Neuro-ophthalmological manifestations and therapeutic development in Wolfram syndrome.

Wolfram syndrome (WS) is a rare, progressive monogenic neurodegenerative disorder in which childhood-onset, insulin-deficient diabetes mellitus usually precedes optic atrophy and other multisystemic manifestations such as hearing loss, diabetes insipidus, urological and neuro-psychiatric abnormalities. This review summarises the underlying genetic basis and pathophysiology of Wolfram syndrome type 1 (WS1) and Wolfram syndrome type 2 (WS2), their neuro-ophthalmologic manifestations and phenotypic spectrum, as well as the multimodal biomarkers that are being used to objectively measure disease severity. Although classically known as a recessive condition with complex, severe, multiorgan involvement, WS1 caused by dominant WFS1 variants and a more limited form of the disease are increasingly being recognized. Biomarkers based on optical coherence tomography (OCT) parameters show promise for early diagnosis and disease monitoring. Lastly, emerging therapeutic options and future directions for treatment trials are discussed.