Molecular diagnostic challenges for non-retinal developmental eye disorders in the United Kingdom.

Overall, approximately one-quarter of patients with genetic eye diseases will receive a molecular diagnosis. Patients with developmental eye disorders face a number of diagnostic challenges including phenotypic heterogeneity with significant asymmetry, coexisting ocular and systemic disease, limited understanding of human eye development and the associated genetic repertoire, and lack of access to next generation sequencing as regarded not to impact on patient outcomes/management with cost implications. Herein, we report our real world experience from a pediatric ocular genetics service over a 12 month period with 72 consecutive patients from 62 families, and that from a cohort of 322 patients undergoing whole genome sequencing (WGS) through the Genomics England 100,000 Genomes Project; encompassing microphthalmia, anophthalmia, ocular coloboma (MAC), anterior segment dysgenesis anomalies (ASDA), primary congenital glaucoma, congenital cataract, infantile nystagmus, and albinism. Overall molecular diagnostic rates reached 24.9% for those recruited to the 100,000 Genomes Project (73/293 families were solved), but up to 33.9% in the clinic setting (20/59 families). WGS was able to improve genetic diagnosis for MAC patients (15.7%), but not for ASDA (15.0%) and congenital cataracts (44.7%). Increased sample sizes and accurate human phenotype ontology (HPO) terms are required to improve diagnostic accuracy. The significant mixed complex ocular phenotypes distort these rates and lead to missed variants if the correct gene panel is not applied. Increased molecular diagnoses will help to explain the genotype-phenotype relationships of these developmental eye disorders. In turn, this will lead to improved integrated care pathways, understanding of disease, and future therapeutic development.

A previously unidentified deletion in G protein-coupled receptor 143 causing X-linked congenital nystagmus in a Chinese family.

BACKGROUND: Congenital nystagmus (CN) is characterized by conjugated, spontaneous, and involuntary ocular oscillations. It is an inherited disease and the most common inheritance pattern is X-linked CN. In this study, our aim is to identify the disease-causing mutation in a large sixth-generation Chinese family with X-linked CN. METHODS: It has been reported that mutations in four-point-one, ezrin, radixin, moesin domain-containing 7 gene (FRMD7) and G protein-coupled receptor 143 gene (GPR143) account for the majority patients of X-linked nystagmus. We collected 8 ml blood samples from members of a large sixth-generation pedigree with X-linked CN and 100 normal controls. FRMD7 and GPR143 were scanned by polymerase chain reaction (PCR)-based DNA sequencing assays, and multiplex PCR assays were applied to detect deletions. RESULTS: We identified a previously unreported deletion covering 7 exons in GPR143 in a Chinese family. The heterozygous deletion from exon 3 to exon 9 of GPR143 was detected in all affected males in the family, while it was not detected in other unaffected relatives or 100 normal controls. CONCLUSIONS: This is the first report of molecular characterization in GPR143 gene in the CN family. Our results expand the spectrum of GPR143 mutations causing CN and further confirm the role of GPR143 in the pathogenesis of CN.

Incidence of fovea plana in normal children.

PURPOSE: To characterize the prevalence and features of subclinical foveal hypoplasia detected by optical coherence tomography (OCT) in children. METHODS: Fast macular OCT scans were performed on normal children with normal vision for the development of a normative OCT-3 database; from this data, eyes with no discernable foveal depression were identified. When possible, the ocular imaging was repeated 3 years later using both OCT-3 and spectral domain OCT (SD-OCT). SD-OCT results were compared to age-matched controls. RESULTS: Of the 286 normal children (mean age, 8.6 ± 3.1 years) scanned, 9 (mean age, 8 ± 2.9 years; 6 males) were found to have bilateral shallow foveal depression on OCT-3 imaging, including 8 of 154 white children (5.4%) and 1 child of mixed ethnicity (white/black). Children with shallow foveas (n = 9) had larger average foveal thickness (FT) compared to the cohort of controls (n = 277) with a defined fovea (FT = 231.4 ± 8.8 vs 188.8 ± 25.0, resp. [P < 0.0001]). Mean macular volume did not differ from that of controls. SD-OCT performed 3 years later on 5 of the 9 children with shallow foveal depression showed persistence of the inner macular layers over the foveal center, corresponding to grades 1 or 2 of foveal hypoplasia. The FT was increased compared to 5 age-matched controls with a defined fovea (FT = 294.5 ± 5.1 vs 219.75 ± 5.68 µm, resp. [P = 0.029]). CONCLUSIONS: Up to 3% of children with clinically normal eyes had an anatomically underdeveloped foveal pit bilaterally on OCT.

