The clinical and molecular genetic features of idiopathic infantile periodic alternating nystagmus

Abstract

Periodic alternating nystagmus consists of involuntary oscillations of the eyes with cyclical changes of nystagmus direction. It can occur during infancy (e.g. idiopathic infantile periodic alternating nystagmus) or later in life. Acquired forms are often associated with cerebellar dysfunction arising due to instability of the optokinetic-vestibular systems. Idiopathic infantile periodic alternating nystagmus can be familial or occur in isolation; however, very little is known about the clinical characteristics, genetic aetiology and neural substrates involved. Five loci (NYS1-5) have been identified for idiopathic infantile nystagmus; three are autosomal (NYS2, NYS3 and NYS4) and two are X-chromosomal (NYS1 and NYS5). We previously identified the FRMD7 gene on chromosome Xq26 (NYS1 locus); mutations of FRMD7 are causative of idiopathic infantile nystagmus influencing neuronal outgrowth and development. It is unclear whether the periodic alternating nystagmus phenotype is linked to NYS1, NYS5 (Xp11.4-p11.3) or a separate locus. From a cohort of 31 X-linked families and 14 singletons (70 patients) with idiopathic infantile nystagmus we identified 10 families and one singleton (21 patients) with periodic alternating nystagmus of which we describe clinical phenotype, genetic aetiology and neural substrates involved. Periodic alternating nystagmus was not detected clinically but only on eye movement recordings. The cycle duration varied from 90 to 280 s. Optokinetic reflex was not detectable horizontally. Mutations of the FRMD7 gene were found in all 10 families and the singleton (including three novel mutations). Periodic alternating nystagmus was predominantly associated with missense mutations within the FERM domain. There was significant sibship clustering of the phenotype although in some families not all affected members had periodic alternating nystagmus. In situ hybridization studies during mid-late human embryonic stages in normal tissue showed restricted FRMD7 expression in neuronal tissue with strong hybridization signals within the afferent arms of the vestibulo-ocular reflex consisting of the otic vesicle, cranial nerve VIII and vestibular ganglia. Similarly within the afferent arm of the optokinetic reflex we showed expression in the developing neural retina and ventricular zone of the optic stalk. Strong FRMD7 expression was seen in rhombomeres 1 to 4, which give rise to the cerebellum and the common integrator site for both these reflexes (vestibular nuclei). Based on the expression and phenotypic data, we hypothesize that periodic alternating nystagmus arises from instability of the optokinetic-vestibular systems. This study shows for the first time that mutations in FRMD7 can cause idiopathic infantile periodic alternating nystagmus and may affect neuronal circuits that have been implicated in acquired forms.

Figure 1

Families with idiopathic infantile PAN. In Families 1–4 eye movement recordings were performed in three or more affected individuals, whereas in Families 4–7 eye movement recordings were obtained in two or more affected individuals. In Families 8–10 eye movement recordings were only performed in one affected individual.

Figure 2

Original eye movement recordings from Family F1. Overviews of the three phases of the PAN cycle and excerpts from within each phase of the cycle are shown in this figure. A typical PAN cycle consists of three phases: (i) left jerk (LJ), where the quick phase is directed to the left; (ii) a quiet phase (QP), where the intensity of the nystagmus is minimal; and (iii) a right jerk (RJ), where the quick phase is directed to the right. One of the examined family members (III:3) did not have PAN, but a pendular (P) nystagmus. Scale for the excerpts are shown in the bottom right with waveform deflection upwards and downwards representing horizontal eye movements to the right and left, respectively.

Figure 3

Compressed eye movement recordings showing an overview of the various phases of the PAN cycle (A). In the above example one cycle consists of right jerk (RJ) followed by a quiet phase (QP), left jerk phase (LJ) and another quiet phase (QP). Upward deflection of the horizontal (H) position and velocity trace represents right-beating nystagmus and downward deflection represents left-beating nystagmus. The optokinetic response was measured for optokinetic nystagmus stimuli (B) moving in the horizontal [rightwards (L→R) and leftwards (R→L)] and in the vertical direction [downwards (U→D) and upwards (D→U)]. The patient (II-PAN) shows no horizontal optokinetic response to the stimulus; the nystagmus is unchanged in the right jerk phase during optokinetic nystagmus testing. However for the vertical optokinetic nystagmus stimuli, a vertical optokinetic response is seen in the vertical trace (V) for the patient. The idiopathic infantile PAN cycle was not changed by the horizontal optokinetic nystagmus stimuli as shown in (C). The transition (QP) between left jerk and right jerk is seen during an extended horizontal optokinetic nystagmus task.

Figure 4

Country of origin, mutations of the FRMD7 gene in the families (F1–10) and singleton (S1) with idiopathic infantile PAN are shown in (A). The electropherograms from the respective families and singleton are shown with the wild-type allele (WA) represented on top of the mutant allele (MA). All mutant electropherograms show hemizygous mutations of the FRMD7 gene except for the female probands in Families F4 and F10, where a heterozygous mutation is shown. The type of mutation and domain affected is shown in (B). Missense mutations were the most common and changes to amino acid at positions 271 and 335 occurred in two families (271: F3 and S1; 335: F5 and F6). F1 = Family 1; S1 = Singleton 1; B41 = Band 4.1; FA = FERM adjacent domain.

Figure 5

FRMD7 expression in developing human brain. Panel A shows low magnification views of the sections from which higher magnification views are shown in (B–E). (F) gives a simplified overview of the vestibulo-ocular reflex (VOR) and optokinetic reflex (OKR) arcs indicating the afferent arm of the reflex arc starting at the semicircular canals (SCC) and retina followed by the cranial nerves (CN) involved in the respective arcs. The neural signal is integrated at the vestibular nucleus (VN) that is subject to the feedback loop through the cerebellum. The efferent arm of the reflex consists of the oculomotor nerves innervating the effector organ i.e. the extraocular muscles (EOM). (A) shows the following images from left to right: Carnegie Stage 16 section through forebrain and hindbrain; Carnegie Stage 19 whole embryo sagittal section; Carnegie Stage 22 section through midbrain and hind brain; Carnegie Stage 23 section through midbrain, hindbrain and forebrain; and Carnegie Stage 23 head sagittal section. In (C–F) images of sections hybridized with antisense probes (signal detected as purple stain) are shown above corresponding sections hybridized to sense control probes (no signal detected). Scale bar for the low magnification images (A) represents 1 mm for all images except the Carnegie Stage 16 image where the scale bar is 0.5 mm. For all high magnification images (B–E) the scale bar represents 0.3 mm except the preoptic image (Carnegie Stage 23) where it represents 0.6 mm. nr = neural retina; os = optic stalk; po = preoptic area; ov = otic vesicle; vc = vestibulocochlear ganglion; Rh1–4 = rhombomere 1–4.