Congenital Nystagmus Research Articles

A family with congenital motor nystagmus

A family with congenital motor nystagmus

Identification and functional characterization of a novel missense mutation in FRMD7 responsible for idiopathic congenital nystagmus.

Idiopathic congenital nystagmus (ICN) is a genetically heterogeneous eye movement disorder which seriously reduces childhood visual acuity. X-linked inheritance is the most common pattern, and mutations in FERM domain-containing protein 7 (FRMD7) are the major cause. Here, we recruited a four-generation Chinese family with X-linked ICN for the causative mutational screening of FRMD7. A novel missense variant, c.805 A > C, was identified in the proband. The mutation was confirmed in all the affected individuals but was not detected in unaffected family members or 100 unrelated Chinese male controls. The mutation causes a substitution of lysine to glutamine at position 269 (p.Lys269Gln, K269Q). The FRMD7 mutant inhibits the formation and extension of neurites. Moreover, the mutation disrupts FRMD7 interaction with calcium/calmodulin-dependent serine protein kinase and neurite formation. Together, our data expand the mutation spectrum of FRMD7 causing ICN and provide an insight into the pathogenesis of nystagmus.

Whole-Brain Functional Ultrasound Imaging Reveals Brain Modules for Visuomotor Integration

SummaryLarge numbers of brain regions are active during behaviors. A high-resolution, brain-wide activity map could identify brain regions involved in specific behaviors. We have developed functional ultrasound imaging to record whole-brain activity in behaving mice at a resolution of ∼100 μm. We detected 87 active brain regions during visual stimulation that evoked the optokinetic reflex, a visuomotor behavior that stabilizes the gaze both horizontally and vertically. Using a genetic mouse model of congenital nystagmus incapable of generating the horizontal reflex, we identified a subset of regions whose activity was reflex dependent. By blocking eye motion in control animals, we further separated regions whose activity depended on the reflex’s motor output. Remarkably, all reflex-dependent but eye motion-independent regions were located in the thalamus. Our work identifies functional modules of brain regions involved in sensorimotor integration and provides an experimental approach to monitor whole-brain activity of mice in normal and disease states.

Identification of a novel GPR143 mutation in X-linked ocular albinism with marked intrafamilial phenotypic variability

Ocular albinism type 1 (OA1) is an X-linked inherited disease characterized by impaired visual acuity, congenital nystagmus, foveal hypoplasia, hypopigmentation of iris and fundus. It is caused by mutations in the G protein-coupled receptor143 (GPR143) gene. The genetic characteristics of OA1 have not been well defined in Asians. In this study, six members from three consecutive generations of a Korean family with OA1 were enrolled. We performed whole-exome sequencing followed by validation and segregation analysis. Two affected patients underwent detailed ophthalmic examinations and eye movement recordings. Of the two affected males, the proband had all classical phenotypes of OA1, but the other showed isolated foveal hypoplasia without nystagmus. We identified a hemizygous missense (c.623C > A, p.Ala208Glu) mutation of GPR143 in affected males. This mutation was also present as heterozygous in two obligate female carriers, and was not found in unaffected members. Our data expands thespectrum of phenotypes and genotype in GPR143 in Asians, and highlights the phenotypic heterogeneity in OA1.

Application of horizontal rectus muscle suture clamp for the treatment of congenital nystagmus without intermediate band

Objective To evaluate the efficacy of application of horizontal rectus muscle suture clamp for the treatment of congenital nystagmus (CN) without intermediate band. Methods The data of 11 patients with no intermediate band CN from Jan.2016 to Jun.2017 were retrospectively analyzed. All cases received the self designed surgery of horizontal rectus muscle suture clamp. The visual acuity(LogMAR), the amplitude and frequency of nystagmus before and after operation were summarized. Results The best corrected visual acuity of right eye before and 1, 3 months after operation were 0.65±0.25, 0.42±0.26 and 0.38±0.23, respectively. Those of left eye were 0.62±0.26, 0.38±0.17 and 0.35±0.14, respectively. The postoperative best corrected visual acuity at 1 and 3 months of binocular were improved (P<0.05). The amplitude and frequency of nystagmus at 3 months after operation were decreased. The difference was statistically significant between before and after operation (P<0.05). Conclusion Horizontal rectus muscle suture clamp for the treatment of CN without intermediate band can effectively decrease amplitude and frequency of nystagmus, and significantly improve visual function. Key words: Nystagmus, congenital, without intermediate band; Suture, clamp

The prevalence of vision impairment and refractive error in 3654 first year students at Tianjin Medical University.

