Congenital Motor Nystagmus Research Articles

Small-incision lenticule extraction in a patient with congenital motor nystagmus: case report

Introduction: In patients with congenital motor nystagmus, vision correction might be challenging, and laser refractive surgery is thought to be not advisable because of the patient's inability to fixate and uncontrollable eye movements. Patient and Clinical Findings: A 25-year-old man presented with congenital motor nystagmus and reported that he could not wear contact lenses and that spectacles gave him headaches. Diagnosis, Intervention, and Outcomes: Diagnosis of motor nystagmus was established clinically, with exclusion of other abnormalities, intact vision, and a history dating back decades. Small-incision lenticule extraction (SMILE) surgery using a 2000-kHz VisuMax 800 (VM800) femtosecond laser was performed successfully on both eyes. Preoperative uncorrected distance visual acuity (UDVA) was 6/24-1 in the right eye and 6/60-1 in the left eye, improving to 6/7.5+1 and 6/9-1, respectively, on postoperative day 1. At day 7, UDVA further improved to 6/6+2 and 6/7.5-1, and after 1 month, it reached 6/6 for the right eye and 6/7.5-1 for the left eye. The patient had a vision gain of 1 line compared with preoperative best spectacle-corrected visual acuity. Refraction at 1 month was right +0.25 diopter sphere and left +0.25 diopter sphere. No intraoperative complications were observed. Conclusions: SMILE surgery using VM800 proved effective for a patient with congenital motor nystagmus, resulting in a vision gain of 1 line compared with preoperative best spectacle-corrected visual acuity, with no intraoperative complications. Centration was within 0.2 mm of the target. These objective outcomes demonstrate the feasibility and effectiveness of SMILE surgery using a newer generation laser in this population.

Micro chromosomal deletions at the NYS7 locus and autosomal dominant nystagmus

Nystagmus is an ocular condition characterized by bilateral involuntary ocular oscillation which can severely affect vision. When not associated with other ocular or systemic diseases, it is referred to as idiopathic or congenital motor nystagmus (CMN). Genome-wide linkage studies have previously identified several loci associated with CMN, however the genes responsible for some of these loci have yet to be identified. We have examined a large, five-generation family with autosomal dominant CMN. Our purpose was to characterize the clinical manifestations and reveal the molecular basis of the disease in this family. In addition to full ophthalmic examination and imaging, molecular analysis included copy number variation analysis, linkage studies, and Sanger sequencing. Expression analyses of candidate genes was done by real-time PCR. Of the 68 family members, 27 subjects in five-generations had CMN, in line with an autosomal dominant inheritance pattern. Molecular analysis was performed on 27 members, 15 of them affected by CMN. Copy number variation analysis using array comparative genomic hybridization (aCGH) revealed a novel deletion located on 1q32 (NYS7) among affected individuals. Linkage analysis using polymorphic markers demonstrated full segregation with a heterozygous haplotype in all affected patients, with a LOD score of >5. Sanger sequencing of affected subjects revealed a novel deletion of 732,526 bp in the linkage interval. No protein-coding genes exist within the deleted region; however, the deletion disrupts topologically associated domains encompassing the gene NR5A2 and the non-protein coding MIR181A. Both are strongly associated with other genes expressed in the retina such as PROX1, which in turn is also associated with genes related to nystagmus such as PAX6. We therefore hypothesized that the deletion might affect NR5A2 and MIR181A expression, causing CMN. Expression analysis by real-time PCR showed significantly lower expression of NR5A2, and significantly higher expression of PROX1 among patients compared with controls. To conclude, among a large five-generation family with autosomal dominant CMN, a large deletion in the interval of NYS7 was linked with the disease. No protein-coding genes exist inside the deleted region, and so the exact mechanism in which CMN is caused is uncertain. Based on topological association and expression analyses we suggest a possible mechanism for the pathogenesis.

Vertical Optokinetic Stimulation Induces Diagonal Eye Movements in Patients with Idiopathic Infantile Nystagmus.

