REVIEW URRENT C OPINION
Aetiology of infantile nystagmus Irene Gottlob and Frank A. Proudlock
Purpose of review Mechanisms underlying infantile nystagmus are unclear. The aim of this review is to outline recent developments in understanding the aetiology of infantile nystagmus. Recent findings There have been advances in understanding mechanisms underlying idiopathic infantile nystagmus, which has progressed through determining the role of the FRMD7 gene in controlling neurite outgrowth, and albinism, in which recent models have investigated the possibility of retinal miswiring leading to nystagmus. We also briefly review aetiology of infantile nystagmus in afferent visual deficits caused by ocular disease, and PAX6 mutations. Improved phenotypical characterization of all these infantile nystagmus subtypes has been achieved recently through high-resolution retinal imaging using optical coherence tomography. Several new hypotheses proposing common mechanisms that could underlie various infantile nystagmus subtypes are also highlighted. Summary Although there is still no consensus of opinion regarding the mechanisms causing infantile nystagmus, identification of new genes and determining their cellular function, phenotypical characterization of genetic subtypes, and improvements in animal models have significantly advanced our understanding of infantile nystagmus. These recent developments pave the way to achieving a much clearer picture of infantile nystagmus aetiology in the future. Keywords achromatopsia, albinism, congenital nystagmus, idiopathic infantile nystagmus, infantile nystagmus
INTRODUCTION Infantile nystagmus syndrome (INS) consists of involuntary oscillation of the eyes with onset in the first 3–6 months of life [1]. It is frequently associated with developmental sensory deficits, although the relationship between sensory impairments and motor oscillations is unclear. The aetiology of infantile nystagmus follows a pathophysiological sequence of events commencing with gene mutations and their effect on cell physiology (Fig. 1), leading to disrupted development of neural function and connectivity in the afferent visual pathway (1 in Fig. 1) and/or ocular motor system (2 in Fig. 1). Gene mutations could also directly affect motor (3 in Fig. 1) and/or sensory (4 in Fig. 1) innervation of extraocular muscles. In this review, we consider the recent developments in four main subtypes of infantile nystagmus, namely idiopathic infantile nystagmus, albinism, afferent visual deficits caused by ocular disease and PAX6 mutations. Recent advances have been made concerning these subtypes, particularly in determining the effect of gene mutations on cellular mechanisms and also in accurately characterizing
afferent visual deficits associated with infantile nystagmus subtypes (1 in Fig. 1). We also consider recent mechanisms that have been proposed as the direct motor cause of infantile nystagmus. One key area of controversy is whether infantile nystagmus subtypes share a common mechanism. Is there one rhythm or eye drift generator that is responsible for directly causing nystagmus in different infantile nystagmus subtypes? In outlining mechanisms, we also consider manifest latent nystagmus (MLN), another common subtype of infantile nystagmus, and whether it also shares a common aetiology to other types of infantile nystagmus. This review does not cover the multiplicity
Ophthalmology Group, University of Leicester, Faculty of Medicine & Biological Sciences, Robert Kilpatrick Clinical Sciences Building, Leicester Royal Infirmary, Leicester, UK Correspondence to Irene Gottlob, Ophthalmology Group, University of Leicester, Faculty of Medicine & Biological Sciences, Robert Kilpatrick Clinical Sciences Building, Leicester Royal Infirmary, PO Box 65, Leicester LE2 7LX, UK. Tel: +44 0 116 258 6291; e-mail: [email protected] Curr Opin Neurol 2014, 27:83–91 DOI:10.1097/WCO.0000000000000058
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KEY POINTS
Genetic mutations
Discovery of genetic mutations associated with infantile nystagmus has led to experimental models that have furthered our understanding of the aetiology of infantile nystagmus at a cellular level. The FRMD7 gene, which is associated with idiopathic infantile nystagmus, has been show to promote neurite outgrowth through controlling interactions between plasma membrane and the actin cytoskeleton. Better phenotypical characterization of afferent visual deficits in infantile nystagmus subtypes has been achieved using high-resolution retinal imaging with optical coherence tomography, and suggests underlying foveal deficits are common to most infantile nystagmus subtypes. Several recent models have been proposed to explain how afferent visual deficits can lead to motor oscillations, such as miswired retinal motion sensors and abnormal development of binocular cortical motion centres leading to uncontrolled expression of subcortical motion tracking mechanisms.
of neurological syndromes that can lead to nystagmus in infancy, many of which are more akin to acquired nystagmus types in character. Another area of debate concerns whether the primary disease underlying infantile nystagmus is an afferent visual disorder disturbing foveal vision during development (1 in Fig. 1). If so, this would imply that the mechanism generating nystagmus would be otherwise normal ocular motor circuitry that becomes unstable on receiving abnormal afferent input during visual development. The relationship between afferent visual deficits and infantile nystagmus is becoming clearer with the emergence of high-resolution retinal imaging techniques such as optical coherence tomography (OCT), which has been applied to infantile nystagmus subtypes (Fig. 2) [2–5,6 ,7 ]. These not only permit accurate phenotypical characterization of genetic subtypes of infantile nystagmus but also provide a means by which afferent visual deficits can be directly compared with motor oscillations. &
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IDIOPATHIC NYSTAGMUS The term ‘idiopathic’ infantile nystagmus has been used to describe infantile nystagmus wherein no disease has been found in the brain or retina. However, this terminology may become redundant as recent high-resolution imaging of the retina using OCT has shown that retinal deficits indeed exist in individuals with idiopathic infantile nystagmus, 84
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Cellular mechanisms
1 Afferent visual pathway
2 Ocular motor pathway PROPRIOCEPTIVE FEEDBACK
3 Extraocular muscles 4
Nystagmus waveform
VISUAL FEEDBACK
FIGURE 1. The sequence of pathophysiology that leads to nystagmus generation in infantile nystagmus. Genetic mutations are known to underlie most infantile nystagmus subtypes leading to changes in cellular function, which in turn could effect: the developing afferent visual pathway (1), the developing ocular motor system (2), extraocular muscle structure and/or motor innervation (3), or feedback from extraocular muscle proprioceptors (4).
including foveal thickening, thinning of the retinal nerve fibre layer and shortened cone outer segments [3]. This opens up the possibility that the primary pathology behind most forms of infantile nystagmus could be sensory in origin (1 on Fig. 1). However, as these changes are subclinical, idiopathic infantile nystagmus remains the most likely form of infantile nystagmus to be caused by abnormal development of the ocular motor system (2 on Fig. 1). Since the identification of the first gene associated with idiopathic infantile nystagmus, the FRMD7 gene located at Xq26 [8], studies have aimed to explore the function of the gene. The FRMD7 gene encodes a member of the FERM domain family of proteins. These are plasma membrane–cytoskeleton coupling proteins many of which bind to actin or other cytoskeleton components [9]. In differentiating Neuro2A cells, the FRMD7 protein co-localizes with the actin of primary neurites [10]. FRMD7 protein expression in these cells promotes neurite outgrowth [11] and knock-down of FRMD7 causes a reduction in average neurite length [10]. Watkins et al. [12 ] recently found an interaction between the FRMD7 protein and calcium/ calmodulin-dependent serine protein kinase (CASK). One of the functions of CASK in neurons &&
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l. Examples of OCT images from normal retina and individual with foveal hypoplasia (a) NFL GCL
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Unique foveal elements Foveal pit
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FIGURE 2. Characterization of foveal abnormalities in nystagmus subtypes using optical coherence tomography. In (I), optical coherence tomograms are shown for (a) a normal fovea with a description of the normal foveal elements, and the spectrum of foveal hypoplasia seen in various conditions, including: (b, c) albinism, (d, e) associated with PAX6 mutations, (f, g) isolated cases, and (h, i) an atypical form of foveal hypoplasia seen in achromatopsia. (II) Illustrates principles used to characterize foveal abnormalities using a structural grading scheme where (a) is a schematic of the unique features of a normal fovea. (b) Illustrates typical and atypical grades of foveal hypoplasia. All grades of foveal hypoplasia had incursion of inner retinal layers. Grade 1 foveal hypoplasia is associated with a shallow foveal pit, outer nuclear layer (ONL) widening, and outer segment (OS) lengthening relative to the parafoveal ONL and OS length, respectively. In Grade 2 foveal hypoplasia, all features of grade 1 are present except the presence of a foveal pit. Grade 3 foveal hypoplasia consists of all features of grade 2 foveal hypoplasia except the widening of the cone outer segment. Grade 4 foveal hypoplasia represents all the features seen in grade 3 except there is no widening of the ONL at the fovea. Finally, an atypical form of foveal hypoplasia also is described in which there is a shallower pit with disruption of the inner segment/OS (IS/OS) junction, possibly a sign of photoreceptor degeneration. The atypical form of foveal hypoplasia is seen with achromatopsia, whereas grades 1 through 4 are seen with albinism, PAX6 mutations, and isolated cases. ELM, external limiting membrane; GCL, ganglion cell layer; INL, inner nuclear layer; IPL, inner plexiform layer; OPL, outer plexiform layer; RNFL, retinal nerve fibre layer; RPE, retinal pigment epithelium. Reproduced with permission from Thomas et al. [5].
