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.

Autosomal-dominant nystagmus, foveal hypoplasia and presenile cataract associated with a novel PAX6 mutation

“…Consistently with this, we have observed the expression of FRMD7 within the developing horizontal neural integrator (nucleus prepositus and medial vestibular nuclei). 7,22 In this family, we report horizontal, vertical and torsional nystagmus associated with a PAX6 mutation. Neuroimaging in patients with PAX6 mutations have revealed abnormalities in the cerebellar grey matter.…”

“…We have previously reported a phenotypic heterogeneity associated with nystagmus in families with FRMD7 mutations and also in patients with periodic alternating nystagmus. 7,22 These data suggest that the nystagmus phenotype is not defined solely by genotype.…”

“…Nystagmus has a prevalence of 1 in 1000. 1 To date, two X-linked nystagmus loci (NYS1 (Xq26.2) and NYS5 (Xp11.4)) and three autosomal loci (NYS2 (6p12), NYS3 (7p11.2) and NYS4 (13q31-q33)), [2][3][4][5][6][7] have been mapped, and the NYS1 gene has been identified as FRMD7. 2 Infantile nystagmus has also been described in association with afferent defects such as foveal hypoplasia, aniridia and iris hypoplasia.…”

Zebrafish—on the move towards ophthalmological research

“…98 HCN/INS is characterized by periodic alternation of involuntary oscillations of the eye consisting of slow movement of the eye called slow phase followed by quick phase to focus on the object of interest called saccades. The pathophysiology of the disease is poorly understood.…”

“…Recently, it was shown that mutation of the FRMD7 gene on loci NYS1, which is expressed in neuronal tissue of the developing retina, mid brain, and hindbrain, is associated with INS. 98 INS has been modelled in zebrafish. 4,24 A large number of homozygous belladonna (bel) mutants were found to display a reversed OKR indicative of a projection defect.…”