PurposeIn patients with early ocular misalignment and nystagmus, vertical optokinetic stimulation reportedly increases the horizontal component of the nystagmus present during fixation, resulting in diagonal eye movements. We tested patients with infantile nystagmus syndrome but normal ocular alignment to determine if this crosstalk depends on strabismus.MethodsEye movements were recorded in seven patients with infantile nystagmus. All but one patient had normal ocular alignment with high-grade stereopsis. Nystagmus during interleaved trials of right, left, up, and down optokinetic stimulation was compared with waveforms recorded during fixation. Six patients with strabismus but no nystagmus were also tested.ResultsIn infantile nystagmus syndrome, horizontal motion evoked a mostly jerk nystagmus with virtually no vertical component. A vertical optokinetic pattern produced nystagmus with a diagonal trajectory. It was not simply a combination of a vertical component from optokinetic stimulation and a horizontal component from the subject's congenital nystagmus, rather in six of seven patients, the slow-phase velocity of the horizontal component during vertical optokinetic stimulation differed from that recorded during fixation. In the six strabismus patients without nystagmus, responses to vertical optokinetic stimulation were normal.ConclusionsIn patients with congenital motor nystagmus, a vertical noise pattern drives a diagonal nystagmus. This appears to arise because of crosstalk between the vertical and horizontal components of the optokinetic system. This abnormal response to vertical stimulation is not caused by strabismus because it occurs in patients with infantile nystagmus without strabismus. Moreover, it is absent in patients with strabismus and no spontaneous nystagmus.

Structural variations in a non-coding region at 1q32.1 are responsible for the NYS7 locus in two large families

Congenital motor nystagmus (CMN) is characterized by early-onset bilateral ocular oscillations without other ocular deficits. To date, mutations in only one gene have been identified to be responsible for CMN, i.e., FRMD7 for X-linked CMN. Four loci for autosomal dominant CMN, including NYS7 (OMIM 614826), have been mapped but the causative genes have yet to be identified. NYS7 was mapped to 1q32.1 based on independent genome-wide linkage scan on two large families with CMN. In this study, mutations in all known protein-coding genes, both intronic sequence with predicted effect and coding sequence, in the linkage interval were excluded by whole-genome sequencing. Then, long-read genome sequencing based on the Nanopore platform was performed with a sample from each of the two families. Two deletions with an overlapping region of 775,699 bp, located in a region without any known protein-coding genes, were identified in the two families in the linkage region. The two deletions as well as their breakpoints were confirmed by Sanger sequencing and co-segregated with CMN in the two families. The 775,699 bp deleted region contains uncharacterized non-protein-coding expressed sequences and pseudogenes but no protein-coding genes. However, Hi-C data predicted that the deletions span two topologically associated domains and probably lead to a change in the 3D genomic architecture. These results provide novel evidence of a strong association between structural variations in non-coding genomic regions and human hereditary diseases like CMN with a potential mechanism involving changes in 3D genome architecture, which provides clues regarding the molecular pathogenicity of CMN.

Ophthalmic findings in neonates receiving sildenafil.

To determine the risk of ocular complications of sildenafil therapy in neonates. Retrospective case review of neonates with persistent pulmonary hypertension of the newborn who received sildenafil therapy between 2010 and 2015 in a single, tertiary surgical neonatal intensive care unit in Australia. Ophthalmic examination findings in the neonatal intensive care unit and follow-up were examined. Twenty-seven neonates with persistent pulmonary hypertension of the newborn received sildenafil. The median gestational age (GA) was 38 weeks (range 24-41 weeks), and median birthweight was 2690 g (range 454-4270 g). Ophthalmic review was undertaken in 23 neonates, and 16 neonates were term or near-term infants (GA 31-40 weeks). All of them had a normal initial ophthalmic examination; one child was later diagnosed with hypermetropia and another with infantile esotropia. Amongst the seven premature infants (GA 24-30 weeks), three had retinopathy of prematurity (ROP) diagnosed at the first ophthalmic review and the other four had normal initial examinations. Two patients later developed ROP, one of whom was also diagnosed with congenital motor nystagmus. All five patients diagnosed with ROP were extremely preterm (<28 weeks) with low birthweight (454-635 g). There were no short-term complications attributable to sildenafil therapy identified in term or near-term neonates (GA ≥31 weeks). This cohort of neonates does not typically undergo ophthalmic review as part of the ROP screening protocol in our institution. Routine ophthalmic review of neonates on sildenafil therapy, who are not at risk of ROP, is therefore unlikely to be warranted. Further research is required to clarify the relationship between sildenafil and ROP.

A family with congenital motor nystagmus

A family with congenital motor nystagmus

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.

