Idiopathic Congenital Nystagmus Research Articles

FERM Domain Containing Protein 7 Interacts with the Rho GDP Dissociation Inhibitor and Specifically Activates Rac1 Signaling

The FERM domain containing protein 7 gene (FRMD7) associated with the X-linked disorder idiopathic congenital nystagmus (ICN) is involved in the regulation of neurite elongation during neuronal development. Members of the Rho family of small G-proteins (Rho GTPases) are key regulators of the actin cytoskeleton and are implicated in the control of neuronal morphology. The Rho GDP dissociation inhibitor alpha, RhoGDIα, the main regulator of Rho GTPases, can form a complex with the GDP-bound form of Rho GTPases and inhibit their activation. Here, we demonstrate that the full length of the mouse FRMD7, rather than the N-terminus or the C-terminus alone, directly interacts with RhoGDIα and specifically initiates Rac1 signaling in mouse neuroblastoma cell line (neuro-2a). Moreover, we show that wild-type human FRMD7 protein is able to activate Rac1 signaling by interacting with RhoGDIα and releasing Rac1 from Rac1-RhoGDIα complex. However, two missense mutations (c.781C>G and c.886G>C) of human FRMD7 proteins weaken the ability to interact with RhoGDIα and release less Rac1, that induce the activation of Rac1 to a lesser degree; while an additional mutant, c.1003C>T, which results in a C-terminal truncated protein, almost fails to interact with RhoGDIα and to activate Rac1 signaling. Collectively, these results suggest that FRMD7 interacts with one of the Rho GTPase regulators, RhoGDIα, and activates the Rho subfamily member Rac1, which regulates reorganization of actin filaments and controls neuronal outgrowth. We predict that human mutant FRMD7 thus influences Rac1 signaling activation, which can lead to abnormal neuronal outgrowth and cause the X-linked ICN.

Novel mutation c.980_983delATTA compound with c.986C>A mutation of the FRMD7 gene in a Chinese family with X-linked idiopathic congenital nystagmus

To screen mutations in FERM domain-containing protein 7 (FRMD7) gene in two Chinese families with X-linked idiopathic congenital nystagmus (XLICN). Common ophthalmic data and peripheral blood of two Chinese XLICN families (families A and B) were collected after informed consent. Genomic DNA was prepared from the peripheral blood of members of the two families and from 100 normal controls. Mutations in the FRMD7 gene were determined by directly sequencing polymerase chain reaction (PCR) products. We identified a novel mutation c.980_983delATTA compound with c.986C>A mutation in the 11th exon of FRMD7 in family B, and a previously reported splicing mutation c.781C>G (p.R261G) [corrected] in family A. The mutations were detected in patients and female carriers, while they were absent in other relatives or in the 100 normal controls. Our results expand the spectrum of FRMD7 mutations in association with XLICN, and further confirm that the mutations of FRMD7 are the underlying molecular mechanism for XLICN.

Astigmatism in patients with idiopathic congenital nystagmus

To evaluate the association between astigmatism and idiopathic congenital nystagmus (ICN) in infantile nystagmus syndrome (INS). We analysed refractive errors in a cohort of 488 consecutive patients with ICN (group A) and further compared the results obtained with those of 488 age-matched controls with no nystagmus (group B). Only the worst eye was considered for statistical analysis. All patients were stratified into the following age groups: 1 to 4 years (age group 1); 5 to 12 years (age group 2); and 13 years to 57 years (age group 3) (mean age: 29). Three hundred and seventy patients (69.7 %) in group A and 269 patients (55,12 %) in group B had refractive errors. The types of refractive errors observed were: myopia, hyperopia (>0.50 dioptres) and astigmatism (>1.25 dioptres). Results in group A were as follows: 319 patients (65.37 %) were astigmatic, 34 (6.97 %) were hyperopic, and 17 (3.48 %) were myopic. Mean right-eye astigmatism was 2.72 dioptres, and mean left-eye astigmatism was 2.69 dioptres. Results in group B were as follows: 56 (11.47 %) were astigmatic, 165 (33.81) were hyperopic, and 48 (9.84) were myopic. Mean right-eye astigmatism was 2.05 dioptres, and mean left-eye astigmatism was 2.37 dioptres. The prevalence of astigmatism is greater, in the entire sample, for subjects from age groups 2 and 3 (p<0.005). It shows a tendency to increase with age for patients of group A and in age group 3 (p=0.009). Astigmatism is more common in patients with ICN than in the general population (65.37 % vs 11.47 %) (p<0.001). Astigmatism increases with age, with a very high statistical significance in patients 13 years old and above (age group 3) when nystagmus is also present. Thus, nystagmus appears to be a predisposing factor for both the presence of astigmatism and the development with the age of high values of this refractive error. This findings should be taken into due account when considering visual dysfunctions in nystagmic patients.