Congenital cataract: prevalence and surgery age at Zhongshan Ophthalmic Center (ZOC).

Congenital cataract (CC) is the primary cause of treatable childhood blindness. Population-based assessments of prevalence and surgery age of CC, which are critical for improving management strategies, have been unavailable in China until now. We conducted a hospital-based, cross-sectional study of the hospital charts of CC patients younger than 18 years old from January 2005 to December 2010 at Zhongshan Ophthalmic Center (ZOC) in Guangzhou, China. Residence, gender, age at surgery, hospitalization time, and the presence of other ocular abnormalities were extracted and statistically analyzed in different subgroups. The search identified 1314 patients diagnosed with CC from a total of 136154 hospitalizations, which accounted for 2.39% of all the cataract in-patients and 1.06% of the total in-patients over the six-year study period. Of the identified CC patients, 9.2% had ≥ 2 hospitalizations due to the necessity of additional surgeries, with a total ratio of boys to girls of 1.75 ∶ 1. Based on a subgroup analysis according to age, patients 2-6 years old constituted the highest proportion (29.22%) of all hospitalized CC patients, and those 13-18 years old constituted the lowest proportion (13.47%) of the total number. The average age at surgery was 27.62 ± 23.36 months, but CC patients ≤ 6 years old (especially ≤ 6 months old) became increasingly prevalent throughout the 6-year study period. A total of 276 cases (20.93%) of CC were associated with one or more other ocular abnormalities, the highest incidence rates were observed for exotropia (6.24%), nystagmus (6.16%), and refractive error (3.65%). In conclusion, CC patients accounted for 2.39% of all cataract in-patients in a review of 6 years of hospitalization charts from ZOC. The age at the time of surgery decreased over the 6-year study period, which probably reflects the continuing improvement of public awareness of children's eye care in China.

The prevalence of ocular structural disorders and nystagmus among preschool-aged children.

PURPOSE: To describe the prevalence of structural disorders of the eye and nystagmus in preschool-aged children. METHODS: Population-based evaluation of children 6 months through 71 months of age in Baltimore, Maryland, United States. RESULTS: Among 4,132 children identified from 54 census tracts, 3,990 eligible children (97%) were enrolled and 2,546 children (62%) were examined. Structural disorders were found in 41 children and nystagmus in 9 children for an overall prevalence of 1.96% (95% CI, 1.46%-2.59%). Only 11 (0.43%; 95% CI, 0.22%-0.77%) had vision loss in at least one eye, most often due to posterior segment disease. CONCLUSIONS: Structural ocular abnormalities and nystagmus combined are present in nearly 2% of preschool-aged children in this population-based study. Vision loss due to these abnormalities is uncommon.

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

Congenital nystagmus (NYS) is characterized by bilateral, spontaneous, and involuntary movements of the eyeballs that most commonly presents between 2 and 6 months of life. To date, 44 different FRMD7 gene mutations have been found to be etiological factors for the NYS1 locus at Xq26-q27. The aim of this study was to find the FRMD7 gene mutations in a large eleven-generation Indian pedigree with 71 members who are affected by NYS. Mutation analysis of the entire coding region and splice junctions of the FRMD7 gene revealed a novel missense mutation, c.A917G, predicts a substitution of Arg for Gln at codon 305 (Q305R) within exon 10 of FRMD7. The mutation was detected in hemizygous males, and in homozygous and heterozygous states in affected female members of the family. This mutation was not detected in unaffected members of the family or in 100 unrelated control subjects. This mutation was found to be at a highly conserved residue within the FERM-adjacent domain in affected members of the family. Structure prediction and energetic analysis of wild-type FRMD7 compared with mutant (Q305R) revealed that this change in amino acid led to a change in secondary structure predicted to be an energetically unstable protein. The present study represents the first confirmation of FRMD7 gene mutations in a multigenerational Indian family and expands the mutation spectrum for this locus.

Infantile and acquired nystagmus in childhood.