Incidence and Types of Pediatric Nystagmus

To report the incidence, prevalent subtypes, and clinical characteristics of pediatric nystagmus diagnosed over a 30-year period. Retrospective, population-based study. Using the Rochester Epidemiology Project, we reviewed the medical records of all children (<19 years) diagnosed as residents in Olmsted County, Minnesota, with any form of nystagmus from January 1, 1976, through December 31, 2005. Seventy-one children were diagnosed during the 30-year period, yielding an annual incidence of 6.72 per 100,000 younger than 19 years (95% confidence interval [CI], 5.15-8.28) Infantile nystagmus, onset by 6months, comprised 62 (87.3%) of the study patients, corresponding to a birth prevalence of 1 in 821. The median age at diagnosis for the cohort was 12.7months (range, 0days to 18.6 years) and 42 subjects (59.2%) were male. The main types of nystagmus, in declining order, were nystagmus associated with retinal/optic nerve disease in 23 (32.4%), idiopathic or congenital motor nystagmus in 22 (31.0%), manifest latent nystagmus or latent nystagmus in 17 (24.0%), and 2 (2.8%) each associated with Chiari malformation, medication use, tumor of the central nervous system, and no diagnosis. Developmental delay was diagnosed in 31 (43.6%), strabismus in 25 (35.2%), and amblyopia in 10 (14.1%). Eighty percent had 20/40 (or equivalent) or better vision at presentation in at least 1 eye. This study provides population-based data on incidence and clinical characteristics of childhood nystagmus in North America. Idiopathic and nystagmus associated with retinal/optic nerve disease were the most common presentations, with most patients having good vision. Developmental delay, strabismus, and amblyopia were common in this cohort.

Novel mutations of FRMD7 in Chinese patients with congenital motor nystagmus.

The purpose of the current study was to identify novel mutations in the FRMD7 (FERM domain containing 7) gene and to characterize clinical features in Chinese patients with congenital motor nystagmus. For this purpose, 18 patients with congenital motor nystagmus were selected from the ocular genetic diseases bank of the Pediatric and Genetic Clinic of Zhongshan Ophthalmic Center (Guangdong, China). Direct sequencing was used to analyze the exons and adjacent introns of the FRMD7 gene. The heteroduplex-single strand conformation polypeptide method was used to analyze 96 unrelated normal controls and gene-screening positive patients. Slit lamp photography of the anterior segment, fundus photography, optical coherence tomography and electroretinogram were carried out to identify the clinical features of congenital motor nystagmus. The authors noted that in, 18 patients with congenital motor nystagmus, there were 7FRMD7 gene mutations (six new mutations). The screening rate was 38.89%, including c.41_43delAGA (p.13-15delK); c.473T>A (p.I158N); c.605T>A (p.I202N); c.580G>T (p.A194S); c.811T>A (p.C271S); c.1493insA (p.Y498X); c.57+1G>A (slice mutation). There were no such mutations in the 96 normal controls. These results enriched the gene mutation spectrum of FRMD7. The authors systematically investigated the clinical phenotype of congenital motor nystagmus in a Chinese population. The study provides further evidence for clinical diagnosis and differential diagnosis and genetic counseling.

Incidence and types of pediatric nystagmus

Purpose To report the incidence, prevalent subtypes, and clinical characteristics of pediatric nystagmus diagnosed over a 30-year period. Design Retrospective, population-based study. Methods Using the Rochester Epidemiology Project, we reviewed the medical records of all children ( Results Seventy-one children were diagnosed during the 30-year period, yielding an annual incidence of 6.72 per 100,000 younger than 19 years (95% confidence interval [CI], 5.15–8.28) Infantile nystagmus, onset by 6 months, comprised 62 (87.3%) of the study patients, corresponding to a birth prevalence of 1 in 821. The median age at diagnosis for the cohort was 12.7 months (range, 0 days to 18.6 years) and 42 subjects (59.2%) were male. The main types of nystagmus, in declining order, were nystagmus associated with retinal/optic nerve disease in 23 (32.4%), idiopathic or congenital motor nystagmus in 22 (31.0%), manifest latent nystagmus or latent nystagmus in 17 (24.0%), and 2 (2.8%) each associated with Chiari malformation, medication use, tumor of the central nervous system, and no diagnosis. Developmental delay was diagnosed in 31 (43.6%), strabismus in 25 (35.2%), and amblyopia in 10 (14.1%). Eighty percent had 20/40 (or equivalent) or better vision at presentation in at least 1 eye. Conclusions This study provides population-based data on incidence and clinical characteristics of childhood nystagmus in North America. Idiopathic and nystagmus associated with retinal/optic nerve disease were the most common presentations, with most patients having good vision. Developmental delay, strabismus, and amblyopia were common in this cohort.