is to link the plasma membrane to the actin cytoskeleton. They suggest that FRMD7 mutations could act by disrupting the interaction between FRMD7 and CASK needed to promote membrane extension during neurite outgrowth (Fig. 3). The FRMD7
protein has also been shown to interact with RhoGDIa, the main regulator of Rho GTPases, which are key regulators of the actin cytoskeleton [13 ]. Expression of FRMD7 in the human embryo occurs in both the developing neural retina as well
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ll. Grading scheme devised to grade foveal hypoplasia based upon stage at which retinal development was arrested Normal foveal structural features detectable using optical coherence tomography
Illustration RNFL
(a) Extrusion of plexiform layers (b) Foveal pit (c) OS lengthening (d) ONL widening
GCL INL
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Median logMAR visual acuity (interquartile range)
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(a) Extrusion of plexiform layers (b) Foveal pit (c) OS lengthening (d) ONL widening
(a) Absent (b) Absent (c) Absent (d) Absent
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(a) Extrusion of plexiform layers (b) Foveal pit–Shallow (e) IS/OS dicruption
(a) Absent (b) Present (e) Present
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FIGURE 2. (Continued )
as in ocular motor structures such as the cerebellum and vestibulo-optokinetic system [8,14]. The FRMD7 protein, therefore, could primarily influence the developing afferent or motor system. The medications gabapentin and memantine have been shown to influence idiopathic infantile nystagmus [15] by reducing nystagmus intensity leading to improved visual acuity. These two medications are central nervous system inhibitors. Gabapentin probably increases synaptic concentration of the inhibitory transmitter GABA through voltage-sensitive calcium channels, whereas memantine inhibits the excitatory neurotransmitter glutamate by blocking N-methyl-D-aspartate (NMDA)-type glutamate receptors. These two transmitter systems are found in both sensory and motor systems, however.
ALBINISM Unlike idiopathic infantile nystagmus, albinism leads to profound impairments throughout the visual pathway including high refractive errors [16], iris abnormalities [17], foveal hypoplasia (see Fig. 2) [2,5], a shift in the line of decussation of retinal 86
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ganglion cells [18], abnormal optic nerve and chiasm morphology [19], and cortical thickening [20 ]. Recent studies have shown a spectrum of disrupted development in retinal [2] and cortical [20 ] morphology in albinism that is correlated to the degree of visual deficit. OCT studies show that the human retina in albinism is invariably marked by continuation of inner retinal layers at the fovea (usually these layers are extruded to form the foveal pit) and shorter outer segments of the cone photoreceptor layer [2] (Fig. 2b and c , part I). Cone outer segments are usually longer and thinner in the normal fovea to increase cone packing, a requirement for high acuity vision. Hence, cone outer segment length is a strong predictor of visual acuity in albinism [2]. Despite widely different visual pathway anomalies, the nystagmus characteristics in albinism and idiopathic (FRMD7-associated) infantile nystagmus show several similarities, such as a predominantly horizontal waveform, a combination of jerk and pendulum waveforms, and similar proportions of periodic alternating nystagmus [21]. The similarities might suggest a shared underlying &
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Anti–GFP
Recent studies using transgenic mice have indicated that deficits in the intermediate metabolite, L-3,4-dihydroxyphenylalanine (L-DOPA), lead to the visual system abnormalities seen in albinism rather than the absence of the pigment melanin, which is the end product of the process leading to hypopigmentation [22 ]. In the normal pigmented mouse retina, the change in L-DOPA content in the retina reflects the onset and completion of retinal development. However, in the embryonic albino retina of mice (OCA1 model), L-DOPA is absent during retinal development and is greatly reduced in postnatal albino retina. One interesting hypothesis that has reemerged in relation to nystagmus generation in albinism has been that a subset of motion detectors could be miswired. This has been modelled using several different experimental paradigms. The belladonna (bel) mutant zebrafish demonstrates disrupted commissural and retinal axon guidance in the forebrain leading to miswiring of retinal ganglion cells [23]. The mutant shows reversal of physiological optokinetic responses and also spontaneous pathological eye movements under static full field visual stimulation [24]. Huang et al. [25] have noted that the spontaneous eye movements in this zebrafish model resemble the range of infantile nystagmus waveforms observed in humans. Huber-Reggi et al. [26 ] further demonstrated the strong correlation between the degree of optic fibre misrouting and the nystagmus phenotype. Similar observations have been made by Traber et al. [27 ] in several different albino mouse models. They observed reversal of optokinetic responses when the temporal retina is stimulated, which is where most of the misrouting occurs. They also found infantile nystagmus-like spontaneous nystagmus waveforms in the mouse models with jerk and pendular components. Miswiring of the visual field has also been modelled in normal humans by Huang et al. [28]. Using a gaze contingent display in which the visual feedback was controlled using online eye movement recordings, Huang et al. were able to simulate reversal of retinal slip (so that an eye movement to the right would result in movement of a vertical striped pattern on the display moving to the left). In addition, they found that it was also possible to generate the plethora of nystagmus waveforms described in infantile nystagmus for normal humans. &
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MERGE
FIGURE 3. Co-localization and interaction of the FRMD7 protein (implicated in idiopathic infantile nystagmus) and calcium/calmodulin-dependent kinase in Neuro2A cells. Neuro2A cells were seeded onto coverslips, transiently cotransfected with myc-tagged wild-type (WT) FRMD7 and green fluorescent protein (GFP)-tagged WT CASK and then fixed in methanol 24 h later. Immunofluorescence microscopy was performed using antimyc (green) and anti-GFP (red) antibodies and chromatin was stained with 4,6-diamidino-2phenylindole (blue). Arrows indicate areas of FRMD7 and CASK co-localization at the plasma membrane. Scale bar, 10 mm. Reproduced with permission from Watkins et al. [12 ]. &&
mechanism between nystagmus generation in albinism and idiopathic infantile nystagmus. However, some differences exist between the two nystagmus forms, with higher proportions of pendular nystagmus, less head postures and less nystagmus in the primary position in FRMD7-associated idiopathic infantile nystagmus compared with albinism [21]. To date five genes have been associated with the two most common forms of albinism, oculocutaneous albinism [recessive mutations in at least four autosomal genes: TYR (OCA1), OCA2 (OCA2), TYRP1 (OCA3) and SLC45A2 (OCA4)] and ocular albinism (the X-linked gene OA), as well as less common genes associated with conditions such as Hermansky–Pudlak syndrome. However, in many people with albinism no gene mutation can be found, and this is currently an active area of research.
