozygous carriers of WFS1 mutations are eight times more likely to be hospitalized for psychiatric disorders than non-carriers. They are also at risk of developing low frequency sensorineural hearing loss and diabetes mellitus. Molecular prenatal diagnosis is available. Differential diagnosis includes autoimmune type I diabetes and Leber optic atrophy or LHON (see this term). Treatment is symptomatic. Care management is based on screening for and treating the predictable disorders associated with the disease. Annual screening for diabetes, vision and hearing loss, and a baseline MRI are recommended. Daily insulin injections and a controlled diet are required to treat DM. Management of diabetes insipidus, apnea and urinary disorders (i.e. prophylactic antibiotherapy for urinary infections) is needed. As mental health problems are highly prevalent in WFS patients, 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.

Expert reviewer(s)

• Dr Virginia NUNES MARTÍNEZ