“lesions,” only miscalibrated motor control systems. However, it hinges on a perturbation in the developing visual system and does not explain the occasional finding of hereditary and spontaneous infantile nystagmus documented at birth, long before any problems with the visual system could have precipitated an oscillation.

Barriero et al have presented a mathematical model in which infantile nystagmus can be derived from an abnormal neural integrator network tuned by adaptive cerebellar neurons.50a However, too much positive feedback around a leaky neural integrator would cause acceleration in a centrifugal direction, while in infantile nystagmus, the slow phases drift centripetally toward the neutral region. This neural integrator model would also produce a nystagmus that is dependent on the saccade that preceded nystagmus, which does not happen in infantile nystagmus.

Dell’Osso et al have concluded that infantile nystagmus conforms to an increase in the oscillation of the normally functioning pursuit system. Indeed, some infants display a transient nystagmus that disappears as the visual system matures during the postnatal period.225 Nystagmus may be associated with visual system deficits or be present with no visual system deficits. In the former situation, the visual system deficits precipitate one or more ocular motor system instabilities that cause it. In the latter situation, a number of genetic mutations may facilitate the instability.

A number of genetic mutations may also facilitate this oscillation. There are at least three distinct loci for autosomal dominant infantile nystagmus.491 In practice, pedigrees that include male-to-male transmission (and are therefore not X-linked) are much rarer than apparent X-linked pedigrees. For example, the FRMD7 mutation, which is associated with X-linked infantile nystagmus, is expressed in the ventricular layer of the forebrain, midbrain, cerebellar primordium, spinal cord, and developing neural retina. This protein is homologous to another protein that is known to alter the neurite length and degree of branching of neurons as they develop in the midbrain, cerebellum, and retina, which could provide a motor and combined visual and motor underpinning for the occurrence of infantile nystagmus.526 Leigh and Khanna364 recently raised the possibility that infantile nystagmus could result from a congenital channelopathy, which causes similar hereditary acquired forms of nystagmus such as episodic ataxia type 2. Harris and Berry proposed the infantile nystagmus may develop as a developmental response to reduced contrast sensitivity to high-spatial frequencies in an early critical period. Because contrast sensitivity to low spatial frequencies is enhanced by motion of the image across the retina, they propose that the jerk nystagmus with increasing velocity waveforms may provide the best com-

promise between moving the image and maintaining the image near the fovea (or its remnant). As succinctly stated by Kommerell, “The pathogenesis of infantile nystagmus is still an unresolved riddle.”341

Visual Disorders Precipitating Infantile

Nystagmus

Albinism

Albinism is an evolutionary maladaptation424 that is ubiquitous in mammalian vertebrates. It is likely that the myriad mutations that underlie this complex phenotype may confer some nonvisual evolutionary advantage, at least in the heterozygote. Part of our fascination with this disorder lies in its atavistic effects on the developing visual system, causing the frontal-eyed animal to exhibit the same predominance of crossed axons as is normally found in lat- eral-eyed afoveate animals. The other part lies in the complex interrelationship between the pigmentary abnormalities, structural derangements, and neurologic rerouting that together characterize the albinotic visual system.245 Despite these problems, the great majority of children with albinism are intellectually bright and neurodevelopmentally normal.

The preponderance of evidence suggests that hypopigmentation within the retinal pigment epithelium disrupts retinal maturation183,311,569 and causes the associated chiasmal misdirection.101,299,300,377,378,458 Because the position of the vertical retinal meridian is determined primarily by the decussation of ganglion cells at the chiasm and retrograde influence may also determine the position at which the fovea develops,425 it has also been argued that chiasmal misrouting could secondarily interfere with foveal development later in gestation.505,545 While it is likely that all of the clinical findings in albinism are dictated to various degrees by genetic determinants that simultaneously affect pigmentation and axonal migration, van Genderen et al545 documented crossed VEP asymmetry in three darkly pigmented patients with foveal hypoplasia.

