Phenotypical characteristics of idiopathic infantile nystagmus with and without mutations in FRMD7

Abstract

Idiopathic infantile nystagmus (IIN) consists of involuntary oscillations of the eyes. The familial form is most commonly X-linked. We recently found mutations in a novel gene FRMD7 (Xq26.2), which provided an opportunity to investigate a genetically defined and homogeneous group of patients with nystagmus. We compared clinical features and eye movement recordings of 90 subjects with mutation in the gene (FRMD7 group) to 48 subjects without mutations but with clinical IIN (non-FRMD7 group). Fifty-eight female obligate carriers of the mutation were also investigated. The median visual acuity (VA) was 0.2 logMAR (Snellen equivalent 6/9) in both groups and most patients had good stereopsis. The prevalence of strabismus was also similar (FRMD7: 7.8%, non-FRMD7: 10%). The presence of anomalous head posture (AHP) was significantly higher in the non-FRMD7 group (P < 0.0001). The amplitude of nystagmus was more strongly dependent on the direction of gaze in the FRMD7 group being lower at primary position (P < 0.0001), compared to non-FRMD7 group (P = 0.83). Pendular nystagmus waveforms were also more frequent in the FRMD7 group (P = 0.003). Fifty-three percent of the obligate female carriers of an FRMD7 mutation were clinically affected. The VA's in affected females were slightly better compared to affected males (P = 0.014). Subnormal optokinetic responses were found in a subgroup of obligate unaffected carriers, which may be interpreted as a sub-clinical manifestation. FRMD7 is a major cause of X-linked IIN. Most clinical and eye movement characteristics were similar in the FRMD7 group and non-FRMD7 group with most patients having good VA and stereopsis and low incidence of strabismus. Fewer patients in the FRMD7 group had AHPs, their amplitude of nystagmus being lower in primary position. Our findings are helpful in the clinical identification of IIN and genetic counselling of nystagmus patients.

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.…”

The clinical evaluation of infantile nystagmus: what to do first, and why

“…The discovery of FRMD7 as a "motor" nystagmus gene is fascinating and the function of this gene and protein should pave the way to better understanding of the mechanisms behind nystagmus and of treatment targets (39). Likewise, while Down syndrome has long been known to be a predisposition for nystagmus, only recently have the ocular or neurologic aberrations responsible for nystagmus in trisomy 21 patients been studied and reported (40).…”

Novel homozygous, heterozygous and hemizygous FRMD7 gene mutations segregated in the same consanguineous family with congenital X-linked nystagmus

“…This is consistent with a previously published report. 25 The clinical significance of hemi/homozygous as compared with heterozygous mutation is not yet known, although Kaplan et al 13 found a missense mutation, R229G, in the FRMD7 gene in heterozygous and homozygous condition in members of a large X-linked NYS family without phenotypic variation. The location of the present residues is highly conserved in multiple species (Figure 1c) suggesting that the mutation at codon 305 is likely to have a significant effect on FRMD7 protein functionality.…”