Spectral-domain optical coherence tomography in patients with congenital nystagmus.

To study macular features in patients with congenital nystagmus and to assess the utility of spectral-domain optical coherence tomography (SD-OCT) in nystagmus. The macular areas of 51 outpatients with congenital nystagmus were examined using SD-OCT. Morphological changes in the retinal layers of the macular area were analysed. Macular images were successfully obtained with SD-OCT from 50 (98%) patients. Patients with ocular albinism mainly have macular hypoplasia, abnormal foveal depression, and increased foveal thickness with persistence of an inner nuclear layer, an inner plexiform layer, a ganglion cell layer and a nerve fiber layer. Macular morphology similar to albinism was observed in three patients with idiopathic macular hypoplasia. The OCT findings of cone dystrophy included unclear, disrupted or invisible photoreceptor outer segment/inner segment in the fovea; fusion, thickening and uneven reflection of the outer segment/inner segment with external limiting membrane. Some patients with congenital idiopathic nystagmus showed normal macular morphology and structure, and others showed indistinct macular external limiting membrane reflection. SD-OCT is an effective and reliable method to detect the macular morphology of congenital nystagmus patients. This technique has diagnostic value in particular for patients with macular hypoplasia and cone cell dystrophy with no distinct abnormality on fundoscopy.

Surgery and visual function restoration for congenital idiopathic nystagmus with or without strabismus

Background The surgery for congenital idiopathic nystagmus has make great progression recent year,but the influence of surgery on visual function is closely concerned.Objective This work was to study the surgeries for congenital idiopathic nystagmus with or without strabismus and explore the effect of horizontal rectus muscle surgery on the visual function and ocular movement in congenital idiopathic nystagmus.Methods This was a case-observational study.Sixty cases with idiopathic congenital nystagmus were enrolled assigned to four groups as follows:The patients of group Ⅰ appeared the head postures of less than 15 ° and heterotropia less than 15△underwent extraocular proprioceptiou resection,and those of group Ⅱ presented with the head postures of less than 20° and heterotropia more than 15△ underwent extraocular proprioception resection and stabismus surgery.In the group Ⅲ,the patients had the head postures of more than 15° and heterotropia less than 15△ underwent Park's surgery and part of them underwent extraocular proprioception resection) and the cases in group Ⅳ were selected with the head postures of more than15° and heterotropia more than 15△ underwent Park' s surgery and strabismus surgery ( part of them underwent extraocular proprioception resection).Baseline and follow-up evaluations included the best distance and near corrected visual acuity,head posture,ocular movement and Titmus stereotest.The examination results were compared between before and after operation.Results One year after operation,monocular and binocular distance visual acuity improved significantly in all four groups ( monocular:t =6.00,8.94,11.76,16.41,P =0.00 ; binocular:t=4.81,P=0.01 ; t =6.27,4.25,4.18,P =0.00 ),but monocular and binocular near visual acuity improved significantly only in groups Ⅲ and Ⅳ after operation compared with before operation ( monocular:t=2.91,P=0.01 ; t =5.32,P =0.00 ; binocular:t =3.36,t =4.30,P =0.00 ).The compensatory head posture from 39 subjects was disappeared after operation,showing an evident difference between before and after surgery ( group Ⅲ:t =29.90,P=0.00;group Ⅳ:t=16.91,P=0.00).Strabismus were corrected rightly for 24 patients and undercorrection for 2 patients.( group Ⅱ:t =29.15,P =0.00 ; group Ⅳ:t =36.79,P =0.00 ).The binocular visual function of 23 cases with the age below 12 years were improved throughout the follow up duration ( t =12.06,P =0.00).Conclusions Park' s surgery,extraocular proprioception resection and strabismus corrective operation can improve the visual function and head posture in congenital idiopathic nystagmus patients. Key words: Eyeball nystagmus/congenital, Idiopathic; Strabismus; Park's surgery; Extraocular proprioception resection

Molecular genetics advances of congenital idiopathic nystagmus

Congenital idiopathic nystagmus (CIN) is genetically heterogeneous. Autosomal dominant, autosomal recessive and X-linked patterns of inheritance have described. At least three distinct loci are related to autosomal dominant and X-linked patterns. One causative gene for X-linked form has been identified (FRMD7, Xq26.2) through linkage analysis. The molecular genetics advances of the congenital idiopathic nystagmus (CIN) are reviewed.