Nystagmus is an involuntary, periodic eye movement caused by a slow drift of fixation which is followed by a fast refixation saccade (jerk nystagmus) or a slow movement back to fixation (pendular nystagmus). In childhood most cases are benign forms of nystagmus: idiopathic infantile, ocular or latent nystagmus. They arise at the age of 3 months, without oscillopsia and show the absence of the physiologic opto-kinetic nystagmus. A full ophthalmologic evaluation is all that is needed in most cases: albinism, macular or optic nerve hypoplasia and congenital retinal dystrophies are the most common forms of ocular nystagmus. Idiopathic infantile nystagmus can be hereditary, the most common and best analyzed form being a mutation of the FRMD7 gene on chromosome Xq26.2. The mutation shows a mild genotype-phenotype correlation. In all female carriers the opto-kinetic nystagmus is absent and half had mild nystagmus. Latent nystagmus is part of the infantile esotropia syndrome and shows the unique feature of change of direction when the fixing eye changes: it is always beating to the side of the fixing eye. There is no cure for infantile nystagmus but therapeutic options include magnifying visual aids or eye muscle surgery at the age of 6-8 y in patients with head turn. Less than 20% of childhood nystagmus are acquired and need further neurological and imaging work-up. Alarming signs and symptoms are: onset after the age of 4 months, oscillopsia, dissociated (asymmetric) nystagmus, preserved opto-kinetic nystagmus, afferent pupillary defect, papilloedema and neurological symptoms like vertigo and nausea. The most common cause is due to pathology of the anterior optic pathway (e.g. optic nerve gliomas). It shows the same clinical feature of dissociated nystagmus as spasmus nutans but has a higher frequency as in INO. Other forms of acquired nystagmus are due to brainstem, cerebellar or metabolic diseases.

[The appearance of refractive errors and eyeballs position disorders in the group of premature babies treated at the Chair and Clinic of Ophthalmology of the Pomeranian Medical University in the years 1999-2005]. / Wystepowanie wad refrakcji i zaburzen w ustawieniu galek ocznych w grupie wczesniaków leczonych w Katedrze i Klinice Okulistyki PAM w latach 1999-2005.

INTRODUCTION: Retinopathy of prematurity (ROP) is a disease of the retina and the vitreous body present in children prematurely born. In the groups of babies with retinopathy of prematurity as well as among in the group of babies without pathological lesions, however, with retinal immaturity, occurrence of complications in the form of refractive errors and abnormality in the eyeballs position can be observed. The aim of the study was to analyze the frequency of occurrence of hypermetropia, myopia, astigmatism and eyeballs position disorders in the form of strabismus and nystagmus in premature babies. MATERIAL AND METHODS: The study material consisted of 1052 newborns treated in the Outpatient Clinic of Ophthalmology for Premature Infants in Szczecin, between 1999-2005. Refractive errors were estimated, after cycloplegic retinoscopy (0.5% Tropicamidum and 2.5% Phenylephryni hydrochloridum). Refractive errors were recognized when hypermetropia was > or = +3.0 D, myopia > or = -0.5 D, astigmatism > or = 1.0 Dcyl. Among 65 babies of the analyzed group laser treatment of the retina was applied, the rest of the 987 infants were observed or have underwent a conservative treatment. The studied group of premature babies has been divided into the following subgroups: Group I--conservatively treated babies (n = 987), group II--diode laser treated babies (n = 65). The statistic analysis of refractive errors was done on the basis of Statistica v.7.1 [StatSoft, Inc. (2005). Statistica (data analysis system), version 7.1.]. The incidence of refractive errors was described with the help of chi-square test. RESULTS: Refractive errors were recognized among 695 babies (70.49%) from group I and in 49 babies (75.39%) from group II. In the group of 987 infants whom were not treated with laser but conservatively a more frequent occurrence ofhypermetropia and astigmatism was observed--655 babies (66.33%) and 202 (20.46%) respectively. Myopia was most common in the laser treated group of babies: 19 patients (29.23%). In this group astigmatism was present in 9 babies (13.84%). Eyeballs position disorders in the form of strabismus and nystagmus were more common in the group of babies treated with laser (29.23% and 9.23%) comparing with conservatively treated babies (10.63% and 1.63%) respectively. CONCLUSIONS: Hypermetropia and astigmatism could be more often observed in the group of premature babies in whom pathological ocular fundus lesions or a low stage of advancement of retinopathy of prematurity susceptible to self-regression were not recognized. Myopia was more often identified in the group of babies with an active stage of retinopathy of prematurity as well as in those in whom laser treatment was required. Eyeballs position disorders in the form of strabismus and nystagmus were more frequent in the group of babies with an active stage of retinopathy of prematurity in whom diode laser treatment was applied.

