Overview
Wolfram syndrome (DIDMOAD) is a rare autosomal recessive neurodegenerative disorder caused by mutations in WFS1 or CISD2, characterized by diabetes insipidus, diabetes mellitus, optic atrophy, and deafness. Optic atrophy typically presents in the first decade after diabetes mellitus onset, causing progressive bilateral central vision loss. Additional features include urinary tract abnormalities, psychiatric illness, and brainstem neurodegeneration. Life expectancy is reduced, with neurological complications causing death in the 3rd–4th decade.
Genetics
WFS1 mutations account for ~90% of cases. CISD2 mutations cause Wolfram syndrome type 2. Both genes affect ER stress and mitochondrial function. Autosomal recessive.
| Gene | Locus | Inheritance | Notes |
|---|---|---|---|
| WFS1 | 4p16.1 | AR | Wolframin; ER transmembrane protein; ~90% of cases |
| CISD2 | 4q24 | AR | CDGSH iron-sulfur domain protein 2; Wolfram syndrome type 2 |
Clinical Presentation
1st decade
- Diabetes mellitus (mean age 6 years)
- Optic atrophy with vision loss
- Diabetes insipidus
2nd–3rd decade
- Sensorineural hearing loss
- Urinary tract abnormalities
- Psychiatric illness (depression, psychosis)
Advanced
- Brainstem neurodegeneration
- Ataxia, dysphagia
- Premature death (mean ~35 years)
Diagnosis
- Clinical: Diabetes mellitus + optic atrophy in a child
- OCT: RNFL thinning
- MRI brain: Brainstem and cerebellar atrophy in advanced disease
- Genetic testing: WFS1 and CISD2 sequencing
- Endocrine evaluation: Glucose, ADH, renal function
Current Research & Treatment
No disease-modifying treatments approved. Clinical trials are investigating sodium valproate (neuroprotection), GLP-1 receptor agonists, and dantrolene (ER stress reduction). The Wolfram Syndrome International Registry coordinates global research efforts.
Active Clinical Trials
The following active clinical trials are investigating treatments for Wolfram Syndrome. Trial status and enrollment may change; always verify directly on ClinicalTrials.gov.