Wolfram syndrome presenting with progressive ataxia and optic pathway degeneration: clinical and neuroimaging correlates

Abstract

Case Presentation: A 43-year-old presents with a two-year history of progressive ataxia associated with visual disturbances initially attributed to DM and myopia, that partially improved after corrective lenses but have worsened over the past year; he also reports urinary retention and depressive symptoms, and denies paresthesias, dysesthesias, or cognitive decline. His past medical history is notable for insulin-dependent diabetes mellitus since the age of 2 and anosmia following a car accident at age 30. Family history reveals one healthy older brother with a healthy child, and one older sister who developed diabetes mellitus at age 2, followed by visual impairment, bladder dysfunction, and ataxia at age 30, who died at age 32. Neurological examination demonstrates an ataxic gait, dysdiadochokinesia, truncal asynergia, and a fatigable, unidirectional horizontal nystagmus to the left at extreme gaze. Brain magnetic resonance shows mild cortical atrophy, slight thinning of the corpus callosum, marked cerebellar atrophy, and atrophy of the pons and midbrain, along with ventricular enlargement. Diffusion tensor imaging (DTI) reveals altered signals in the optic radiations and ventral pons, associated with volumetric reduction of optic pathways. Whole-exome sequencing identified a mutation in the WFS1 gene, confirming the diagnosis of Wolfram syndrome (WS). Discussion: WS is autosomal recessive disorder caused primarily by mutations in the WFS1 gene, which encodes wolframin, a protein expressed in multiple tissues, including the brain, pancreatic β-cells, retina. The classic phenotype begins in childhood with non-autoimmune insulin-dependent diabetes mellitus, followed by progressive visual impairment. As the disease advances, patients frequently develop additional manifestations, including sensorineural hearing loss, central diabetes insipidus (DIDMOAD acronym (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, and Deafness); as well as cerebellar ataxia, brainstem atrophy, neurogenic bladder, and psychiatric symptoms. Visual dysfunction appears at age of 11 and is a central part of the diagnosis manifested by reduced contrast sensitivity, and visual field defects, often with central scotomas. As the disease progresses, structural involvement may extend along the visual pathways, including the optic tracts and radiations, as suggested by advanced imaging techniques such as DTI. Final Comments: Because of its marked phenotypic variability, and the fact that early manifestations often overlap with more common conditions such as type 1 DM and its complications, diagnosis is frequently delayed. Recognizing the characteristic pattern of progressive optic neuropathy in association with multisystem neurodegeneration is essential for early diagnosis, appropriate genetic counseling, and multidisciplinary management.