Visual Neuroscience Visual Pathways in Humans With Ephrin-B1 Deficiency Associated With the Cranio-Fronto-Nasal Syndrome Michael B. Hoffmann,1,2 Hagen Thieme,1 Karin Liedecke,1 Synke Meltendorf,1 Martin Zenker,3 and Ilse Wieland3 1Department of Ophthalmology, Otto-von-Guericke-University, Magdeburg, Germany 2Center for Behavioural Brain Sciences, Magdeburg, Germany 3Institute for Human Genetics, Otto-von-Guericke-University, Magdeburg, Germany Correspondence: Michael B. Hoff- PURPOSE. Numerous animal studies demonstrated the importance of components of the mann, Universit¨ats-Augenklinik, Vi- ephrin/Eph system for correct visual system development. Analogous investigations in sual Processing Laboratory, Leipziger humans are entirely missing. Here, we examined the visual system in humans with ephrin-B1 Str. 44, 39120 Magdeburg, Germany; deficiency, which is x-linked and associated with the cranio-fronto-nasal syndrome (CFNS) in [email protected]. heterozygous females. Submitted: July 15, 2015 Accepted: October 6, 2015 METHODS. For one male hemizygous for ephrin-B1 deficiency and three affected heterozygous females with molecular-genetically confirmed mutations, the integrity of the partial Citation: Hoffmann MB, Thieme H, decussation of the optic nerves was assessed with visual evoked potentials (VEPs) and Liedecke K, Meltendorf S, Zenker M, compared with albinotic, achiasmic, and control participants with healthy vision. Further, Wieland I. Visual pathways in humans with ephrin-B1 deficiency associated retinal morphology and function and the gross-retinotopic representation of the primary with the cranio-fronto-nasal syn- visual cortex were examined with spectral-domain optical coherence tomography (SD-OCT), drome. Invest Ophthalmol Vis Sci. ERG, and multifocal (mf) VEPs for the male participant and part of the carriers. 2015;56:7427–7437. DOI:10.1167/ RESULTS. Strabismus and lack of stereovision was evident in the male and two of the females. iovs.15-17705 Other characteristics of the visual system organization and function were normal: (1) retina: SD-OCT and funduscopy indicated normal foveal and optic nerve head morphology. Electroretinograms indicated normal retinal function, (2) optic chiasm: conventional (c)VEP showed no evidence for misrouting and mfVEPs were only suggestive of, if any, very minor local misrouting, and (3) visual cortex: mfVEP characteristics indicated normal retinotopic gross-representations of the contralateral visual hemifield in each hemisphere. CONCLUSIONS. While ephrin-B1 deficiency leads to abnormal visual pathways in mice, it leaves the human visual system, apart from deficits in binocular vision, largely normal. We presume that other components of the ephrin-system can substitute the lack of ephrin-B1 in humans. Keywords: optic chiasm, misrouting, ephrin, eph, guidance molecules, visual cortex he optic chiasm is a key structure in the visual system.1 Molecular mechanisms shape a number of different pro- T Here, the fate of axons of the retinal ganglion cells is cesses of optic chiasm formation.6 They promote crossed or decided during early development such that axons carrying uncrossed projections, or guide the general patterning of the information from the right visual hemifield are guided to the left optic chiasm. In animal studies, particular attention has been hemisphere and vice versa. In the human visual system this paid to the Eph/ephrin receptor/ligand families of cell surface results in a partial crossing of the optic nerves at the chiasm: signalling proteins. There are 14 Eph receptors and eight fibers from the nasal retina receive input from the ipsilateral ephrin ligands in mammals,7 both subdivided into A and B visual field and consequently cross the midline separating the classes. Remarkably, there is promiscuity within each class (i.e., hemispheres, and fibers from the temporal retina receive input EphA receptors can bind with diverse ephrin-As, and likewise from the contralateral visual field and consequently remain EphB with ephrin-Bs).8 Eph/ephrin interactions are important uncrossed. Remarkably, deviations from this pattern have been in development, especially in cell–cell interactions involved in observed in specific patient groups (i.e., in albinism with nervous system patterning and axon guidance. Investigations of enhanced crossing of the temporal fibres at the chiasm2,3 and in the development of the visual system demonstrated an achiasma4,5 with reduced or absent crossing of the nasal fibers). importance of A and B class proteins for retinotopic map Although it might appear that such misrouting of the optic formation and for chiasm formation.6,8–10 Some studies suggest nerves should completely obstruct vision in the affected specific mechanisms that lead to enhanced