To determine the prevalence of vision impairment (VI) and refractive error in first year university students at the Tianjin Medical University. This is a cross-sectional observational cohort study of VI and refractive error among first year university students at the Tianjin Medical University. The first year university students were involved in this study and were given a detailed questionnaire including age, birth date, and spectacle wearing history. A standardized ophthalmologic examination including visual acuity (VA), slit-lamp examination, non-cycloplegic auto-refraction, objective refraction, fundus photography, and examination of their spectacles were recorded. A total of 3654 participants were included in this study. Totally 3436 (94.03%) individuals had VI in this population. Totally 150 (4.10%) individuals had VI due to ocular disease, including amblyopia, congenital cataract, retinal atrophy or degeneration, strabismus, congenital nystagmus, refractive surgery orthokeratology. Totally 3286 (89.93%) subjects had VI due to refractive error. Only 218 (5.97%) students were emmetropia. Moreover, refractive error was the main cause for the VI (95.63%). Totally 3242 (92.52%) students were myopia and the prevalence of mild, moderate, and high myopia subgroup was 27.05%, 44.35%, and 21.26% respectively. Totally 44 (1.29%) subjects were hyperopic. The rates of uncorrected visual acuity (UCVA), presenting visual acuity (PVA) and best corrected visual acuity (BCVA) which better than 20/20 in both eyes were 5.65%, 22.32% and 82.13% respectively. The rates of correction, under correction and well correction in myopia subjects were 82.73%, 84.39% and 15.61%, respectively. We present a high prevalence of refractive errors and high rates of under correction refractive error among first year university students. These results may help to promote vision protection work in young adults.

Low Vision and Blindness in Bulgarian Children with Developmental Delay

Introduction. Visual impairment and blindness are very common in children with developmental delay, seriously harming their intellectual, social, learning and even physical development. Most common reasons for mild visual impairment are refractive errors and amblyopia, while optic nerve atrophy, retinal diseases and central cortical impairment are the leading causes for low vision (moderate and severe visual impairment) and blindness. Visual and ocular problems in intellectually disabled children are often neglected and even treatable diseases are ignored. Purpose. The aim of our study was to determine the incidence and main reasons for low vision and blindness in Bulgarian children with mental retardation. Patients and Methods. A prospective study of ocular status of 403 children (0 – 18 years) with mental retardation was performed. All patients had detail ophthalmologic exam according to their age and intellectual disabilities. Results. A total of 403 patients – 241 (59.8%) males and 162 (40.2%) females were enrolled in the study. Binocular moderate to severe visual impairment and blindness were diagnosed in 42 (10.4%) children. Detected ocular pathologies were congenital nystagmus (3.2%), optic nerve atrophy (2.7%), retinopathy of prematurity (2.5%), central cortical blindness (1.2%) and congenital anomalies (0.7%). Conclusion. Children with mental retardation are risk group for ocular and visual pathologies, causing not just visual impairment but severe problems and blindness. And nevertheless, most cases of low vision and blindness are unavoidable, implementation of yearly screening ocular exams of mentally retarded children must be adopted on national level for encompassing the high rate of treatable or correctable visual problems.

Two Paired Box 6 mutations identified in Chinese patients with classic congenital aniridia and cataract.

Congenital aniridia is a rare genetic disorder characterized by a variable degree of hypoplasia or absence of iris. It is frequently associated with keratopathy, cataract, juvenile-onset glaucoma and foveal and optic nerve hypoplasia. Mutations in the Paired Box 6 (PAX6) gene on chromosome 11p13 have been demonstrated to cause aniridia. The aim of the present study was to investigate the genetic variations of PAX6 in two sporadic patients from southern China with classic congenital aniridia and cataract. Complete ophthalmic and physical examinations were performed, including best-corrected visual acuity, intraocular pressure, slit-lamp examination, fundus examination, optical coherence tomography, ultrasound biomicroscopy, and Pentacam scanning. Genomic DNA was extracted from leukocytes of peripheral blood collected from the two patients, their unaffected parents and 200 unrelated control subjects from the same population. Exons 4–13 of the PAX6 gene were amplified by polymerase chain reaction and sequenced directly. Patient 1 was affected with aniridia accompanied by congenital cataract and nystagmus. A novel heterozygous PAX6 frameshift mutation c.277delG (p.Glu93SerfsX31) in exon 6 was identified in this patient. Patient 2 was presented with aniridia, congenital cataract, lens subluxation and glaucoma. A recurrent nonsense mutation c.718C>T (p.Arg240X) in exon 9 was identified in this patient. The present results expand the mutation spectrum of PAX6 and will be valuable for genetic counseling in the affected families. Additionally, the identification of these mutations reiterates the importance of PAX6 in ocular development and sheds light on the pathogenesis of congenital aniridia.