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AFFERENT VISUAL DEFICITS CAUSED BY OCULAR DISEASE Afferent deficits resulting from anterior or posterior eye disease through conditions such as congenital
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cataract [29,30], congenital retinal dystrophies [4,6 ,31] and optic nerve hypoplasia remain one of the purest ways to investigate infantile nystagmus because the initial disease is almost certainly sensory in origin (1 on Fig. 1). Congenital cataracts can lead to a combination of square wave jerks with both MLN (decelerating slow phases) and infantile nystagmus (accelerating and pendular slow phases) waveforms [29,30]. The most common nystagmus waveform in congenital cataract is MLN, which is also observed in bilateral cataracts and becomes more frequent after removal of cataracts [29]. Recent OCT imaging studies in achromatopsia indicate that this condition might actually be a progressive disease [4,6 ]. The retinae of achromats on OCT images are characterized by a distinct punched out hyporeflective zone [4] in the region of the cone outer segments (Fig. 2i, part I), which increases in size with age [6 ]. Nystagmus associated with achromatopsia is dissimilar in character to that associated with idiopathic infantile nystagmus and albinism. The existence of vertical waveforms and also high frequency fine pendular oscillations is more common and the waveform also appears to evolve from pendular to predominantly jerk nystagmus probably as the disease progresses [32]. The nystagmus observed in congenital stationary night blindness is also characterized by a marked vertical component, high frequency fine pendular oscillations and sometimes disconjugate waveforms [31]. &
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PAX6 MUTATIONS PAX6 mutations are associated with apparent visual sensory deficits such as aniridia and foveal and optic nerve hypoplasia, although direct developmental abnormalities of the ocular motor pathways cannot be ruled out [7 ]. OCT images of the fovea in PAX6 mutations show a spectrum of foveal hypoplasia with shallower or absent foveal pits, continuation of inner retinal layers, shorter outer segments at the fovea and thinner retinal nerve fibre layer [7 ] (Fig. 2d and e, part I). Nystagmus in individuals with PAX6 shows large intrafamilial variability with nystagmus oscillations in different planes (horizontal, vertical and torsional) and a combination of pendular and jerk oscillations [7 ]. OCT findings indicate that foveal deficits are a common theme to all four of these nystagmus subtypes, and in particular disruption to cone specialization or function as evident from shortened or missing cone outer segments. However, the striking differences between the features of the nystagmus associated with idiopathic infantile nystagmus or albinism and afferent visual deficits caused by ocular disease or PAX6 mutations suggest that these may be &
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separate entities with perhaps different primary mechanisms. In the light of these observations, the current trend of viewing all infantile nystagmus as a single entity (i.e., infantile nystagmus syndrome) may not help in progressing our understanding of infantile nystagmus aetiology.
A COMMON MECHANISM FOR NYSTAGMUS GENERATION IN INFANTILE NYSTAGMUS Pathology of many components of both the ocular motor and afferent visual systems has been implicated in nystagmus generation in infancy. Elements of the ocular motor system implicated include the neural integrator [33 ], superior colliculus [34], saccadic system [35], smooth pursuit system [36], optokinetic system [37 ], cerebellum [38], proprioceptive inputs from eye muscles [39] as well as changes in the properties of extraocular muscles themselves [40 ]. The vergence system is also known to influence infantile nystagmus in the form of convergence damping [41]. Visual system abnormalities have included rod and cone dysfunction [4,6 ,31], foveal maldevelopment (hypoplasia) [42], miswiring of retinal motion detectors through chiasmal abnormalities [25,26 ,27 ,28], and disrupted development of cortical binocular motion centres [37 ]. For nystagmus to be generated by afferent visual system pathology alone (1 on Fig. 1) in most cases would require components of otherwise normal ocular motor circuitry transforming into a renegade eye oscillator or drift generator. Several recent hypotheses have been proposed to explain how sensory deficits alone could lead to nystagmus generation. Brodsky and Dell’Osso [37 ] have suggested that infantile nystagmus could result through disrupted development of a dual pursuit/motion tracking system that exists in humans. The first system, the subcortical optokinetic nystagmus (OKN) system, feeds directly through contralateral projections into the nucleus of the optic tract–dorsal terminal nucleus of the accessory optic system (NOT-DTN). This system is thought to be functional from birth and tracks retinal slip with a strong bias for movement in the nasalward direction. The second system, the foveal pursuit system, is more sophisticated and is able to track motion in three-dimensional space as well as subtract movement of a single moving object over a complex background. This system develops later on in infancy and relies on the integrity of cortical binocular motion centres. Brodsky and Dell’Osso suggest that infantile nystagmus is caused by disrupted development of cortical &
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binocular motion centres leading to uncontrolled expression of the subcortical OKN system. This hypothesis is a development of a theory proposed by Brodsky and Tusa in 2004 to explain MLN [43], a form of infantile nystagmus that is invariably associated with infantile esotropia and is characterized by a nasalward drift of the viewing eye when the contralateral eye is occluded. Brodsky and Tusa argue that MLN is also an expression of the subcortical OKN pathway due to disrupted development of cortical binocular motion centres, which leads to a nasalward drift of the eyes [44]. Brodsky and Dell’Osso [37 ] propose that infantile nystagmus and MLN share a common aetiology and lie on a continuum. The nystagmus waveforms in MLN are an expression of unequal inputs into the two eyes (i.e., with decelerating or linear nasalward slow phases), whereas the nystagmus waveforms in infantile nystagmus are due to reduced central vision in both eyes, which leads to the subcortical OKN system developing into an oscillator (i.e., leading to underlying sinusoidal oscillations). In contrast to Brodsky’s subcortical ‘downstairs’ view of MLN, Tychsen et al. [45] have suggested an ‘upstairs’ view wherein the asymmetry to motion can be explained by cortical development alone. He suggests that nasalward responses to motion are mediated by a direct crossed pathway to the cortex present from birth, whereas temporalward responses await the development of binocular connections in primary visual cortex. Harris [46] also argues that OKN responses in humans are predominantly cortical even in infancy since the response to stimulation has a rapid onset in infancy, in contrast to subcortical OKN, which has a slow build up. However, Harris proposes that MLN is due to the associated strabismus modifying inter-ocular velocity differences of 3D motion in the visual field, which in turn leads to inappropriate training of the neural integrator. Harris and Berry [42] have proposed an alternative theory also based on an underlying afferent visual disease being behind infantile nystagmus. They suggest that nystagmus is generated by deprivation of the normal visual system to high-spatial frequency contrast stimulation during visual development. This leads to eye movement oscillations that occur to improve contrast sensitivity to lower spatial frequency stimuli. Another proposal to explain how sensory deficits alone could lead to nystagmus generation has recently come from Schneider et al. [33 ] by recording eye movements from individuals with earlyonset monocular visual loss. Monocular deprivation results in vertical eye drifts about the visual axis in the abnormal eye, a phenomenon known as &&
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the Heimann–Bielschowsky phenomenon. The same individuals are able to make accurate conjugate upward saccadic eye movements, which stand in contrast to the slow disconjugate eye movement associated with the Heimann–Bielschowsky phenomenon. As inputs to the motoneurons innervating the elevator muscles bypass the neural integrator, Schneider et al. suggest that the slow drifts are due to disrupted calibration of the neural integrator. Interestingly, gabapentin has been reported to suppress the Heimann–Bielschowsky phenomenon [47], a medication that has also been shown to be effective at reducing infantile nystagmus [15]. One challenge in understanding the mechanisms generating infantile nystagmus has been trying to explain the variety of waveforms observed in infantile nystagmus even from a single common cause. For example, the same FRMD7 gene mutation (i.e., in the same family) can lead to quite different waveforms (see Figure 4 in reference [48]) including even the presence or absence of periodic alternating nystagmus [14]. This could be explained by variable gene expression or environmental factors; however, an alternative has been suggested by Shaikh et al. [49] from modelling oculopalatal tremor. This is a condition associated with lesions in the Guillain– Mollaret triangle leading to hypertrophy of the inferior olive. Shaikh et al. suggest that the inferior olive alone is insufficient to generate the oscillations observed in the eyes and palate but that learning processes in the cerebellum amplify and shape the waveforms. It is possible that the cerebellum could also modify waveforms associated with infantile nystagmus in a highly plastic fashion without being the source of the underlying oscillations.
PERIPHERAL MECHANISMS OF NYSTAGMUS GENERATION Although the majority of this review is focused on central nervous system pathophysiology, it is worth highlighting that abnormalities in both the sensory and motor peripheral innervation of extraocular muscles in infantile nystagmus have been implicated in infantile nystagmus generation (3 and 4 on Fig. 1, respectively). Extraocular muscles of individuals with idiopathic infantile nystagmus demonstrate a hypo-innervated phenotype with reduced nerve fibre and neuromuscular junction density [40 ]. They also contain significantly more centrally nucleated myofibres, consistent with cycles of degeneration and regeneration. This could lead to a reduction in tonic firing of extraocular muscles and problems with gaze-holding. The role of proprioceptors in eye muscles is controversial, but the changes in nystagmus
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resulting from muscle tenotomy, a form of surgery that is likely to modify the input from palisade endings in myotendious junction, have led some to suggest aberrant proprioceptive input could have a role in generating infantile nystagmus [39]. It should be added, however, that it has not yet been decisively shown whether palisade endings are sensory or motor in function, although most indicators point to them being sensory [50].
