Wolfram Syndrome

PRACTICAL IMPLICATIONS

WS is diagnosed in a patient who presents with progressive neurologic symptoms including cerebellar ataxia, sensorineural hearing loss, hyposmia, and OA against a background of type I DM, central DI, hypothyroidism, and hydronephrosis.

A 29-year-old woman presented with symptoms of progressive cerebellar ataxia, dyschromatopsia, sensorineural hearing loss, vertigo, and hyposmia. She was diagnosed with type 1 diabetes mellitus (DM) at 7 years of age. She had been diagnosed with central diabetes insipidus (DI), hypothyroidism, and hydronephrosis. Neurological evaluation revealed bilateral dysmetria, dysdiadochokinesia, and mild cerebellar tremor.

We considered Wolfram syndrome (WS) as a possible diagnosis. A brain MRI scan revealed atrophy of both optic nerves, the neurohypophysis, and the ventral pons (figure). Wolfram syndrome 1 (WFS1) gene sequencing (4p16.1) revealed a pathogenic variant of heterozygosis in exon 8 as c.2002C>T; p.Gln668*, a probable pathogenic variant c.2452C>G; p.Leu829Val and a variant of uncertain significance c.2452C>T; and p.Arg818Lys. We believe these are 2 damaging mutations in heterozygosity, considering the negative family history and the autosomal recessive transmission of the disease.

Figure. MRI scan findings.

(A) Coronal T2 image showing bilateral optic nerve atrophy, (B) axial T2 image showing ventral pontine hyperintensity, and (C) sagittal T1 image showing the absence of neurohypophysis.

This is a rare case of a patient with WS presenting with cerebellar ataxia. We considered mitochondrial disorders, Friedreich ataxia, and Bardet–Biedl syndrome as possible differential diagnoses.^1,2

WS is a rare autosomal recessive disease featuring DI, DM, optic atrophy (OA), and deafness, and hence is known as DIDMOAD (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, and Deafness) syndrome. WS is caused by a WFS1 gene mutation that encodes wolframin, a transmembrane protein of pancreatic B cells. WFS1 downregulation in neurons leads to inhibited mitochondrial fusion, altered mitochondrial trafficking, and augmented mitophagy. WFS1 deficiency induces endoplasmic reticulum stress and disturbed cytosolic Ca²⁺ homeostasis.³

Usually diagnosed in patients approximately 6 years of age, DM is typically the initial manifestation of WS.¹ Optic nerve atrophy causes color blindness and loss of peripheral vision.² Central DI is another common manifestation, affecting approximately 70% of patients.⁴ Urinary tract dysfunction affects from 60% to 90% of patients.^4,5 More than 60% of patients develop neurologic dysfunction, including vertigo and ataxia, which begin in early adulthood; approximately 65% of patients develop sensorineural hearing loss. Brainstem atrophy can cause death because of central apnea.^1–5

MRI scan of WS may reveal atrophy of the brain stem, the middle cerebellar peduncle, and the cerebellum. Hyperintensity of the ventral pons is usually seen in a T2-weighted image.^6,7

Although WS is a rare disease, it should always be considered when DM is followed by other clinical features including progressive OA, deafness, hyposmia, vertigo, central DI, and urinary tract dysfunction. Patients with symptoms characteristic of WS should undergo genetic testing. Cerebellar ataxia may be a neurologic presentation of WS.

This case report aims to create awareness of this neurodegenerative disorder among neurologists. We suggest screening for WS in patients who present with ataxia associated with OA and DM at any age. It is important to include WS-related genes as part of custom-built targeted gene sequencing panels in patients with undiagnosed ataxia.

Appendix. Authors

Study funding

No targeted funding reported.

Disclosure

The authors report no disclosures relevant to the manuscript. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/cp.