Mapping the disease gene in two congenital motor nystagmus families

Mapping the disease gene in two congenital motor nystagmus families

Confirmation and refinement of an autosomal dominant congenital motor nystagmus locus in chromosome 1q31.3–q32.1

Congenital motor nystagmus (CMN) is characterized by early-onset bilateral ocular oscillations. To identify the disease locus for autosomal dominant CMN in a Chinese family 86001, clinical data, including slit lamp and funduscopic examination and blood samples were collected from family. Genomic DNA was prepared from leukocytes, and a genome-wide linkage scan was performed using 382 polymorphic microsatellite markers and two-point linkage analysis using the logarithm of odds (LOD) score method as implemented in the LINKAGE program package. Maximum two-point scores were calculated using ILINK, and LINKMAP was used for multipoint analysis. All nine affected individuals in the family showed typical phenotypes for CMN. Maximum two-point LOD scores (3.61 at θ=0) were obtained with D1S2619, D1S2877 and D1S2622.The 24.6 cM (28.07 Mb) linked region is flanked by markers D1S218 and D1S2655, placing the disease locus on chromosome 1q25.2-1q32.1. Multipoint analysis confirmed linkage to the region of D1S218 and D1S2655 with Maximum two-point scores of 3.61. The linkage interval overlaps with that of a newly reported CMN locus on 1q31-q32.2 and narrows down the linked region to 5.90 cM (5.92 Mb). This study confirms and refines a novel locus for autosomal dominant CMN to chromosome 1q31.3-q32.1 (5.90 cM) and demonstrates its presence in the Chinese population.

A novel locus for autosomal dominant congenital motor nystagmus mapped to 1q31-q32.2 between D1S2816 and D1S2692

Congenital motor nystagmus (CMN) is characterized by bilateral involuntary ocular oscillation without any other underlying ocular or systemic diseases. An autosomal dominant CMN was identified in a large Chinese family where all patients had nystagmus since infancy. The nystagmus in the family is independent of any known ocular or systemic diseases. After exclusion of known CMN loci, a genome-wide scan was performed by genotyping microsatellite markers at about 10 cM intervals, together with two-point linkage analysis. Exome sequencing was used to screen coding exons of well-annotated genes. Sanger-dideoxy sequencing was used to verify candidate variations inside the linkage interval. Congenital motor nystagmus in this family shows linkage to markers in a 11.39 Mb (12.1 cM) region on chromosome 1q31-q32.2 between D1S2816 and D1S2692. All nine markers in the linkage interval gave positive lod scores, with D1S2655 and D1S2636 yielding lod scores of 5.16 and 5.18, respectively, at θ = 0. No causative mutation in the linkage interval was identified by exome sequencing of gDNA from four patients. A linkage study of additional families and further analysis of candidate genes may ultimately lead to identification of the gene responsible for dominantly inherited CMN.

A Population-based Study of Visual Impairment Among Pre-school Children in Beijing: The Beijing Study of Visual Impairment in Children

To evaluate the prevalence and causes of visual impairment among Chinese children aged 3 to 6 years in Beijing. Population-based prevalence survey. Presenting and pinhole visual acuity were tested using picture optotypes or, in children with pinhole vision < 6/18, a Snellen tumbling E chart. Comprehensive eye examinations and cycloplegic refraction were carried out for children with pinhole vision < 6/18 in the better-seeing eye. All examinations were completed on 17,699 children aged 3 to 6 years (95.3% of sample). Subjects with bilateral correctable low vision (presenting vision < 6/18 correctable to >or= 6/18) numbered 57 (0.322%; 95% confidence interval [CI], 0.237% to 0.403%), while 14 (0.079%; 95% CI, 0.038% to 0.120%) had bilateral uncorrectable low vision (best-corrected vision of < 6/18 and >or= 3/60), and 5 subjects (0.028%; 95% CI, 0.004% to 0.054%) were bilaterally blind (best-corrected acuity < 3/60). The etiology of 76 cases of visual impairment included: refractive error in 57 children (75%), hereditary factors (microphthalmos, congenital cataract, congenital motor nystagmus, albinism, and optic nerve disease) in 13 children (17.1 %), amblyopia in 3 children (3.95%), and cortical blindness in 1 child (1.3%). The cause of visual impairment could not be established in 2 (2.63%) children. The prevalence of visual impairment did not differ by gender, but correctable low vision was significantly (P < .0001) more common among urban as compared with rural children. The leading causes of visual impairment among Chinese preschool-aged children are refractive error and hereditary eye diseases. A higher prevalence of refractive error is already present among urban as compared with rural children in this preschool population.

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

Linkage analysis of two families with X-linked recessive congenital motor nystagmus

X-linked recessive congenital motor nystagmus was identified in two Chinese families living in the Guangdong province of China. Nystagmus was noticed in early childhood. Only males in the families were affected and all obligate carriers did not have nystagmus. Linkage study was performed using microsatellite markers at about 10 cM intervals on the X chromosome. The nystagmus in these two families is linked to markers in the region of chromosome Xq23-q27, including DXS1001, DXS8009, and DXS1047. DXS1047 gave the highest lod score of 3.53 at theta = 0.