CONCLUSION This overview highlights the lack of consensus with respect to the mechanisms that underlie infantile nystagmus. The range of causes that have been proposed include: exclusively afferent visual pathway pathology that causes a tonic neural drive generating infantile nystagmus (e.g., miswiring of retinal ganglion cells [25,26 ,27 ,28]); underlying visual disease that leads to modifications in otherwise normal motor circuitry during visual development, which in turn drive the oscillations in infantile nystagmus (e.g., uncontrolled expression of the subcortical OKN system following disrupted binocular cortical development, as suggested by Brodsky and Dell’Osso [37 ]); (iii) aberrant development of motor CNS circuitry without the need for an afferent deficit (e.g., cerebellar abnormalities [38]); and also (iv) pathological changes in extraocular muscle structure or in motor and sensory peripheral innervation as the primary generator of infantile nystagmus rather than changes in sensory or motor CNS [40 ]. Future research into the identification of unknown genetic mutations associated with infantile nystagmus will open up avenues for developing cellular and animal models. Further phenotypical characterization of infantile nystagmus subtypes through techniques such as high-resolution retinal imaging (Fig. 2) will improve genotype–phenotype correlations as well as allow more accurate comparisons of afferent visual deficits to nystagmus characteristics. The recent availability of instrumentation that can acquire high-resolution three-dimensional images of the retina in infancy also allows phenotypical characterization of infantile nystagmus subtypes during visual development [51]. &
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Acknowledgements We wish to acknowledge the financial support of the Ulverscroft Foundation, National Eye Research Council, Fight for Sight, Medisearch, Nystagmus Network and the Medical Research Council. We also wish to acknowledge the Nystagmus Network for all their support in our studies. (Please note that none of this support is exclusive to this article). 90
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Conflicts of interest There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Hertle RW. Nystagmus in infancy and childhood: characteristics and evidence for treatment. Am Orthop J 2010; 60:48–58. 2. Mohammad S, Gottlob I, Kumar A, et al. The functional significance of foveal abnormalities in albinism measured using spectral-domain optical coherence tomography. Ophthalmology 2011; 118:1645–1652. 3. Thomas MG, Crosier M, Lindsay S, et al. Retinal changes in idiopathic infantile nystagmus associated with FRMD7 mutations. Invest Ophthalmol Vis Sci 2012; 53:520. 4. Thomas MG, Kumar A, Kohl S, et al. High-resolution in vivo imaging in achromatopsia. Ophthalmology 2011; 118:882–887. 5. Thomas MG, Kumar A, Mohammad S, et al. Structural grading of foveal hypoplasia using spectral-domain optical coherence tomography a predictor of visual acuity? Ophthalmology 2011; 118:1653–1660. 6. Thomas MG, McLean RJ, Kohl S, et al. Early signs of longitudinal progressive & cone photoreceptor degeneration in achromatopsia. Br J Ophthalmol 2012; 96:1232–1236. An OCT study showing that achromatopsia is a progressive disease. 7. Thomas S, Thomas MG, Andrews C, et al. Autosomal-dominant nystagmus, & foveal hypoplasia and presenile cataract associated with a novel PAX6 mutation. Eur J Hum Genet 2013. [Epub ahead of print] A genotype–phenotype correlation of infantile nystagmus associated with PAX6 mutations. 8. Tarpey P, Thomas S, Sarvananthan N, et al. Mutations in FRMD7, a newly identified member of the FERM family, cause X-linked idiopathic congenital nystagmus. Nat Genet 2006; 38:1242–1244. 9. Diakowski W, Grzybek M, Sikorski AF. Protein 4.1, a component of the erythrocyte membrane skeleton and its related homologue proteins forming the protein 4.1/FERM superfamily. Folia Histochem Cytobiol 2006; 44:231–248. 10. Betts-Henderson J, Bartesaghi S, Crosier M, et al. The nystagmus-associated FRMD7 gene regulates neuronal outgrowth and development. Hum Mol Genet 2010; 19:342–351. 11. Pu J, Lu X, Zhao G, et al. FERM domain containing protein 7 (FRMD7) upregulates the expression of neuronal cytoskeletal proteins and promotes neurite outgrowth in Neuro-2a cells. Mol Vis 2012; 18:1428–1435. 12. Watkins RJ, Patil R, Goult BT, et al. A novel interaction between FRMD7 and && CASK: evidence for a causal role in idiopathic infantile nystagmus. Hum Mol Genet 2013; 22:2105–2118. A study showing that the FRMD7 protein co-localizes with CASK. The study suggests that FRMD7 mutations could disrupting the interaction between FRMD7 and CASK needed to promote membrane extension during neurite outgrowth. 13. Pu J, Mao Y, Lei X, et al. FERM domain containing protein 7 interacts with the & Rho GDP dissociation inhibitor and specifically activates Rac1 signaling. PloS One 2013; 8:e73108. The authors show that FRMD7 protein interacts with RhoGDIa, the main regulator of Rho GTPases, key regulators of the actin cytoskeleton. 14. Thomas MG, Crosier M, Lindsay S, et al. The clinical and molecular genetic features of idiopathic infantile periodic alternating nystagmus. Brain 2011; 134 (Pt 3):892–902. 15. McLean R, Proudlock F, Thomas S, et al. Congenital nystagmus: randomized, controlled, double-masked trial of memantine/gabapentin. Ann Neurol 2007; 61:130–138. 16. Wang J, Wyatt LM, Felius J, et al. Onset and progression of with-the-rule astigmatism in children with infantile nystagmus syndrome. Invest Ophthalmol Vis Sci 2010; 51:594–601. 17. Sheth V, Gottlob I, Mohammad S, et al. Diagnostic potential of iris crosssectional imaging in albinism using optical coherence tomography. Ophthalmology 2013; 120:2082–2090. 18. von dem Hagen EA, Houston GC, Hoffmann MB, Morland AB. Pigmentation predicts the shift in the line of decussation in humans with albinism. Eur J Neurosci 2007; 25:503–511. 19. Schmitz B, Krick C, Kasmann-Kellner B. [Morphology of the optic chiasm in albinism]. Der Ophthalmologe: Zeitschrift der Deutschen Ophthalmologischen Gesellschaft 2007; 104:662–665. 20. Bridge H, von dem Hagen EA, Davies G, et al. Changes in brain morphology in & albinism reflect reduced visual acuity. Cortex 2012. [Epub ahead of print] Abnormalities of the visual cortex are described in albinism such as increased cortical thickness and decreased gyrification. 21. Kumar A, Gottlob I, McLean RJ, et al. Clinical and oculomotor characteristics of albinism compared to FRMD7 associated infantile nystagmus. Invest Ophthalmol Vis Sci 2011; 52:2306–2313.