Erratum: Corrigendum: Mutations in FRMD7, a newly identified member of the FERM family, cause X-linked idiopathic congenital nystagmus

Nat. Genet. 38, 1242–1244 (2006); published online 1 October 2006; corrected after print 6 June 2011 In the version of this article initially published, the author Andrew Bastawrous was omitted from the author list. The error has been corrected in the HTML and PDF versions of the article.

Current advance in molecular genetics of congenital idiopathic nystagmus

Congenital idiopathic nystagmus (CIN) is characterized by monoocular or biocular involuntary,rhythmical,repeated oscillations.CIN is often referred to congenital 'motor' nystagmus since nystagmus occurs in the absence of a clinically demonstrable defect in the visual sensory system.CIN is genetically heterogeneous,and patterns of its inheritance have been well-known to include autosomal dominant.autosomal recessive and X-linked patterns.In recent years, many different genetic loci for CIN have been mapped,and researchers have found some candidate causing-disease genes.This review focuses on the recent advances of gene mapping and candidate gene analysis for molecular research of CIN. Key words: Nystagmus/congenital idiopathic; Gene; FRMD7gene; GPR143 gene; Inheritance

Cerebellar and visual gray matter brain volume increases in congenital nystagmus

Structural brain abnormalities associated with congenital nystagmus (CN) are still unknown. In some patients with CN additional sensory, metabolic, or gross structural alterations can be detected. In the present study voxel-based morphometry was used to compare the gray matter (GM) brain volumes of 14 individuals with CN without associated sensory, metabolic, or obvious structural alterations (i.e., idiopathic CN) to those of a group of controls. Further, GM brain volumes were correlated with nystagmus severity as measured by sway path. Intergroup comparison exhibited significant volume increases in the human motion sensitive complex V5/MT+, the fusiform gyrus, and the middle occipital gyrus bilaterally in CN. These volume increases may be associated with excess visual motion stimulation due to involuntary retinal slip of the visual scene. A positive correlation (linear model) of nystagmus sway path with cerebellar GM volume was seen in the following areas: vermal parts VIII-X as well as hemisphere lobule II, hemisphere VI, crus I, crus II, and lobule VII-IX bilaterally. There is evidence that the reported GM volume changes in the vestibulo-cerebellum, which correlated with nystagmus sway path, might be related to the subjects‘ attempt to maintain fixation, rather than be due to the generation of nystagmus.

Cerebellar and Visual Gray Matter Brain Volume Increases in Congenital Nystagmus

Structural brain abnormalities associated with congenital nystagmus (CN) are still unknown. In some patients with CN additional sensory, metabolic, or gross structural alterations can be detected. In the present study voxel-based morphometry was used to compare the gray matter (GM) brain volumes of 14 individuals with CN without associated sensory, metabolic, or obvious structural alterations (i.e., idiopathic CN) to those of a group of controls. Further, GM brain volumes were correlated with nystagmus severity as measured by sway path. Intergroup comparison exhibited significant volume increases in the human motion sensitive complex V5/MT+, the fusiform gyrus, and the middle occipital gyrus bilaterally in CN. These volume increases may be associated with excess visual motion stimulation due to involuntary retinal slip of the visual scene. A positive correlation (linear model) of nystagmus sway path with cerebellar GM volume was seen in the following areas: vermal parts VIII-X as well as hemisphere lobule II, hemisphere VI, crus I, crus II, and lobule VII-IX bilaterally. There is evidence that the reported GM volume changes in the vestibulo-cerebellum, which correlated with nystagmus sway path, might be related to the subjects‘ attempt to maintain fixation, rather than be due to the generation of nystagmus.

