A Unifying Neurologic Mechanism for Infantile Nystagmus

Brodsky, Michael C.; Dell’Osso, Louis F.

doi:10.1001/jamaophthalmol.2013.5833

Cited by 43 publications

(30 citation statements)

References 80 publications

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“…It has been suggested that congenital nystagmus originates from a disruption in the interaction of the subcortical optokinetic pathways (AOS) and cortical foveal pursuit system (1). In contrast, our findings show that the cause of congenital nystagmus associated with CSNB lies within the retina in the afoveate mouse.…”

Section: Discussioncontrasting

confidence: 82%

Nystagmus in patients with congenital stationary night blindness (CSNB) originates from synchronously firing direction-selective retinal ganglion cells

Winkelman

Howlett

Hölzel

et al. 2019

Preprint

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Congenital nystagmus, involuntary oscillating small eye movements, is commonly thought to originate from aberrant interactions between brainstem nuclei and foveal cortical pathways.Here we investigated whether nystagmus associated with congenital stationary nightblindness (CSNB) can result from primary deficits in the retina. We found that CSNB patients as well 25 as an animal model (nob mice), both of which lack functional nyctalopin protein (NYX, nyx) in ON bipolar cells (ON-BC) at their synapse with photoreceptors, showed oscillating eye movements at a frequency of 4-7Hz. nob ON direction selective ganglion cells (ON-DSGC), which detect global motion and project to the accessory optic system (AOS), oscillated with the same frequency as their eyes. In the dark, individual ganglion cells (GC) oscillated 30 asynchronously, but their oscillations became synchronized by light stimulation. Likewise, both patient and nob mice oscillating eye movements were only present in the light. Retinal pharmacological manipulations that blocked nob ON-DSGC oscillations also eliminated their oscillating eye movements, and retinal pharmacological manipulations that reduced oscillation frequency of nob ON-DSGCs also reduced oscillation frequency of their eye 35 movements. We conclude that, in nob mice, oscillations of retinal ON-DSGCs cause nystagmus with properties similar to those associated with CSNB in humans. These results show that the nob mouse is the first animal model for a form of congenital nystagmus paving the way for development of therapeutic strategies.

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Section: Discussioncontrasting

confidence: 82%

Nystagmus in patients with congenital stationary night blindness (CSNB) originates from synchronously firing direction-selective retinal ganglion cells

Winkelman

Howlett

Hölzel

et al. 2019

Preprint

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“…Animal models with various alterations in chiasmatic routing such as in belladonna zebrafish mutant (achiasma in a model with normally only crossed projection), Shh mutant mice (achiasma) and albino mice all lead to nystagmus (Huang et al, ; Traber et al, ), suggesting that the miswiring of RGCs could be the origin of nystagmus, although no clear mechanism has yet been identified. Another hypothesis is that, in addition to retinal defects, there is an abnormal development of binocular cortical motor system controlling the optokinetic system (Brodsky and Dell'Osso, ). However, recent evidence has implicated local circuitry within the retina as mutations in FRMD7 gene have been associated with idiopathic infantile nystagmus (Tarpey et al, ).…”

Section: Disorders Associated With Misrouted Retinal Axonsmentioning

confidence: 99%

“…RGCs could be the origin of nystagmus, although no clear mechanism has yet been identified. Another hypothesis is that, in addition to retinal defects, there is an abnormal development of binocular cortical motor system controlling the optokinetic system (Brodsky and Dell'Osso, 2014). However, recent evidence has implicated local circuitry within the retina as mutations in FRMD7 gene have been associated with idiopathic infantile nystagmus (Tarpey et al, 2006).…”

Section: Nystagmus In Achiasma and Albinismmentioning

confidence: 99%

Retinal axon guidance at the midline: Chiasmatic misrouting and consequences

Prieur

Rebsam

2017

Developmental Neurobiology

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The visual representation of the outside world relies on the appropriate connectivity between the eyes and the brain. Retinal ganglion cells are the sole neurons that send an axon from the retina to the brain, and thus the guidance decisions of retinal axons en route to their targets in the brain shape the neural circuitry that forms the basis of vision. Here, we focus on the choice made by retinal axons to cross or avoid the midline at the optic chiasm. This decision allows each brain hemisphere to receive inputs from both eyes corresponding to the same visual hemifield, and is thus crucial for binocular vision. In achiasmatic conditions, all retinal axons from one eye project to the ipsilateral brain hemisphere. In albinism, abnormal guidance of retinal axons at the optic chiasm leads to a change in the ratio of contralateral and ipsilateral projections with the consequence that each brain hemisphere receives inputs primarily from the contralateral eye instead of an almost equal distribution from both eyes in humans. In both cases, this misrouting of retinal axons leads to reduced visual acuity and poor depth perception. While this defect has been known for decades, mouse genetics have led to a better understanding of the molecular mechanisms at play in retinal axon guidance and at the origin of the guidance defect in albinism. In addition, fMRI studies on humans have now confirmed the anatomical and functional consequences of axonal misrouting at the chiasm that were previously only assumed from animal models. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 77: 844-860, 2017.

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“…38 These observations are in agreement with the hypothesis that impairment of neuronal connections between subcortical and cortical optokinetic pathways may be associated with pathogenesis of congenital/infantile nystagmus. 9 Nevertheless, how the mutations in MANBA and other lysosomal disease-associated genes are attributed to the pathogenesis of nystagmus is still not clear. Variable phenotypes and reduced penetrance, as well as potential genetic modifiers, may also contribute to the underlying complex mechanisms.…”

Section: Discussionmentioning

confidence: 99%

“…The diagnosis was made based on the 10 general features of infantile nystagmus. 9 The patients showed horizontal, conjugate, and pendular nystagmus predominant in the primary position ( Table 1) No detectable abnormality was found during fundal examination, which included the optic disc, macula, and retina. No strabismus accompanied the nystagmus.…”

Section: Clinical Presentationsmentioning

confidence: 93%