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Aetiology of infantile nystagmus Gottlob and Proudlock 22. Roffler-Tarlov S, Liu JH, Naumova EN, et al. L-Dopa and the albino riddle: content of L-Dopa in the developing retina of pigmented and albino mice. PloS One 2013; 8:e57184. The authors highlight the role L-DOPA depletion has in visual system abnormalities seen in albinism rather than the absence of the pigment melanin. 23. Seth A, Culverwell J, Walkowicz M, et al. Belladonna/(Ihx2) is required for neural patterning and midline axon guidance in the zebrafish forebrain. Development 2006; 133:725–735. 24. Huang YY, Rinner O, Hedinger P, et al. Oculomotor instabilities in zebrafish mutant belladonna: a behavioral model for congenital nystagmus caused by axonal misrouting. J Neurosci 2006; 26:9873–9880. 25. Huang MY, Chen CC, Huber-Reggi SP, et al. Comparison of infantile nystagmus syndrome in achiasmatic zebrafish and humans. Ann N Y Acad Sci 2011; 1233:285–291. 26. Huber-Reggi SP, Chen CC, Grimm L, et al. Severity of infantile nystagmus & syndrome-like ocular motor phenotype is linked to the extent of the underlying optic nerve projection defect in zebrafish belladonna mutant. J Neurosci 2012; 32:18079–18086. A study showing the correlation between the degree of optic fibre misrouting and the nystagmus phenotype in the belladonna (bel) mutant zebrafish. 27. Traber GL, Chen CC, Huang YY, et al. Albino mice as an animal model for && infantile nystagmus syndrome. Invest Ophthalmol Vis Sci 2012; 53:5737– 5747. A study describing albino mouse strains that demonstrate pathological nystagmus waveforms that resemble those observed in humans with infantile nystagmus. These albino mice are presented as new animal models for INS. 28. Huang MYY, Chen C-C, Bockisch CJ, Straumann D. Doomed to move the eyes: infantile nystagmus-like eye movements in healthy human subjects. Invest Ophthalmol Vis Sci 2011; 52:3016. 29. Abadi RV, Forster JE, Lloyd IC. Ocular motor outcomes after bilateral and unilateral infantile cataracts. Vision Res 2006; 46:940–952. 30. Birch EE, Wang J, Felius J, et al. Fixation control and eye alignment in children treated for dense congenital or developmental cataracts. J AAPOS 2012; 16:156–160. 31. Pieh C, Simonsz-Toth B, Gottlob I. Nystagmus characteristics in congenital stationary night blindness (CSNB). Br J Ophthalmol 2008; 92:236–240. 32. Gottlob I, Reinecke RD. Eye and head movements in patients with achromatopsia. Graefes Arch Clin Exp Ophthalmol 1994; 232:392–401. 33. Schneider RM, Thurtell MJ, Eisele S, et al. Neurological basis for eye move& ments of the blind. PloS One 2013; 8:e56556. A study postulating that slow disconjugate eye movements resulting from visual deprivation are caused by disrupted calibration of the neural integrator. 34. Akman OE, Broomhead DS, Abadi RV, Clement RA. Components of the neural signal underlying congenital nystagmus. Exp Brain Res 2012; 220:213–221. 35. Akman OE, Broomhead DS, Abadi RV, Clement RA. Eye movement instabilities and nystagmus can be predicted by a nonlinear dynamics model of the saccadic system. J Math Biol 2005; 51:661–694. &
36. Dell’Osso LF. Biologically relevant models of infantile nystagmus syndrome: the requirement for behavioral ocular motor system models. Semin Ophthalmol 2006; 21:71–77. 37. Brodsky MC, Dell’Osso LF. A unifying hypothetical mechanism for infantile && nystagmus. JAMA Ophthalmol 2013. (in press). A new hypothesis that explains how motor oscillations in infantile nystagmus can result from afferent visual deficits. The hypothesis is based on disrupted development of binocular cortical motion centres leading to uncontrolled expression of the subcortical OKN system. 38. Leguire LE, Kashou NH, Fogt N, et al. Neural circuit involved in idiopathic infantile nystagmus syndrome based on FMRI. J Pediatr Ophthalmol Strabismus 2011; 48:347–356. 39. Dell’Osso LF, Wang ZI. Extraocular proprioception and new treatments for infantile nystagmus syndrome. Prog Brain Res 2008; 171:67–75. 40. Berg KT, Hunter DG, Bothun ED, et al. Extraocular muscles in patients with & infantile nystagmus: adaptations at the effector level. Arch Ophthalmol 2012; 130:343–349. A description of the changes in extraocular muscle composition and innervation in infantile nystagmus. 41. Serra A, Dell’Osso LF, Jacobs JB, Burnstine RA. Combined gaze-angle and vergence variation in infantile nystagmus: two therapies that improve the highvisual-acuity field and methods to measure it. Invest Ophthalmol Vis Sci 2006; 47:2451–2460. 42. Harris C, Berry D. A developmental model of infantile nystagmus. Semin Ophthalmol 2006; 21:63–69. 43. Brodsky MC, Tusa RJ. Latent nystagmus: vestibular nystagmus with a twist. Arch Ophthalmol 2004; 122:202–209. 44. Valmaggia C, Rutsche A, Baumann A, et al. Age related change of optokinetic nystagmus in healthy subjects: a study from infancy to senescence. Br J Ophthalmol 2004; 88:1577–1581. 45. Tychsen L, Richards M, Wong A, et al. The neural mechanism for latent (fusion maldevelopment) nystagmus. J Neuroophthalmol 2010; 30:276– 283. 46. Harris CM. Latent nystagmus. Optometry Today 2013; 54:49–53. 47. Rahman W, Proudlock F, Gottlob I. Oral gabapentin treatment for symptomatic Heimann-Bielschowsky phenomenon. Am J Ophthal 2006; 141:221– 222. 48. Thomas S, Proudlock FA, Sarvananthan N, et al. Phenotypical characteristics of idiopathic infantile nystagmus with and without mutations in FRMD7. Brain 2008; 131 (Pt 5):1259–1267. 49. Shaikh AG, Hong S, Liao K, et al. Oculopalatal tremor explained by a model of inferior olivary hypertrophy and cerebellar plasticity. Brain 2010; 133 (Pt 3):923–940. 50. Lienbacher K, Mustari M, Hess B, et al. Is there any sense in the palisade endings of eye muscles? Ann N Y Acad Sci 2011; 1233:1–7. 51. Lee H, Sheth V, Bibi M, et al. Potential of handheld optical coherence tomography to determine cause of infantile nystagmus in children by using foveal morphology. Ophthalmology 2013; 120:2714–2724.
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Aetiology of infantile nystagmus Irene Gottlob and Frank A. Proudlock
Purpose of review Mechanisms underlying infantile nystagmus are unclear. The aim of this review is to outline recent developments in understanding the aetiology of infantile nystagmus. Recent findings There have been advances in understanding mechanisms underlying idiopathic infantile nystagmus, which has progressed through determining the role of the FRMD7 gene in controlling neurite outgrowth, and albinism, in which recent models have investigated the possibility of retinal miswiring leading to nystagmus. We also briefly review aetiology of infantile nystagmus in afferent visual deficits caused by ocular disease, and PAX6 mutations. Improved phenotypical characterization of all these infantile nystagmus subtypes has been achieved recently through high-resolution retinal imaging using optical coherence tomography. Several new hypotheses proposing common mechanisms that could underlie various infantile nystagmus subtypes are also highlighted. Summary Although there is still no consensus of opinion regarding the mechanisms causing infantile nystagmus, identification of new genes and determining their cellular function, phenotypical characterization of genetic subtypes, and improvements in animal models have significantly advanced our understanding of infantile nystagmus. These recent developments pave the way to achieving a much clearer picture of infantile nystagmus aetiology in the future. Keywords achromatopsia, albinism, congenital nystagmus, idiopathic infantile nystagmus, infantile nystagmus
INTRODUCTION Infantile nystagmus syndrome (INS) consists of involuntary oscillation of the eyes with onset in the first 3–6 months of life [1]. It is frequently associated with developmental sensory deficits, although the relationship between sensory impairments and motor oscillations is unclear. The aetiology of infantile nystagmus follows a pathophysiological sequence of events commencing with gene mutations and their effect on cell physiology (Fig. 1), leading to disrupted development of neural function and connectivity in the afferent visual pathway (1 in Fig. 1) and/or ocular motor system (2 in Fig. 1). Gene mutations could also directly affect motor (3 in Fig. 1) and/or sensory (4 in Fig. 1) innervation of extraocular muscles. In this review, we consider the recent developments in four main subtypes of infantile nystagmus, namely idiopathic infantile nystagmus, albinism, afferent visual deficits caused by ocular disease and PAX6 mutations. Recent advances have been made concerning these subtypes, particularly in determining the effect of gene mutations on cellular mechanisms and also in accurately characterizing
afferent visual deficits associated with infantile nystagmus subtypes (1 in Fig. 1). We also consider recent mechanisms that have been proposed as the direct motor cause of infantile nystagmus. One key area of controversy is whether infantile nystagmus subtypes share a common mechanism. Is there one rhythm or eye drift generator that is responsible for directly causing nystagmus in different infantile nystagmus subtypes? In outlining mechanisms, we also consider manifest latent nystagmus (MLN), another common subtype of infantile nystagmus, and whether it also shares a common aetiology to other types of infantile nystagmus. This review does not cover the multiplicity
Ophthalmology Group, University of Leicester, Faculty of Medicine & Biological Sciences, Robert Kilpatrick Clinical Sciences Building, Leicester Royal Infirmary, Leicester, UK Correspondence to Irene Gottlob, Ophthalmology Group, University of Leicester, Faculty of Medicine & Biological Sciences, Robert Kilpatrick Clinical Sciences Building, Leicester Royal Infirmary, PO Box 65, Leicester LE2 7LX, UK. Tel: +44 0 116 258 6291; e-mail: [email protected] Curr Opin Neurol 2014, 27:83–91 DOI:10.1097/WCO.0000000000000058
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KEY POINTS
Genetic mutations
Discovery of genetic mutations associated with infantile nystagmus has led to experimental models that have furthered our understanding of the aetiology of infantile nystagmus at a cellular level. The FRMD7 gene, which is associated with idiopathic infantile nystagmus, has been show to promote neurite outgrowth through controlling interactions between plasma membrane and the actin cytoskeleton. Better phenotypical characterization of afferent visual deficits in infantile nystagmus subtypes has been achieved using high-resolution retinal imaging with optical coherence tomography, and suggests underlying foveal deficits are common to most infantile nystagmus subtypes. Several recent models have been proposed to explain how afferent visual deficits can lead to motor oscillations, such as miswired retinal motion sensors and abnormal development of binocular cortical motion centres leading to uncontrolled expression of subcortical motion tracking mechanisms.
