Genotype-Phenotype Studies in Infantile Nystagmus with Emphasis on the Novel Frmd7 Gene

FRMD7 mutations are a major cause of idiopathic infantile nystagmus (IIN). Infantile nystagmus can also be associated with albinism, PAX6 mutations and achromatopsia; these disorders are associated with afferent visual anomalies which pose the question could this be a common aetiological factor for infantile nystagmus. The underlying neuroanatomical defects associated with FRMD7 mutations are yet to be determined. A large scale sequencing project was undertaken to genotypically characterize the causative mutations in IIN. The total number of FRMD7 mutations identified was 37 of which 23 were novel. Penetrance of nystagmus in female carriers is related to mutation location rather than mutation type. The genetic basis of idiopathic infantile periodic alternating nystagmus (II-PAN) was unknown. Sequence analysis in II-PAN patients showed that FRMD7 mutations were causative of this disorder. In-situ hybridization results in human embryonic and foetal tissue suggested that the optokinetic reflex and vestibulo-ocular reflex arcs could be involved in the disease pathogenesis. Detailed spatiotemporal expression profiles in the retina suggested that FRMD7 could have a significant role in retinal development. This formed the basis of performing optical coherence tomography (OCT) studies in patients with FRMD7 mutations. Retinal phenotyping studies in patients with FRMD7 mutations showed foveal hypoplasia and abnormal optic nerve head morphology. These findings were also seen in patients with PAX6 mutations and albinism. However in patients with achromatopsia, progressive retinal changes were observed at the fovea: outer nuclear layer thinning and disruption of the inner-outer segment junctions. Atypical foveal hypoplasia was also observed in patients with achromatopsia. The different retinal phenotypes observed with achromatopsia is linked to cone photoreceptor degeneration. A structural grading system was developed for foveal hypoplasia; this takes into account the stage at which the retinal development was arrested. The grade of foveal hypoplasia was a strong predictor of visual acuity. Therefore this thesis shows for the first time that arrested retinal development could be a common aetiological factor to the development of infantile nystagmus. The stage at which the retinal development was arrested is a strong indicator of visual acuity.