Albinism is not a single entity; it encompasses a heterogenous group of congenital hypomelanotic disorders. These disorders can be divided into three general categories of regional hypopigmentation involving neuroectoderm (ocular albinism), neural crest (albinoidism), or both (oculocutaneous albinism).288 In ocular albinism, there is hypopigmentation of ocular neuroectoderm (iris and retinal pigment epithelium) that manifests clinically with iris transillumination, macular hypoplasia, chorioretinal hypopigmentation, photophobia, and nystagmus. The

term albinoidism is applied to a condition in which hypopigmentation is limited to tissues of neural crest origin (skin, hair, and iris stroma). Unlike patients with ocular albinism, those with albinoidism do not manifest macular hypoplasia, nystagmus, photophobia, or decreased vision.288 In oculocutaneous albinism, there is diffuse hypopigmentation involving tissue of neuroectodermal and neural crest origin. Considerable clinical heterogeneity occurs in human albinism, as evidenced by the multiple forms of oculocutaneous and ocular albinism that have been defined at the molecular level.7

Molecular mechanisms underlying many different types of albinism have been elucidated.97 The normal process of melanogenesis involves conversion of the amino acid tyrosine into melanin by the action of the enzyme tyrosinase.7,334 In albinism, there appears to be an intracellular block of this metabolic pathway. Pigmentary dilution in oculocutaneous albinism is due to inadequate melanization of a normal number of melanosomes,7 while in ocular albinism, it is due to an abnormally low number of mature ocular melanosomes.434 In 2008, Eiberg et al at the University of Copenhagen found the genetic mutation common to all blue-eyed people to be a single letter change, from A to G, on the long arm of chromosome 15, which reduces the expression of the OCA2 gene that is involved in the manufacture of pigment that darkens the eyes.187 Oculocutaneous albinism also results from mutations in OCA 1-4.187 Eiberg calculated that this mutation occurred only 6,000–10,000 years ago, in an individual near the Black Sea.187 As people in northern climates become more dependent on grain as a food source, which is deficient in vitamin D, it has been hypothesized that the paler skin associated with this trait may admit more sunlight for the synthesis of vitamin D, and thereby enhanced survival.469 Alternatively, it may have enhanced sexual selection if blue eyed descendents happened to be more attractive to the opposite sex in that geographic region.469

An interesting question that arises is whether melanopsin, the nonvisual photoreceptor that is localized to retinal ganglion cells and plays a predominant role in circadian phototransduction, can be normally synthesized in these disorders. Experimental evidence suggests that it continues to be synthesized in albino rats.258 As aberrant circadian rhythms have long ago been noted in some patients with albinism,438 this problem clearly merits further study. Although some children with albinism show delayed visual development (see Chap. 1), they show surprisingly normal neurodevelopment without significant problems with motor coordination, balance, or ambulation.354

A number of inherited diseases with nystagmus show a combination of immunological and pigmentation defects. Chediak-Higashi, Hermansky-Pudlak, Griscelli, and paroxysmal autonomic instability with dystonia syndromes are all autosomal diseases with these characteristics. The

molecular links between immunodeficiencies and albinism reflect the fact that both melanosomes and secretory lysosomes are not secreted normally.242 Key proteins such as Rab27a are critical for secretion of specialized “secretory granules,” which are modified lysosomes. These secretory lysosomes use specialized mechanisms of secretion not found in other cell types. Chediak-Higashi syndrome, a disease characterized by repeated infections and albinism, shows the presence of abnormally large lysosomes and melanosomes, suggesting that melanosomes are not secreted normally and supporting a functional link with the secretory lysosomes of hematopoietic cells. These disorders share a defect in the molecular mechanisms controlling sorting to a novel lysosomal compartment that acts as a secretory organelle in a number of hemopoietic cell types and melanocytes.242 In the Vici syndrome, albinism, immunodeficiency, cataracts, and cardiomyopathy are associated with agenesis of the corpus callosum.102a

Individuals with mild ocular or oculocutaneous albinism are often misdiagnosed as having idiopathic infantile nystagmus.503 Periodic alternating nystagmus is said to be particularly common in albinism.7,252,349 Abadi and Pascal7 reported periodic alternating nystagmus in over 30% of their patients with albinism. Infants with albinism may also rarely display a seesaw nystagmus that later reverts to horizontal nystagmus.297

The finding of subtle signs of ocular hypopigmentation in some infantile nystagmus patients with good vision once led to speculation that patients with idiopathic infantile nystagmus may actually be heterozygous for albinism. Simon et al503 have found that when patients with infantile nystagmus are carefully examined, many show iris transillumination, blunting of the macular reflex, and chorioretinal hypopigmentation consistent with albinism. In evaluating the infantile nystagmus patient, it is critical to carefully perform a slit lamp examination with the room lights turned off, the door closed, and a retro-illumination through a thin, axial light beam to detect basal iris transillumination. Varying degrees of macular hypoplasia (absence of the foveal pit, macula lutea pigment, and normal macular pigment epithelial hyperpigmentation and the passage of retinal vessels through the fovea), together with other signs of ocular hypopigmentation, suggest the diagnosis of albinism. Moreover, isolated foveal hypoplasia may also occur as a hereditary condition in children with normal pigmentation.437 This finding should be sought in all children who seem to have idiopathic infantile nystagmus. Multifocal ERG, which shows a uniform cone response across the macular area in patients with albinism, may provide a more definitive way to confirm the presence of foveal hypoplasia in patients with infantile nystagmus.325