of neurological syndromes that can lead to nystagmus in infancy, many of which are more akin to acquired nystagmus types in character. Another area of debate concerns whether the primary disease underlying infantile nystagmus is an afferent visual disorder disturbing foveal vision during development (1 in Fig. 1). If so, this would imply that the mechanism generating nystagmus would be otherwise normal ocular motor circuitry that becomes unstable on receiving abnormal afferent input during visual development. The relationship between afferent visual deficits and infantile nystagmus is becoming clearer with the emergence of high-resolution retinal imaging techniques such as optical coherence tomography (OCT), which has been applied to infantile nystagmus subtypes (Fig. 2) [2–5,6 ,7 ]. These not only permit accurate phenotypical characterization of genetic subtypes of infantile nystagmus but also provide a means by which afferent visual deficits can be directly compared with motor oscillations. &
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IDIOPATHIC NYSTAGMUS The term ‘idiopathic’ infantile nystagmus has been used to describe infantile nystagmus wherein no disease has been found in the brain or retina. However, this terminology may become redundant as recent high-resolution imaging of the retina using OCT has shown that retinal deficits indeed exist in individuals with idiopathic infantile nystagmus, 84
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Cellular mechanisms
1 Afferent visual pathway
2 Ocular motor pathway PROPRIOCEPTIVE FEEDBACK
3 Extraocular muscles 4
Nystagmus waveform
VISUAL FEEDBACK
FIGURE 1. The sequence of pathophysiology that leads to nystagmus generation in infantile nystagmus. Genetic mutations are known to underlie most infantile nystagmus subtypes leading to changes in cellular function, which in turn could effect: the developing afferent visual pathway (1), the developing ocular motor system (2), extraocular muscle structure and/or motor innervation (3), or feedback from extraocular muscle proprioceptors (4).
including foveal thickening, thinning of the retinal nerve fibre layer and shortened cone outer segments [3]. This opens up the possibility that the primary pathology behind most forms of infantile nystagmus could be sensory in origin (1 on Fig. 1). However, as these changes are subclinical, idiopathic infantile nystagmus remains the most likely form of infantile nystagmus to be caused by abnormal development of the ocular motor system (2 on Fig. 1). Since the identification of the first gene associated with idiopathic infantile nystagmus, the FRMD7 gene located at Xq26 [8], studies have aimed to explore the function of the gene. The FRMD7 gene encodes a member of the FERM domain family of proteins. These are plasma membrane–cytoskeleton coupling proteins many of which bind to actin or other cytoskeleton components [9]. In differentiating Neuro2A cells, the FRMD7 protein co-localizes with the actin of primary neurites [10]. FRMD7 protein expression in these cells promotes neurite outgrowth [11] and knock-down of FRMD7 causes a reduction in average neurite length [10]. Watkins et al. [12 ] recently found an interaction between the FRMD7 protein and calcium/ calmodulin-dependent serine protein kinase (CASK). One of the functions of CASK in neurons &&
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l. Examples of OCT images from normal retina and individual with foveal hypoplasia (a) NFL GCL
Normal
Unique foveal elements Foveal pit
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INL OPL ONL
ONL widening OS lengthening
(b)
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Albinism
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FIGURE 2. Characterization of foveal abnormalities in nystagmus subtypes using optical coherence tomography. In (I), optical coherence tomograms are shown for (a) a normal fovea with a description of the normal foveal elements, and the spectrum of foveal hypoplasia seen in various conditions, including: (b, c) albinism, (d, e) associated with PAX6 mutations, (f, g) isolated cases, and (h, i) an atypical form of foveal hypoplasia seen in achromatopsia. (II) Illustrates principles used to characterize foveal abnormalities using a structural grading scheme where (a) is a schematic of the unique features of a normal fovea. (b) Illustrates typical and atypical grades of foveal hypoplasia. All grades of foveal hypoplasia had incursion of inner retinal layers. Grade 1 foveal hypoplasia is associated with a shallow foveal pit, outer nuclear layer (ONL) widening, and outer segment (OS) lengthening relative to the parafoveal ONL and OS length, respectively. In Grade 2 foveal hypoplasia, all features of grade 1 are present except the presence of a foveal pit. Grade 3 foveal hypoplasia consists of all features of grade 2 foveal hypoplasia except the widening of the cone outer segment. Grade 4 foveal hypoplasia represents all the features seen in grade 3 except there is no widening of the ONL at the fovea. Finally, an atypical form of foveal hypoplasia also is described in which there is a shallower pit with disruption of the inner segment/OS (IS/OS) junction, possibly a sign of photoreceptor degeneration. The atypical form of foveal hypoplasia is seen with achromatopsia, whereas grades 1 through 4 are seen with albinism, PAX6 mutations, and isolated cases. ELM, external limiting membrane; GCL, ganglion cell layer; INL, inner nuclear layer; IPL, inner plexiform layer; OPL, outer plexiform layer; RNFL, retinal nerve fibre layer; RPE, retinal pigment epithelium. Reproduced with permission from Thomas et al. [5].
is to link the plasma membrane to the actin cytoskeleton. They suggest that FRMD7 mutations could act by disrupting the interaction between FRMD7 and CASK needed to promote membrane extension during neurite outgrowth (Fig. 3). The FRMD7
protein has also been shown to interact with RhoGDIa, the main regulator of Rho GTPases, which are key regulators of the actin cytoskeleton [13 ]. Expression of FRMD7 in the human embryo occurs in both the developing neural retina as well
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ll. Grading scheme devised to grade foveal hypoplasia based upon stage at which retinal development was arrested Normal foveal structural features detectable using optical coherence tomography
Illustration RNFL
(a) Extrusion of plexiform layers (b) Foveal pit (c) OS lengthening (d) ONL widening
GCL INL
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ONL
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Grade of foveal hypoplasia
Structural features detected on optical coherence tomography
Present or absent
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(a) Extrusion of plexiform layers (b) Foveal pit – Shallow (c) OS lengthening (d) ONL widening
(a) Absent (b) Present (c) Present (d) Present
Median logMAR visual acuity (interquartile range)
Illustration
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(a) Absent (b) Absent (c) Present (d) Present
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0.44 (0.18)
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(a) Extrusion of plexiform layers (b) Foveal pit (c) OS lengthening (d) ONL widening
(a) Absent (b) Absent (c) Absent (d) Present
4
(a) Extrusion of plexiform layers (b) Foveal pit (c) OS lengthening (d) ONL widening
(a) Absent (b) Absent (c) Absent (d) Absent
Atypical
(a) Extrusion of plexiform layers (b) Foveal pit–Shallow (e) IS/OS dicruption
(a) Absent (b) Present (e) Present
(d)
0.60 (0.0)
0.78 (0.11)
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FIGURE 2. (Continued )
as in ocular motor structures such as the cerebellum and vestibulo-optokinetic system [8,14]. The FRMD7 protein, therefore, could primarily influence the developing afferent or motor system. The medications gabapentin and memantine have been shown to influence idiopathic infantile nystagmus [15] by reducing nystagmus intensity leading to improved visual acuity. These two medications are central nervous system inhibitors. Gabapentin probably increases synaptic concentration of the inhibitory transmitter GABA through voltage-sensitive calcium channels, whereas memantine inhibits the excitatory neurotransmitter glutamate by blocking N-methyl-D-aspartate (NMDA)-type glutamate receptors. These two transmitter systems are found in both sensory and motor systems, however.
