Wolfram Syndrome

Wolfram syndrome is a rare autosomal recessive neurodegenerative disorder defined by early onset non-autoimmune diabetes mellitus and progressive optic atrophy. Diabetes insipidus, sensorineural deafness and other features complete the full picture.

Prevalence is of the order of 1 in 500,000. Diabetes usually starts in the first decade, optic atrophy at around 10 to 15 years, and death often occurs in the third to fourth decades from brainstem failure.

It is caused by biallelic variants in WFS1 (Wolfram syndrome type 1) and rarely CISD2 (type 2, with bleeding ulcers and no diabetes insipidus). Heterozygous WFS1 variants cause dominant deafness or milder disease.

Pathophysiology.

WFS1 encodes wolframin, an endoplasmic reticulum protein. Loss of function causes chronic endoplasmic reticulum stress and calcium dysregulation.

Beta cells, optic nerve and brainstem neurons are particularly sensitive, producing apoptosis, insulin deficient diabetes and neurodegeneration.

• Insulin requiring diabetes in childhood, with negative islet autoantibodies and low insulin need.
• Progressive loss of visual acuity and colour vision, then visual field constriction. High frequency sensorineural deafness. Central diabetes insipidus with polyuria and nocturia.
• Neurogenic bladder, ureteric dilatation and recurrent urinary infection. Ataxia, peripheral neuropathy, central sleep apnoea and brainstem dysfunction. Depression, psychosis and suicide risk.
• Hypogonadism, short stature and anosmia may occur.

Red flags.

• Suicidal thoughts or psychotic features.
• Central apnoea, dysphagia or bulbar signs.
• Hydronephrosis or recurrent urosepsis.

• Suspect in any child with diabetes and unexplained optic atrophy, or antibody negative childhood diabetes with deafness or polyuria.
• Biallelic WFS1 variants confirm the diagnosis. Test CISD2 if WFS1 is negative.
• Ophthalmology with visual acuity, colour vision, visual fields and optical coherence tomography.
• Audiometry, water deprivation or desmopressin test for diabetes insipidus, renal tract ultrasound, urodynamics and MRI brain (loss of the posterior pituitary bright spot, brainstem and cerebellar atrophy).
• Psychiatric assessment and a sleep study if apnoea is suspected.

Differential diagnosis.

• Type 1 diabetes with other optic neuropathy.
• Maternally inherited diabetes and deafness (mitochondrial m.3243A>G).
• Thiamine responsive megaloblastic anaemia (diabetes, deafness, megaloblastic anaemia).
• Leber hereditary optic neuropathy, dominant optic atrophy (OPA1), Friedreich ataxia, Alstrom and Bardet-Biedl syndromes.

• No treatment alters the course. Care is symptomatic and delivered by a multidisciplinary clinic.
• Diabetes: insulin, usually at low doses, with usual targets. Screen for microvascular disease annually.
• Diabetes insipidus: desmopressin, adult dose 100 micrograms orally at night, titrated to 100 to 200 micrograms two to three times daily; check serum sodium 1 week after starting and after each change because of hyponatraemia risk.
• Vision: low vision aids and rehabilitation. Hearing: aids or cochlear implantation.
• Bladder: intermittent catheterisation and an antimuscarinic such as oxybutynin 2.5 to 5 mg two to three times daily; treat infections promptly and consider prophylaxis for recurrent infection.
• Mental health: screen at each visit and treat depression and psychosis. Respiratory: sleep study and non-invasive ventilation for central apnoea.

Genetic counselling. The recurrence risk is 25% for each pregnancy of carrier parents. Carriers have higher rates of deafness and psychiatric disorders.

Monitoring. Annual ophthalmology, audiology and renal tract ultrasound, urodynamics as indicated, HbA1c every 3 months and serum sodium during desmopressin dose changes.

Referral and escalation. Paediatric or adult endocrinology, ophthalmology, neurology, urology, psychiatry and clinical genetics. Urgent review for suicidality or respiratory failure.