Other valuable clinical signs of albinism are often overlooked. For example, patients with albinism have a positive angle kappa that is usually absent in patients with idiopathic

Fig. 8.5  Child with albinism showing positive angle kappa bilaterally.

Use with permission, from Brodsky MC et al84

Fig. 8.6  Distribution of optic axons from nasal and temporal retina in left eye (viewed from above) in albinism. In ocularly pigmented humans, nasotemporal border corresponds with fovea. In albinism, nasotemporal border is shifted approximately 20 degrees into temporal retina, resulting in majority of retinal ganglion fibers crossing at optic chiasm. Adapted, with permission, from Brodsky MC et al78

infantile nystagmus (Fig. 8.5). This positive angle kappa can simulate exotropia on Krimsky testing, while alternate cover testing shows the absence of a manifest exodeviation.84,388 This clinical sign presumably reflects the temporal displacement of the zone of transition between crossed and uncrossed retinogeniculate axons. In Siamese cats (which are homozygous for an allele of the albino gene), the nasotemporal transition is located 1.7–3.0 mm temporal to the area centralis. Because there is minimal foveal development in albinism, this altered nasotemporal junction may reposition the fixation point temporally to prevent any gap in the continuous representation of visual space. A temporal displacement of the fixation point for each retina corresponds to the observed nasal displacement of the corneal light reflex. Unfortunately, this temporal displacement of the fixation point has not been factored into the interpretation of visual field testing, hemispheric VEP testing, or functional magnetic resonance (MR) testing in patients with albinism.75

Schatz and Pollock480 have identified a characteristic optic disc appearance in albinos consisting of a small, cupless disc, with temporal entrance and situs inversus of the vessels and an oblique long axis of the disc (Fig. 2.33). The major retinal vessels also traverse the central retina abnormally close to the position where the fovea is normally located. We have observed that most infants with albinism also have gray optic discs and that the gray cast often disappears over the first few years of life.77 The temporal entrance of the retinal vessels and the mild optic nerve hypoplasia that is evident both clinically and on MR imaging483 probably corresponds to the relative absence of the papillomacular nerve fiber bundle associated with macular hypoplasia.

The visual and auditory pathways in albinos have anomalous neuroanatomical connections that are similar in all types of animals studied.7 Initially, the loss of a nonpigmentary function of tyrosinase was considered responsible for these

neural defects, but work by Silver and Sapiro and Strongin and Guillery has implicated the presence of melanin and the stage-specific lysis of melanosomes at the distal end of the developing optic stalk close to the optic disc as being vital for normal retinofugal axonal migration.30,502,520 In humans and animals with albinism, the extent of chiasmal misrouting is inversely proportional to pigmentation level.552

Neuroanatomical and electrophysiological studies of albino visual pathways have demonstrated that retinogeniculate axons arising from ganglion cells in the portion of the temporal retina within 20 degrees of the vertical meridian decussate abnormally in the optic chiasm to synapse in the contralateral lateral geniculate nucleus (Fig. 8.6).118,119,121,246–248,496 Although hemispheric VEPs probably provide the most sensitive and specific means by which to establish the diagnosis of albinism, an absence of asymmetry is occasionally seen in patients with otherwise clear clinical signs of albinism. MR imaging of the anterior visual pathways shows smaller optic nerves, chiasm, and tracts, with a wider angle between the two optic nerves and the two optic tracts.483

New molecular findings in the albino retina underscore the hypothesis that zinc finger transcription factor, Zic2, determines the uncrossed retinal projection.458 Zic2 is a vertebrate homolog of the Drosophila gene odd-paired that is expressed in retinal ganglion cells with an uncrossed trajectory during the period when this subpopulation grows from the ventrotemporal retina toward the optic chiasm. Zic2 controls downstream events that may direct the avoidance of chiasm midline cells by retinal ganglion cells with an uncrossed trajectory. Zic2 may be necessary and sufficient to regulate retinal ganglion cell axon repulsion by cues at the optic chiasm midline. Zic2 expression reflects the extent of binocularity in different species, suggesting that it serves as an evolutionarily conserved determinant of retinal ganglion cells that project ipsilaterally.