ALBINISM Unlike idiopathic infantile nystagmus, albinism leads to profound impairments throughout the visual pathway including high refractive errors [16], iris abnormalities [17], foveal hypoplasia (see Fig. 2) [2,5], a shift in the line of decussation of retinal 86
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ganglion cells [18], abnormal optic nerve and chiasm morphology [19], and cortical thickening [20 ]. Recent studies have shown a spectrum of disrupted development in retinal [2] and cortical [20 ] morphology in albinism that is correlated to the degree of visual deficit. OCT studies show that the human retina in albinism is invariably marked by continuation of inner retinal layers at the fovea (usually these layers are extruded to form the foveal pit) and shorter outer segments of the cone photoreceptor layer [2] (Fig. 2b and c , part I). Cone outer segments are usually longer and thinner in the normal fovea to increase cone packing, a requirement for high acuity vision. Hence, cone outer segment length is a strong predictor of visual acuity in albinism [2]. Despite widely different visual pathway anomalies, the nystagmus characteristics in albinism and idiopathic (FRMD7-associated) infantile nystagmus show several similarities, such as a predominantly horizontal waveform, a combination of jerk and pendulum waveforms, and similar proportions of periodic alternating nystagmus [21]. The similarities might suggest a shared underlying &
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Anti–GFP
Recent studies using transgenic mice have indicated that deficits in the intermediate metabolite, L-3,4-dihydroxyphenylalanine (L-DOPA), lead to the visual system abnormalities seen in albinism rather than the absence of the pigment melanin, which is the end product of the process leading to hypopigmentation [22 ]. In the normal pigmented mouse retina, the change in L-DOPA content in the retina reflects the onset and completion of retinal development. However, in the embryonic albino retina of mice (OCA1 model), L-DOPA is absent during retinal development and is greatly reduced in postnatal albino retina. One interesting hypothesis that has reemerged in relation to nystagmus generation in albinism has been that a subset of motion detectors could be miswired. This has been modelled using several different experimental paradigms. The belladonna (bel) mutant zebrafish demonstrates disrupted commissural and retinal axon guidance in the forebrain leading to miswiring of retinal ganglion cells [23]. The mutant shows reversal of physiological optokinetic responses and also spontaneous pathological eye movements under static full field visual stimulation [24]. Huang et al. [25] have noted that the spontaneous eye movements in this zebrafish model resemble the range of infantile nystagmus waveforms observed in humans. Huber-Reggi et al. [26 ] further demonstrated the strong correlation between the degree of optic fibre misrouting and the nystagmus phenotype. Similar observations have been made by Traber et al. [27 ] in several different albino mouse models. They observed reversal of optokinetic responses when the temporal retina is stimulated, which is where most of the misrouting occurs. They also found infantile nystagmus-like spontaneous nystagmus waveforms in the mouse models with jerk and pendular components. Miswiring of the visual field has also been modelled in normal humans by Huang et al. [28]. Using a gaze contingent display in which the visual feedback was controlled using online eye movement recordings, Huang et al. were able to simulate reversal of retinal slip (so that an eye movement to the right would result in movement of a vertical striped pattern on the display moving to the left). In addition, they found that it was also possible to generate the plethora of nystagmus waveforms described in infantile nystagmus for normal humans. &
Myc
MERGE
FIGURE 3. Co-localization and interaction of the FRMD7 protein (implicated in idiopathic infantile nystagmus) and calcium/calmodulin-dependent kinase in Neuro2A cells. Neuro2A cells were seeded onto coverslips, transiently cotransfected with myc-tagged wild-type (WT) FRMD7 and green fluorescent protein (GFP)-tagged WT CASK and then fixed in methanol 24 h later. Immunofluorescence microscopy was performed using antimyc (green) and anti-GFP (red) antibodies and chromatin was stained with 4,6-diamidino-2phenylindole (blue). Arrows indicate areas of FRMD7 and CASK co-localization at the plasma membrane. Scale bar, 10 mm. Reproduced with permission from Watkins et al. [12 ]. &&
mechanism between nystagmus generation in albinism and idiopathic infantile nystagmus. However, some differences exist between the two nystagmus forms, with higher proportions of pendular nystagmus, less head postures and less nystagmus in the primary position in FRMD7-associated idiopathic infantile nystagmus compared with albinism [21]. To date five genes have been associated with the two most common forms of albinism, oculocutaneous albinism [recessive mutations in at least four autosomal genes: TYR (OCA1), OCA2 (OCA2), TYRP1 (OCA3) and SLC45A2 (OCA4)] and ocular albinism (the X-linked gene OA), as well as less common genes associated with conditions such as Hermansky–Pudlak syndrome. However, in many people with albinism no gene mutation can be found, and this is currently an active area of research.
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AFFERENT VISUAL DEFICITS CAUSED BY OCULAR DISEASE Afferent deficits resulting from anterior or posterior eye disease through conditions such as congenital
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cataract [29,30], congenital retinal dystrophies [4,6 ,31] and optic nerve hypoplasia remain one of the purest ways to investigate infantile nystagmus because the initial disease is almost certainly sensory in origin (1 on Fig. 1). Congenital cataracts can lead to a combination of square wave jerks with both MLN (decelerating slow phases) and infantile nystagmus (accelerating and pendular slow phases) waveforms [29,30]. The most common nystagmus waveform in congenital cataract is MLN, which is also observed in bilateral cataracts and becomes more frequent after removal of cataracts [29]. Recent OCT imaging studies in achromatopsia indicate that this condition might actually be a progressive disease [4,6 ]. The retinae of achromats on OCT images are characterized by a distinct punched out hyporeflective zone [4] in the region of the cone outer segments (Fig. 2i, part I), which increases in size with age [6 ]. Nystagmus associated with achromatopsia is dissimilar in character to that associated with idiopathic infantile nystagmus and albinism. The existence of vertical waveforms and also high frequency fine pendular oscillations is more common and the waveform also appears to evolve from pendular to predominantly jerk nystagmus probably as the disease progresses [32]. The nystagmus observed in congenital stationary night blindness is also characterized by a marked vertical component, high frequency fine pendular oscillations and sometimes disconjugate waveforms [31]. &
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PAX6 MUTATIONS PAX6 mutations are associated with apparent visual sensory deficits such as aniridia and foveal and optic nerve hypoplasia, although direct developmental abnormalities of the ocular motor pathways cannot be ruled out [7 ]. OCT images of the fovea in PAX6 mutations show a spectrum of foveal hypoplasia with shallower or absent foveal pits, continuation of inner retinal layers, shorter outer segments at the fovea and thinner retinal nerve fibre layer [7 ] (Fig. 2d and e, part I). Nystagmus in individuals with PAX6 shows large intrafamilial variability with nystagmus oscillations in different planes (horizontal, vertical and torsional) and a combination of pendular and jerk oscillations [7 ]. OCT findings indicate that foveal deficits are a common theme to all four of these nystagmus subtypes, and in particular disruption to cone specialization or function as evident from shortened or missing cone outer segments. However, the striking differences between the features of the nystagmus associated with idiopathic infantile nystagmus or albinism and afferent visual deficits caused by ocular disease or PAX6 mutations suggest that these may be &
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separate entities with perhaps different primary mechanisms. In the light of these observations, the current trend of viewing all infantile nystagmus as a single entity (i.e., infantile nystagmus syndrome) may not help in progressing our understanding of infantile nystagmus aetiology.