Diagnosis of idiopathic infantile nystagmus and ocular albinism: a clinical challenge

Advances in knowledge concerning the neural circuitry of eye movement control have provided understanding of the pathophysiology of various forms of nystagmus. Furthermore, advances in the molecular genetics and the newer methods of investigation, such as multichannel visual evoked potentials, electroretinograms and optical coherence tomography, have improved the ability to diagnose and differentiate between forms of nystagmus. Diagnosis of oculocutaneous albinism is usually straightforward. However, the clinical diagnosis of ocular albinism is often difficult owing to its varied phenotypical presentation and similarities to idiopathic infantile nystagmus and other congenital nystagmus forms. In our pediatric clinics, we have frequently encountered the misdiagnosis of patients with ocular albinism nystagmus as idiopathic infantile nystagmus instead. The main importance in diagnosing the different types of nystagmus lies in the treatment of these conditions and the visual prognosis, as well as genetic counseling. In this article, the genotypical and phenotypical characteristics of both idiopathic congenital nystagmus and ocular albinism will be highlighted, including the different types of examination required to correctly distinguish between these two types of nystagmus. The clinical characteristics and additional investigations often provide the pieces of a puzzle that need to be fitted together in order to solve diagnostic uncertainty.

Frmd7 expression in developing mouse brain

Mutations in the FERM domain containing 7 (FRMD7) genes are known to cause a significant number of cases of congenital idiopathic nystagmus (CIN). Only limited expression data exist suggesting low levels of expression in all tissues. In this study, we assess the expression profile of the murine homologue of FRMD7 (Frmd7) in tissue from three murine organs during development. cDNA was extracted from heart, lung, and brain tissues of MF-1 mice at 12 developmental time points, embryonic days 11-19, postnatal days 1 and 8, and from adult mice. Relative expression of Frmd7 mRNA was calculated using quantitative real-time PCR techniques with two normalising genes (Gapdh and Actb). Expression of Frmd7 was low in all tissues consistent with earlier reports. In heart and lung tissues, expression remained very low with an increase only in adult samples. In brain tissue, expression levels were higher at all time points with a significant increase at embryonic day 18, with no gender-specific influence on Frmd7 expression. Frmd7 is expressed at low levels in all tissues studied suggesting a role in many tissue types. However, higher overall expression and a sharp increase at ED18 in the murine brain suggest a different role in this tissue.Earlier studies have shown that genes expressed in the murine brain during development exhibit temporal functional clustering. The temporal pattern of Frmd7 expression found in this study mirrors that of genes involved in synapse formation/function, and genes related to axon growth/guidance. This suggests a role for Frmd7 in these processes and should direct further expression studies.

A Novel Frameshift Mutation in FRMD7 Causing X-Linked Idiopathic Congenital Nystagmus

Idiopathic congenital nystagmus (ICN) is a common oculomotor disorder characterized by bilateral involuntary, periodic, and predominantly ocular oscillations. X-linked ICN (XLICN) with incomplete penetrance in females is the most common inheritance form, and FERM domain containing (FRMD7) mutation is the major reason for XLICN families. To date, 39 FRMD7 mutations have been identified, and 50% of the XLICN pedigrees have yielded FRMD7 mutations in the Western population. In this study, we identified a novel frameshift mutation (c.1274-1275delTG) in the FRMD7 gene in six XLICN pedigrees. Incorporated with data reported from other two Chinese groups, approximately 47% XLICN pedigrees were caused by the FRMD7 mutation in China. Therefore, this study showed that mutation analysis of the FRMD7 gene had diagnostic value not only in the Western population but also in one of the biggest Eastern populations, Chinese XLICN families. In addition, the results indicated the type of FRMD7 mutation associated with the penetrance of female carriers of XLICN.

Nystagmus characteristics in congenital stationary night blindness (CSNB)

Aim:To analyse nystagmus characteristics in patients with congenital stationary night blindness (CSNB) for differentiation from other forms of early childhood nystagmus.Methods:Horizontal and vertical eye movements of 10 patients (6–46 years,...