Albino mice display a reduction in the number of uncrossed fibers and a concomitant reduction in Zic2-expressing cells. This reduction might arise because the tempo of retinal neurogenesis is accelerated in the albino. A slight alteration in the numbers of cells born on each day of retinal neurogenesis could bias the production of retinal ganglion cells in favor of one population or the other by affecting postmitotic expression of Zic2.458 Although mammals and amphibians use different strategies to establish binocular vision during their lifetime, the fact that Zic2 expression correlates with the degree of binocularity suggests a conserved function for Zic2 in modulating the uncrossed retinal ganglion cell axon projection.275

Other ocular and systemic hypopigmentation disorders should be considered in the differential diagnosis of albinism. Creel et al120 have reported asymmetrical hemispheric VEPs in patients with Prader–Willi syndrome (a condition characterized by hypotonia, hypomentia, hypogonadism, and hyperphagia).120 Albinism is seen in approximately 1% of patients with Prader– Willi syndrome.361 In contradistinction, Apkarian et al32 found no evidence of hemispheric VEP asymmetry in Prader–Willi syndrome but noted lateralization of the VEP response to the right or left hemisphere regardless of which eye was stimulated in half of their Prader–Willi patients. Because both studies were carried out by highly experienced investigators, the discrepancy in findings may merely reflect the greater degree of albinism in the small group of patients tested by Creel et al.120

Patients with oculocutaneous albinism, ocular albinism, Prader–Willi syndrome, and Angelman’s syndrome have mutations of the P gene, which has been mapped to 15 q11q13.361 The P gene codes for a polypeptide that appears to be an integral membrane protein with structural homology to transporters of amino acids, and it has been speculated that this gene might transport tyrosine (the precursor of melanin).361 Interestingly, Prader–Willi syndrome is associated with deletions of the paternally inherited P gene, whereas Angelman’s syndrome (the “happy puppet syndrome”), which has an entirely different phenotype, is associated with deletions of the maternally inherited P gene.429 Differential expression of genetic material depending on the sex of the transmitting parent is referred to as genomic imprinting.

Åland eye disease (Forsius–Eriksson syndrome) is a form of ocular hypopigmentation associated with ERG findings of CSNB.216 It is no longer classified as a form of ocular albinism, and patients with this disorder do not manifest hemispheric VEP asymmetry. Waardenburg reexamined the original Finnish family with this disorder and found the multiple areas of focal fundus depigmentation in Åland eye disease to differ from the diffuse hypopigmentation of albinism.216,561 Other ocular and systemic hypopigmentation disorders such as Waardenburg’s syndrome and phenylketonuria also lack the hemispheric VEP asymmetry seen in albinism.349

The finding of asymmetrical hemispheric VEPs in human albinos provides an electrophysiological correlate to the

neuroanatomical finding of abnormal decussation in animals. For example, a light or pattern stimulus to the albino’s right eye would produce a signal of larger amplitude over the left occipital cortex than the right, due to the preponderance of crossing optic axons in albinos (Fig. 8.7). Although considerable interindividual variability exists,292 the extent of chiasmal misrouting seems to be inversely proportional to the pigmentation levels.552 Functional MR imaging during monocular stimulation has also demonstrated the presence of abnormal decussation,271,291,408 as has magnetoencephalography.359 While the great majority of children with albinism show crossed hemispheric asymmetry, rare children with otherwise classic albinism show normal hemispheric symmetry on VEP testing.69,510

Fig. 8.7  Hemispheric VEP asymmetry to pattern onset responses in adult albino (top), and absence of hemispheric VEP asymmetry in adult with idiopathic infantile nystagmus (bottom). Five traces for each patient are derived from electrodes positioned from left (trace 1) to right occiput (trace 5). Bottom trace is obtained by subtracting trace 4 (right) from trace 2 (left). Contralateral asymmetry in upper figure is shown by polarity reversal of difference potentials (arrows) and by crossover of CI component measured at time instant indicated and plotted as function of electrode for OD and OS. VEP topography for patient with infantile nystagmus shows slight interocular amplitude difference and midline response attenuation. Adapted, with permission, from Apkarian et al34