Lead
Infantile nystagmus syndrome (INS), with so far unknown etiology, is associated with a broad range of visual system deficits. Strong resemblance between ocular motor instabilities in achiasmatic zebrafish and in infantile INS patients leads to the hypothesis that visual pathway abnormality may also be a key factor in human INS.

Lay summary

BACKGROUND: Infantile nystagmus syndrome (INS) is an eye movement disorder characterized by horizontally oscillating eyes. The long-term goal of this project is to expand our knowledge of INS, propose new treatment avenues for INS, and increase our understanding of the ocular motor systems in vertebrates in general. INS is frequently associated with abnormalities in the visual system, for example as present in albinism. We found a zebrafish mutant, called belladonna, that shows horizontally oscillating eyes and an underlying condition of abnormally projecting optic pathways. Our previous data demonstrate that the underlying condition is directly responsible for the oscillating eyes. We hypothesize that abnormally projecting optic pathways may similarly contribute to the eye oscillations in human INS, at least in those patients where such a condition is present.

AIMS: (1) We plan to mimic the effect of abnormally projecting optic pathways in healthy humans with a specially designed experimental setup (the movement of a visual scene is yoked to the eye movement). We anticipate that, under this condition, healthy subjects show eye movements that are similar to those in INS. Conversely, eye oscillations in INS patients are expected to be reduced under this condition. (2) In INS patients, different eye movement systems (e.g., optokinetic and vestibulo-ocular system) are known to be compromised. We will test how the performance of different eye movement systems is altered in zebrafish mutant belladonna through the early development. (3) Abnormalities in the projection of the optic pathways are possibly expressed in different types of eye oscillations. Taking advantage of the correlation between visual pathway configuration and eye movements, we plan to develop a diagnostic algorithm to screen for aberrant visual pathways solely based on eye movement recordings. Additionally, we will test optical and other treatment methods. Finally, we will use zebrafish mutant belladonna to screen for potential new drugs and test existing neurological drugs that have not yet been tested in INS patients.

IMPORTANCE AND IMPACT: The aim of this project is to identify the underlying (developmental) cause of INS and to generally expand our knowledge of the optokinetic system in zebrafish and human. These insights will help better understand and diagnose INS and eventually improve the treatment.