The Effect of Bilateral Horizontal Rectus Recession on Visual Acuity, Ocular Deviation or Head Posture in Patients with Nystagmus

This work was undertaken to evaluate the effect of bilateral horizontal rectus recession on visual acuity, ocular deviation and head posture in patients with nystagmus. Twenty patients underwent recession of 4 horizontal rectus muscles to dampen the nystagmus. At least 2 muscles were recessed posterior to the equator. Monocular and binocular visual acuity improved from 1 to 3 Snellen lines after the procedure in 13 patients (76.5%). Visual changes in log MAR notations were statistically significant with Wilcoxon analysis in each and both eyes. Preoperative binocular visual acuity was 0.73 +/- 0.26 log MAR that reached to 0.62 +/- 0.32 log MAR after surgery (P = 0.02). The greatest improvement was observed in patients with congenital motor nystagmus. Ten patients had horizontal strabismus in addition to nystagmus before the surgery. One-millimeter additional recession of both medial rectus muscles caused an average reduction of 6 PD in esotropia. Corresponding figures for similar additional recessions of the lateral rectus muscles was 11 PD for correction of exotropia. Abnormal head posture decreased in all the cases and improved completely in most of them. Large horizontal rectus recession can improve visual acuity and decrease nystagmus in sensory and motor types. By revision in surgical planning, strabismus and abnormal head posture can also be corrected.

Confirmation and refinement of a genetic locus of congenital motor nystagmus in Xq26.3-q27.1 in a Chinese family

Congenital motor nystagmus (CMN), a subtype of nystagmus, may reduce vision or be associated with other, more serious, conditions that limit vision. The genetic basis for CMN is still unknown. To identify a locus for CMN, genotyping and linkage analysis were performed in 22 individuals from a Chinese family with X-linked CMN using markers from X chromosome. The maximum LOD score obtained for microsatellite maker DXS1192 linked the CMN locus in this family to Xq. By haplotype construction the locus for CMN was finally localized to an approximately 4.4-cM region at chromosome Xq26.3-q27.1. The SLC9A6 and FGF13 genes in this region, were selected and screened for mutation in this family, but no mutation was detected.

A Case of Different Null Zones for Distance and Near Fixation

A compensatory head posture (CHP) is a common clinical feature of congenital motor nystagmus. It is usually caused by an eccentric null zone, which is the eye position where the nystagmus intensity (amplitude x frequency) is least. A patient adopts the posture to maximize the binocular visual acuity. Occasionally, a patient may have more than one null zone, leading to the adoption of different CHPs at various times.A 10-year-old boy with congenital motor nystagmus and orthophoria, and with good corrected vision in both eyes, presented with a face turn that had been noted since infancy. For distance fixation, he consistently adopted a left face turn due to a null zone in right gaze. For near fixation, he adopted a right face turn due to a null zone in left gaze. Eye movement recordings confirmed the different locations of the null zones for distance and near fixation.After a trial of base-out prisms to stimulate convergence, which eliminated his head posture at both positions, he underwent artificial divergence surgery. He has had a satisfactory result for 18 months after surgery with a satisfactory head posture and a well-controlled exophoria.Measures to induce convergence, with prisms and then surgery, can be an effective strategy to correct the head postures caused by two different null zones in a patient with congenital motor nystagmus.

Chiasmal coefficient of flash and pattern visual evoked potentials for detection of chiasmal misrouting in albinism.

The diagnosis of albinism can be confirmed by electrophysiological examination, when chiasmal misrouting can be demonstrated. The present study describes a quantitative analysis method for this purpose. A chiasmal coefficient (CC) was calculated by correlating the differential potential over left and right hemisphere, when stimulating left versus right eye. This CC will be negative in albinism and positive in normal individuals. VEPs were recorded in 20 control subjects, four children with congenital motor nystagmus and six children with albinism. In up to 25% of the controls the CC was negative, when using flash VEP. However, with pattern VEP all had a positive CC. All children with albinism had a negative CC. Three of the four patients with congenital motor nystagmus had a positive CC, and one child had a small negative value with flash stimulation. In conclusion, determination of CC is a valuable and objective analysis method for electrophysiological determination of chiasmal misrouting. The method is relatively simple and only needs two electrode tracings. One should be aware of false-positive results when using flash stimulation. Whenever possible pattern stimulation should be used.