Identification of a novel idiopathic congenital nystagmus‑causing missense mutation, p.G296C, in the FRMD7 gene.

Exploring the genetic basis for idiopathic congenital nystagmus is critical for improving our understanding of its molecular pathogenesis. In the present study, direct sequencing using gene specific primers was performed in order to identify the causative mutations in two brothers from a Chinese family who had been diagnosed with idiopathic congenital nystagmus. A comprehensive ophthalmological examination, including eye movement recordings, fundus examination, and retinal optical coherence tomography imaging was also conducted, to characterize the disease phenotype. The results revealed that the two brothers exhibited clear signs of nystagmus without any other ocular anomalies. Direct sequencing revealed a G to T transition (c.886G>T) in exon 9 of the four-point-one, ezrin, radixin, moesin domain-containing 7 (FRMD7) gene, which resulted in a conservative substitution of glycine to cysteine at codon 296 (p.G296C), leading to idiopathic congenital nystagmus in the two affected brothers. c.886G>T is a novel idiopathic congenital nystagmus-inducing mutation in the FRMD7 gene. This finding expands the spectrum of known gene mutations in idiopathic congenital nystagmus, and may be useful for faster gene diagnosis, prenatal testing, the development of potential gene therapies, and for improving the understanding of the molecular pathogenesis of idiopathic congenital nystagmus.

A 73,128\xa0bp de novo deletion encompassing the OPN1LW/OPN1MW gene cluster in sporadic Blue Cone Monochromacy: a case report

BackgroundBlue Cone Monochromacy (BCM) is a rare congenital cone dysfunction disorder with X-linked recessive mode of inheritance. BCM is caused by mutations at the OPN1LW/MW cone opsin gene cluster including deletions of the locus control region (LCR) and/or parts of the gene cluster. We aimed at investigating the clinical presentation, genetic cause and inheritance underlying a sporadic case of BCM.Case presentationWe report a 24-year-old male presenting with congenital photophobia, nystagmus and colour vision abnormalities. There was no history of retinal dystrophy in the family. Clinical diagnosis of BCM was supported by genetic investigations of the patient and his family members. Molecular genetic analysis of the OPN1LW/OPN1MW gene cluster revealed a novel deletion of about 73 kb in the patient encompassing the LCR. The deletion was absent in the X-chromosomes of both the mother and transmitting grandfather.ConclusionsThe present report provides the clinical findings and the genetic basis underlying a sporadic BCM case which is caused by a de novo deletion within the OPN1LW/MW gene cluster originating from the mother’s germline due to Alu-repeat mediated recombination. This is the first report of a de novo deletion resulting in BCM, highlighting the importance to consider BCM and perform genetic testing for this condition in male patients with cone dysfunction also in the absence of a positive family history.

Comorbid inner ear disorders in 50 patients with congenital nystagmus

Comorbid inner ear disorders in 50 patients with congenital nystagmus

The “light cupula” phenomenon masquerading in congenital nystagmus

Abstract Objective/Hypothesis: Congenital nystagmus alone does not cause vertigo or dizziness, but we often encounter patients with this condition who complain of dizziness or vertigo. These patients also show positional nystagmus under an infrared camera (opened in the dark). Among them, we found a patient who had persistent direction changing positional nystagmus (DCPN) with two neutral points. This type of nystagmus is thought to be due to “light or heavy cupula” of the affected ear’s lateral semi-circular canal (SCC). The neutral point is deviated to the right or left from the supine position (first neutral point), and the deviated side is the affected side. If “light or heavy cupula” reflects the pathological condition of the endolymph in the affected ear lateral SCC, the side of the neutral point is thought to show the side of vestibular disorder. Case Report: The patient was a 51-year-old woman who complained of sudden onset of vertigo and hearing loss in the left ear. After admission therapy, hearing loss improved, but nystagmus did not disappear. She was diagnosed as having congenital nystagmus by typical electronystagmography. After this, she suffered vertiginous episodes and her left hearing level fluctuated and deteriorated. She was diagnosed with Meniere's disease. Simultaneously, she also showed persistent DCPN with two neutral points (“light cupula” type was observed eight times and “heavy cupula” type was twice.), whose first neutral point’s side changed at each time. Finally, she continued showing “light cupula” type persistent DCPN with two neutral points. Conclusion: The clinical characteristics of our patient suggested that bilateral latent vestibular disorder can occur in patients with Meniere's disease suffering from unilateral hearing impairment behind the congenital nystagmus. Persistent DCPN including “light cupula” can be explained by changes of the specific gravity of the surrounding endolymph in the affected ear.