crossing of the optic individuals, visual function is only partially impaired in these nerves in albinism. They demonstrated the relevance of EphB1- cases.1 Typically, nystagmus associated with reduced visual expression, regulated by the transcription factor Zic2,11,12 for acuity and strabismus associated with often absent binocular the normal formation of the ipsilateral projection at the optic vision are observed, while other visual functions such as chiasm. Growth cones of retinal axons that are expressing pattern detection and visuomotor integration appear largely EphB1 are normally repelled by the ligands ephrin-B2 and unaffected. ephrin-B1 expressing glia at the optic chiasm midline, as Copyright 2015 The Association for Research in Vision and Ophthalmology, Inc. iovs.arvojournals.org j ISSN: 1552-5783 7427 Downloaded from iovs.arvojournals.org on 09/25/2021 Visual Pathways in Ephrin-B1 Deficiency IOVS j November 2015 j Vol. 56 j No. 12 j 7428 demonstrated in EphB1À/À mice and EphB2À/À/EphB1À/Y hemifields, if they have the opposite polarity, this is evidence mice.13,14 Accordingly, during human embryogenesis EphB1 for enhanced or reduced crossing of the optic nerves. This is expressed in the ganglion cells of the temporal retina, which paradigm serves as a clinical routine tool for the detection of is projecting ipsilaterally.15 Importantly, in animal models of misrouting of the optic nerves33 and can also be combined albinism the expression of the transcription factor Zic216 and with mfVEPs to identify localized optic nerve misroutings.34–36 consequently EphB117 is reduced, which corresponds to the Enhanced crossing of the optic nerves has long been enhanced crossing of the optic nerves at the chiasm in considered as a pathognomonic sign of albinism. As a albinism. The relation of these changes to the pigmentation consequence, the misrouting VEP has since served as an defect in albinism (i.e., the reduction of ocular or oculocuta- important diagnostic in the detection of albinism as the cause neous melanin levels) is still under investigation. It is of ocular symptoms specified above. In fact, the abnormality is presumably associated with the delaying effect of hypopig- absent in human carriers of albinism34,35,37 and patients mentation on retinal neurogenesis likely mediated via reduced without albinism, but with some ocular symptoms observed retinal levels of the melanin precursor L-DOPA.18–21 in albinism, such as foveal hypoplasia,38 dissociated vertical The above highlights the importance of the interaction of deviation and missing stereopsis,39–41 and congenital nystag- ephrin-ligands and Eph receptors for neural guidance during mus.42,43 Further, normal projections were observed in visual system development. However, it must be noted that it patients with unilateral anophthalmia or severe microphthal- is, at present, uncertain, to which extent these mechanisms mia22 and in patients with generalized lateralization abnormal- actually translate to the development of the human optic ities (i.e., situs inversus in the Kartagener syndrome, and in chiasm, which differs distinctly in its architecture from that of primary ciliary dyskinesia in general).36 However, it must be the relevant murine animal models.22 Specific investigations of noted that comparatively rare incidences of enhanced crossing the visual system in humans are needed, but difficult to in the absence of albinism and the presence of other conduct as humans with deficiencies in the ephrin/Eph system syndromes are also known.44–46 are extremely rare. In fact, currently only one syndrome Here, we present a small case series, comprising one male associated with relevant deficiencies is known (i.e., the cranio- hemizygous and three females heterozygous for ephrin-B1 fronto-nasal syndrome [CFNS MIM 304110]). Remarkably, only deficiency of this rare patient group and thus provide the first a decade ago ephrin-B1 deficiency was demonstrated to be account assessing visual pathways in patients with ephrin-B1 23,24 causal for CFNS, which spurred the notion, that enhanced deficiency. We give a detailed description of the visual system crossing of the optic nerves might also be evident in CFNS- in the participants with a particular focus on the assessment of patients. This patient group might thus provide a key to our the integrity of the cortical visual field representations. understanding of the role of ephrin-B1 in the formation of the Remarkably, while deficits of visual function were evident, human optic chiasm. Cranio-fronto-nasal syndrome is a very there was an absence of major representation abnormalities at rare condition, with an estimated incidence of 1:100,000, and the level of the visual cortex. predominantly affects the phenotype of females. Counterintu-