Reduction of Congenital Nystagmus in a Patient after Smoking Cannabis

Introduction: Smoking cannabis has been described to reduce acquired pendular nystagmus in MS, but its effect on congenital nystagmus is not known. Purpose: To report the effect of smoking cannabis in a case of congenital nystagmus. Methods: A 19-year-old male with congenital horizontal nystagmus presented to the clinic after smoking 10 mg of cannabis. He claimed that the main reason for smoking cannabis was to improve his vision. At the next clinic appointment, he had not smoked cannabis for 3weeks. Full ophthalmologic examination and eye movement recordings were performed at each visit. Results: Visual acuity improved by 3 logMar lines in the left eye and by 2 logMar lines in the right eye after smoking cannabis. The nystagmus intensities were reduced by 30% in primary position and 44%, 11%, 10% and 40% at 20-degree eccentricity to the right, left, elevation and depression, respectively, after smoking cannabis. Conclusion: Cannabis may be beneficial in the treatment of congenital idiopathic nystagmus (CIN). Further research to clarify the safety and efficacy of cannabis in patients with CIN, administered for example by capsules or spray, would be important.

Allelic Variation of the FRMD7 Gene in Congenital Idiopathic Nystagmus

To perform a genotype-phenotype correlation study in an X-linked congenital idiopathic nystagmus pedigree (pedigree 1) and to assess the allelic variance of the FRMD7 gene in congenital idiopathic nystagmus. Subjects from pedigree 1 underwent detailed clinical examination including nystagmology. Screening of FRMD7 was undertaken in pedigree 1 and in 37 other congenital idiopathic nystagmus probands and controls. Direct sequencing confirmed sequence changes. X-inactivation studies were performed in pedigree 1. The nystagmus phenotype was extremely variable in pedigree 1. We identified 2 FRMD7 mutations. However, 80% of X-linked families and 96% of simplex cases showed no mutations. X-inactivation studies demonstrated no clear causal link between skewing and variable penetrance. We confirm profound phenotypic variation in X-linked congenital idiopathic nystagmus pedigrees. We demonstrate that other congenital nystagmus genes exist besides FRMD7. We show that the role of X inactivation in variable penetrance is unclear in congenital idiopathic nystagmus. Clinical Relevance We demonstrate that phenotypic variation of nystagmus occurs in families with FRMD7 mutations. While FRMD7 mutations may be found in some cases of X-linked congenital idiopathic nystagmus, the diagnostic yield is low. X-inactivation assays are unhelpful as a test for carrier status for this disease.

Memantine/gabapentin for the treatment of congenital nystagmus

Introduction: The problem of visual acuity degradation due to congenital idiopathic nystagmus (CIN) has largely been the province of the ophthalmologist, especially those with interest in pediatrics and ocular motility. Congenital nystagmus comes in many forms, and reports abound of the use of many medications in the treatment of individuals or small groups of patients with particular forms of nystagmus. A number of surgical and refractive procedures are used, but these modalities are not within the scope of the present review. This is a Class I study of the use of two pharmacologic agents to reduce or eliminate congenital nystagmus and improve visual acuity (VA).

DMP05 Genetic analysis of a large family with idiopathic congenital motor nystagmus reveals a novel missense mutation

DMP05 Genetic analysis of a large family with idiopathic congenital motor nystagmus reveals a novel missense mutation

Incidence and nature of orthoptic problems found in children previously screened for retinopathy of prematurity: an argument for orthoptic follow-up?

Aim: To determine the incidence and type of visual and/or binocular defects in infants previously screened for and found to have insignificant or no retinopathy of prematurity (ROP). Methods: The case notes of a consecutive cohort of children who had passed screening for ROP were reviewed retrospectively. Details of attendance, orthoptic assessments, related investigations and outcome were documented with particular attention to the incidence and type of ocular defect. Results: One hundred and eight cases were reviewed; 78 cases met the inclusion criteria. Nineteen patients had an ocular defect that required treatment or ongoing orthoptic review. Eleven children had strabismus, of whom 8 had constant esotropia and 3 had intermittent exotropia. Other defects were refractive error (without strabismus), congenital idiopathic nystagmus and a case of an upper lid haemangioma. Conclusions: The review confirmed a higher pre­valence of strabismus and visual/binocular defects in patients who had previously passed screening for ROP compared with the normal population. Constant esotropia was the most common form of strabismus found.

Mutations in FRMD7, a newly identified member of the FERM family, cause X-linked idiopathic congenital nystagmus

Mutations in FRMD7, a newly identified member of the FERM family, cause X-linked idiopathic congenital nystagmus