Medical and legal point of view for low-vision patients

The aim of the study was to highlight the medical and legal difficulties in framing low-vision patients for certification. We performed a retrospective observational study conducted from January 2013 to January 2016, on 63 patients with the mean age of 16.37±3.34 years, evaluated at the Ophthalmology Clinic from "Sf. Spiridon" Hospital, Iași, in order to release a medical certificate required at the Expertise Board. The clinical parameters observed were visual acuity (VA) with correction, objective refraction (in Spherical Equivalent - SEq), intraocular pressure, slit lamp examination of the anterior pole, fundus examination, orthoptic eye exam, and ocular ultrasonography (in selected cases). The main causes for the decreased visual acuity found are refractive or strabic amblyopia determined by: high myopia (28.57%), esotropia (19.04%), astigmatism (17.46); congenital diseases - congenital nystagmus (12.69%), congenital cataract (7.93%), microphthalmia (7.93%); acquired diseases - retinopathy of prematurity (9.52%), optic nerve atrophy (7.93%), bandelette keratopathy (6.34); ocular trauma (7.93%). In 52.38% of the cases for the RE and 53.96% of the cases for the LE, decreased visual acuity was caused by an irreversible condition and could not be improved. Patients come every year for reevaluation in order to receive the medical certificate required at the Expertise Board. Evaluating the patient for a certificate for visual impairment is a time consuming process due to the high number of investigations necessary and, sometimes, difficult collaboration with the patient with associated general pathology. It also requires knowledge of frequently changing legislation to complete legal forms for patients with visual impairment. A medical certificate may now be issued with a validity of up to four years, given that certain diseases are irreversible and visual functional status does not change over time.

A novel PAX6 nonsense mutation identified in an Iranian family with various eye anomalies

PurposeThe aim of this study was to detect the genetic defects in a large pedigree of affected individuals with various phenotypes of ocular anomalies including partial aniridia, congenital cataract, and nystagmus. MethodsThe entire coding region of paired box gene 6 (PAX6) was amplified by polymerase chain reaction (PCR), sequenced, and compared with a GenBank database. ResultsA novel mutation (c.1170 C > T; p.Gln297X) was found in the proband and all affected members. This nonsense mutation leads to PAX6 protein truncation. ConclusionsOur findings suggest that this novel mutation is most likely responsible for the pathogenesis of the congenital aniridia, cataract, and nystagmus in this pedigree. To the best of our knowledge, this is the first report of this mutation of PAX6 gene in a kindred pedigree with various ocular abnormalities.

An unusual case of Waardenburg syndrome in a female child

Ocular albinism is characterized by congenital nystagmus, reduced visual acuity, hypopigmentation of the iris pigment epithelium and the ocular fundus and foveal hypoplasia. We report a case with clinical manifestations consistent with the phenotypes of WS1. The differentiating feature from uniocular albinism is the presence of dystopia canthorum.

Diagnosis and treatment of congenital nystagmus

Diagnosis and treatment of congenital nystagmus

Topical brinzolamide in congenital nystagmus: A retrospective study

Abstract Objective To evaluate the effect of treatment with topical brinzolamide on visual acuity and nystagmus intensity in patients with congenital nystagmus. Materials and methods A retrospective study was designed in which the clinical records of 14 patients with congenital nystagmus were reviewed. All patients underwent a complete ophthalmological examination and a Perea video-oculography (VOG) before, and three days after, initiation of treatment with topical brinzolamide (Azopt). Five expert researchers evaluated the intensity of nystagmus by video before and after treatment. Finally, the subjective improvement of the patients was recorded. Results Statistically significant differences were found in pre- and post-treatment binocular near visual acuity. A slight increase in the frequency of nystagmus was found, which was statistically significant with the horizontal gaze to the left and with the gaze downwards (p = 0.04, p = 0.03, respectively). The kappa index concordance between the researchers evaluating the intensity of nystagmus was 0.014. Only two of the patients noticed improvement in visual acuity, and one patient noticed improvement in the aesthetic aspect. Conclusions In spite of an improvement in nystagmus, it was slight, not cosmetically appreciable by patients in most cases, and was not related to a significant improvement in visual acuity or in patient quality of life. Further studies are needed to evaluate the effects of topical brinzolamide, and to establish potential therapeutic indications in nystagmus.