A COMMON MECHANISM FOR NYSTAGMUS GENERATION IN INFANTILE NYSTAGMUS Pathology of many components of both the ocular motor and afferent visual systems has been implicated in nystagmus generation in infancy. Elements of the ocular motor system implicated include the neural integrator [33 ], superior colliculus [34], saccadic system [35], smooth pursuit system [36], optokinetic system [37 ], cerebellum [38], proprioceptive inputs from eye muscles [39] as well as changes in the properties of extraocular muscles themselves [40 ]. The vergence system is also known to influence infantile nystagmus in the form of convergence damping [41]. Visual system abnormalities have included rod and cone dysfunction [4,6 ,31], foveal maldevelopment (hypoplasia) [42], miswiring of retinal motion detectors through chiasmal abnormalities [25,26 ,27 ,28], and disrupted development of cortical binocular motion centres [37 ]. For nystagmus to be generated by afferent visual system pathology alone (1 on Fig. 1) in most cases would require components of otherwise normal ocular motor circuitry transforming into a renegade eye oscillator or drift generator. Several recent hypotheses have been proposed to explain how sensory deficits alone could lead to nystagmus generation. Brodsky and Dell’Osso [37 ] have suggested that infantile nystagmus could result through disrupted development of a dual pursuit/motion tracking system that exists in humans. The first system, the subcortical optokinetic nystagmus (OKN) system, feeds directly through contralateral projections into the nucleus of the optic tract–dorsal terminal nucleus of the accessory optic system (NOT-DTN). This system is thought to be functional from birth and tracks retinal slip with a strong bias for movement in the nasalward direction. The second system, the foveal pursuit system, is more sophisticated and is able to track motion in three-dimensional space as well as subtract movement of a single moving object over a complex background. This system develops later on in infancy and relies on the integrity of cortical binocular motion centres. Brodsky and Dell’Osso suggest that infantile nystagmus is caused by disrupted development of cortical &
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Aetiology of infantile nystagmus Gottlob and Proudlock
binocular motion centres leading to uncontrolled expression of the subcortical OKN system. This hypothesis is a development of a theory proposed by Brodsky and Tusa in 2004 to explain MLN [43], a form of infantile nystagmus that is invariably associated with infantile esotropia and is characterized by a nasalward drift of the viewing eye when the contralateral eye is occluded. Brodsky and Tusa argue that MLN is also an expression of the subcortical OKN pathway due to disrupted development of cortical binocular motion centres, which leads to a nasalward drift of the eyes [44]. Brodsky and Dell’Osso [37 ] propose that infantile nystagmus and MLN share a common aetiology and lie on a continuum. The nystagmus waveforms in MLN are an expression of unequal inputs into the two eyes (i.e., with decelerating or linear nasalward slow phases), whereas the nystagmus waveforms in infantile nystagmus are due to reduced central vision in both eyes, which leads to the subcortical OKN system developing into an oscillator (i.e., leading to underlying sinusoidal oscillations). In contrast to Brodsky’s subcortical ‘downstairs’ view of MLN, Tychsen et al. [45] have suggested an ‘upstairs’ view wherein the asymmetry to motion can be explained by cortical development alone. He suggests that nasalward responses to motion are mediated by a direct crossed pathway to the cortex present from birth, whereas temporalward responses await the development of binocular connections in primary visual cortex. Harris [46] also argues that OKN responses in humans are predominantly cortical even in infancy since the response to stimulation has a rapid onset in infancy, in contrast to subcortical OKN, which has a slow build up. However, Harris proposes that MLN is due to the associated strabismus modifying inter-ocular velocity differences of 3D motion in the visual field, which in turn leads to inappropriate training of the neural integrator. Harris and Berry [42] have proposed an alternative theory also based on an underlying afferent visual disease being behind infantile nystagmus. They suggest that nystagmus is generated by deprivation of the normal visual system to high-spatial frequency contrast stimulation during visual development. This leads to eye movement oscillations that occur to improve contrast sensitivity to lower spatial frequency stimuli. Another proposal to explain how sensory deficits alone could lead to nystagmus generation has recently come from Schneider et al. [33 ] by recording eye movements from individuals with earlyonset monocular visual loss. Monocular deprivation results in vertical eye drifts about the visual axis in the abnormal eye, a phenomenon known as &&
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the Heimann–Bielschowsky phenomenon. The same individuals are able to make accurate conjugate upward saccadic eye movements, which stand in contrast to the slow disconjugate eye movement associated with the Heimann–Bielschowsky phenomenon. As inputs to the motoneurons innervating the elevator muscles bypass the neural integrator, Schneider et al. suggest that the slow drifts are due to disrupted calibration of the neural integrator. Interestingly, gabapentin has been reported to suppress the Heimann–Bielschowsky phenomenon [47], a medication that has also been shown to be effective at reducing infantile nystagmus [15]. One challenge in understanding the mechanisms generating infantile nystagmus has been trying to explain the variety of waveforms observed in infantile nystagmus even from a single common cause. For example, the same FRMD7 gene mutation (i.e., in the same family) can lead to quite different waveforms (see Figure 4 in reference [48]) including even the presence or absence of periodic alternating nystagmus [14]. This could be explained by variable gene expression or environmental factors; however, an alternative has been suggested by Shaikh et al. [49] from modelling oculopalatal tremor. This is a condition associated with lesions in the Guillain– Mollaret triangle leading to hypertrophy of the inferior olive. Shaikh et al. suggest that the inferior olive alone is insufficient to generate the oscillations observed in the eyes and palate but that learning processes in the cerebellum amplify and shape the waveforms. It is possible that the cerebellum could also modify waveforms associated with infantile nystagmus in a highly plastic fashion without being the source of the underlying oscillations.
PERIPHERAL MECHANISMS OF NYSTAGMUS GENERATION Although the majority of this review is focused on central nervous system pathophysiology, it is worth highlighting that abnormalities in both the sensory and motor peripheral innervation of extraocular muscles in infantile nystagmus have been implicated in infantile nystagmus generation (3 and 4 on Fig. 1, respectively). Extraocular muscles of individuals with idiopathic infantile nystagmus demonstrate a hypo-innervated phenotype with reduced nerve fibre and neuromuscular junction density [40 ]. They also contain significantly more centrally nucleated myofibres, consistent with cycles of degeneration and regeneration. This could lead to a reduction in tonic firing of extraocular muscles and problems with gaze-holding. The role of proprioceptors in eye muscles is controversial, but the changes in nystagmus
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resulting from muscle tenotomy, a form of surgery that is likely to modify the input from palisade endings in myotendious junction, have led some to suggest aberrant proprioceptive input could have a role in generating infantile nystagmus [39]. It should be added, however, that it has not yet been decisively shown whether palisade endings are sensory or motor in function, although most indicators point to them being sensory [50].
CONCLUSION This overview highlights the lack of consensus with respect to the mechanisms that underlie infantile nystagmus. The range of causes that have been proposed include: exclusively afferent visual pathway pathology that causes a tonic neural drive generating infantile nystagmus (e.g., miswiring of retinal ganglion cells [25,26 ,27 ,28]); underlying visual disease that leads to modifications in otherwise normal motor circuitry during visual development, which in turn drive the oscillations in infantile nystagmus (e.g., uncontrolled expression of the subcortical OKN system following disrupted binocular cortical development, as suggested by Brodsky and Dell’Osso [37 ]); (iii) aberrant development of motor CNS circuitry without the need for an afferent deficit (e.g., cerebellar abnormalities [38]); and also (iv) pathological changes in extraocular muscle structure or in motor and sensory peripheral innervation as the primary generator of infantile nystagmus rather than changes in sensory or motor CNS [40 ]. Future research into the identification of unknown genetic mutations associated with infantile nystagmus will open up avenues for developing cellular and animal models. Further phenotypical characterization of infantile nystagmus subtypes through techniques such as high-resolution retinal imaging (Fig. 2) will improve genotype–phenotype correlations as well as allow more accurate comparisons of afferent visual deficits to nystagmus characteristics. The recent availability of instrumentation that can acquire high-resolution three-dimensional images of the retina in infancy also allows phenotypical characterization of infantile nystagmus subtypes during visual development [51]. &
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Acknowledgements We wish to acknowledge the financial support of the Ulverscroft Foundation, National Eye Research Council, Fight for Sight, Medisearch, Nystagmus Network and the Medical Research Council. We also wish to acknowledge the Nystagmus Network for all their support in our studies. (Please note that none of this support is exclusive to this article). 90
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Conflicts of interest There are no conflicts of interest.
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