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At a glance

This is a congenital medical condition characterized by diabetes mellitus (DM) and insipidus (DI) with optic nerve atrophy, mental retardation, and deafness. It is also called DIDMOAD, an acronym that stands for Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, and Deafness. This disorder affects mostly the central nervous system, especially the brain stem. The onset of the disease is during childhood. The first symptom is typically DM, which usually appear at the age of six. Optic atrophy is the second manifestation and the median age is 11 years old. The first retinal signs are loss of color and peripheral vision. This medical condition leads to blindness within 8 years from the initial symptoms. Life expectancy is approximately 30 years with a mortality rate about 65% before the age of 35 years.

Synonyms

Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy and Deafness; DIDMOAD Syndrome.

History

This is a genetic syndrome that was first described in four siblings by D. J. Wolfram in 1938.

Classification

There are two described genetic types of Wolfram Syndrome (WFS), which consists of:

  • WSF Type I: Mediated by the wolframin gene which provides instructions for making the wolframin protein that is active within the body and particularly in heart, lungs, inner ear, and pancreas.

  • WSF Type II: A dysfunction of the CISD2 gene is believed to be responsible for this form of the disease.

Nevertheless, both forms present the same clinical features.

Incidence

The exact incidence remains unknown. It is believed that it affects males and females equally.

Genetic inheritance

Autosomal recessive with mutations on the chromosome 4.

Pathophysiology

Caused by a mutation in the gene encoding wolframin (WFS1) on chromosome 4p16.1. Another locus for the disorder has been mapped to 4q (WFS2). Marked atrophy and degeneration is seen in the pons, the medullary reticular activating system, substantia nigra, superior and inferior olives, and the cerebellum. Microscopically, neuronal loss and axonal destruction, often accompanied by gliosis, is apparent, together with scattered areas of demyelination in the cerebrum and cerebellum, without inflammatory change.

Diagnosis

A combination of juvenile-onset diabetes mellitus and optic nerve atrophy plus one or more of the following: anosmia, brain stem signs (gaze palsies, nystagmus, dysarthria, dysphagia, primary respiratory failure), deafness, seizures or myoclonus, ataxia, axial rigidity, neuropsychiatric or cognitive abnormalities, neurogenic incontinence or dilated urinary tract, hyporeflexia or areflexia, extensor plantar responses, diabetes insipidus, and family history.

Clinical aspects

Diabetes mellitus, diabetes insipidus, optic nerve atrophy, sensorineural hearing loss, autonomic dysfunction, cardiomyopathy, mental retardation, seizures, nystagmus, hydronephrosis, megaloblastic anemia, sideroblastic anemia, neutropenia, and thrombocytopenia. The presentation of ...

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