Clinical manifestation and gene analyses of 15 patients with intellectual disability or developmental delay complicated with congenital nystagmus

Objective: To analyze the clinical and genetic features of 15 cases with intellectual disability or developmental delay (ID/DD) complicated with congenital nystagmus. Method: The clinical characteristics and the results of laboratory tests, images and genetics of 15 patients with ID/DD complicated with congenital nystagmus, confirmed by gene diagnosis in the Department of Neurology, Children's Hospital Affiliated to Capital Institute of Pediatrics from March 2015 to October 2016, were retrospectively analyzed. The physiological function of 13 disease genes and the molecular signaling pathways were also comparatively studied. Result: The patients included 11 males and four females, with an age of 2 months-15 years (median age 27 months). The result of multiplex ligation-dependent probe amplification was positive in two patients only with hypomyelination on head MRI. Positive results were found in 13 patients with or without abnormal head MRI or other deformities using targeted capture technology and next generation sequencing. Two patients were diagnosed with Pelizaeus-Merzbacher disease, two had hypomyelination with an atrophy of the basal ganglia and cerebellum and two had oculocutaneous albinism. Pelizaeus-Merzbacher-like disease was found in one case, cerebro-oculo-facio-skeletal syndrome in one case, Rubinstein-Taybi syndrome in one case, mental retardation type 5 in one case, methylmalonic aciduria combined with hyperhomocysteinemia in 1 case, ataxia telangiectasia in one case, hypomyelinating leukodystrophy type 8 in one case, Marinesco-Sjögren syndrome in one case and CHARGE syndrome in one case. A total of 12 novo mutations were reported in this study. Conclusion: The causes of children with ID/DD complicated with congenital nystagmusis are complex. Comprehensive clinical and auxiliary examinations should be performed to improve the accuracy of the diagnosis. Reasonable application of different genetic testing methods can significantly improve the diagnostic accuracy of molecular genetic etiology in children with ID/DD.

Impact of healthcare strategies on patterns of paediatric sight impairment in a developed population: 1984-2011.

PurposeThe aim of our study was to analyse paediatric sight-impairment trends in Northern Ireland (NI) over a 28-year period to better understand the impact which changes in health-care provision may be having on childhood blindness and to enable us to assess our progress towards achieving the World Health Organisation (WHO) aims.MethodsA database of Certificates of Visual Impairment completed for NI children aged <16 years was used to determine the cause of sight impairment from 1984 to 2011. Causes were classified into preventable or treatable conditions and analysed for trends.ResultsFive hundred and ninety-eight children were registered as having impaired vision over the 28-year period. A total of 22% had preventable or treatable conditions. Optic atrophy was the most common cause responsible for 16% of registrations followed by albinism (12%), cerebral visual impairment (11%), congenital cataract (8%), retinopathy of prematurity (ROP) (8%), and congenital motor nystagmus (7%). The incident rate (per million population aged <16 years) for registerable vision loss due to congenital cataract decreased from 5.89 (CI 2.82-10.83) in 1984-1987 to 2.63 (CI 0.72-6.74) in 2008-2011. For ROP, the incident rate peaked during 2000-2003 at 8.87 (CI 4.85-14.88). Thereafter, there was a statistically significant reduction in incident rate to 1.98 (CI 0.41-5.77) in 2008-2011 (P=0.008).ConclusionsSight-impairment registrations due to preventable or treatable causes have decreased over the past 28 years. This is likely due to better surgical techniques and improved refractive care for conditions such as congenital cataract and ongoing research and treatment protocols for conditions such as ROP. Future advances in this area may help to further reduce the burden of childhood sight impairment and improve quality of life for these patients.

FRMD7 variants associated with congenital nystagmus in Korea

Background: Congenital nystagmus (CN) is the involuntary oscillation of the eyes with onset in the first few months of life. CN can be an idiopathic disease (idiopathic infantile nystagmus, IIN) or can be a feature of other ocular diseases. The inheritance of CN are heterogenous, but the most common form is X-linked-IIN. FRMD7 resides at Xq26-27 and approximately 50% of X-linked IIN families map to this region. Currently, over 70 different mutations within FRMD7 have been reported.