[Astigmatism in ocular neuromuscular nystagmus]. / Astigmatismus bei kongenitalem Nystagmus.

BACKGROUND: Data on refraction of patients with congenital nystagmus are not available in the literature. PATIENTS AND METHODS: We have analysed the refractive errors in a cohort of 224 consecutive patients with congenital nystagmus, aged 1-57 years. RESULTS: Refractive errors, i. e., myopia, hyperopia (> 0.50 dioptres) and astigmatism (> 1.25 dioptres), were found in 179 patients (79.91 %). Of them 8 were myopic (4.46 %), 19 were hyperopic (10.61 %) and 152 were astigmatic (84.91 %). Mean astigmatism was of 2.44 dioptres for right eyes and 2.74 dioptres for left eyes. CONCLUSIONS: Astigmatism is extremely common in congenital nystagmus. Its presence is much higher than that found in normal populations. The amount of astigmatism found in nystagmus patients is noticeable. When considering he visual difficulties of patients with nystagmus, the astigmatic component should be taken in greatest consideration. Its presence should favour early surgery for anomalous head posture. Furthermore, refractive surgery should be considered as early as possible, for improving visual potential.

Autosomal dominant congenital nystagmus is not linked to 6p12, 7p11, and 15q11 in a German family.

PURPOSE: Congenital nystagmus (CN) is an eye-movement disorder that usually starts within the first months of life. Autosomal dominant, autosomal recessive, and X-chromosomal pedigree patterns are observed. Causative genes are yet unknown. Several loci were implicated to contain disease-relevant genes for autosomal dominant CN (AD CN). AD CN cosegregated with a balanced translocation of 7;15 in a family. In a large black pedigree linkage was demonstrated to 6p12. DESIGN: In this study, we describe a large German family with AD congenital nystagmus. Linkage of AD in this family was tested with previously implicated loci. METHODS: Affected family members and unaffected members underwent genetic analysis. Key family members underwent ophthalmologic testing and oculography. RESULTS: No linkage of AD CN to the implicated loci on 6p12, and 7p11, and 15q11 was found in this study. CONCLUSION: In the presented pedigree genes on 15q11, and on the assumption of full penetrance, 6p12 and 7p11 are not involved in the development of AD congenital nystagmus.

[Prevalence of optic atrophy and associated ocular and systemic diseases in a department of paediatric ophthalmology]. / Prävalenz der Optikusatrophie und assoziierte okuläre und systemische Erkrankungen in einer kinderophthalmologischen Sprechstunde.

BACKGROUND: Optic atrophy is one of the most common causes of severe visual impairment in children. So far an analysis of ocular and systemic findings comparing patients with and without optic atrophy has not performed. PATIENTS AND METHODS: Ocular and systemic findings of a total of 1042 patients (examination of all patients in May 1995 [N = 485] and May 2001 [N = 557]) of the department of paediatric ophthalmology in Homburg/Saar were retrospectively evaluated and diagnoses of patients with and without optic atrophy were compared. Optic atrophy was diagnosed ophthalmoscopically and in 1/3rd of the patients by VEP as well. RESULTS: 18 % of all patients (N = 188; 87.2 % [N = 164] were children) had optic atrophy. Nearly half of these children were prematurely born (46.7 %). 53.2 % of patients with optic atrophy (N = 88) showed nystagmus (without atrophy: 10.7 %), especially sensory defect nystagmus. Median of visual acuity level was 0.2 with optic atrophy and 0.8 without. Albinism and buphthalmia were common findings. 69.5 % of all patients with optic atrophy suffered from systemic diseases (without atrophy: 25.2 %), especially mental retardation, neurologic findings and oculocutaneous albinism. In 10.4 % more than two systemic diagnoses could be found. 55.3 % of all the patients with optic atrophy were disabled, 31.9 % multiply disabled. CONCLUSIONS: Sequelae of prematurity, peripartal asphyxia and congenital brain damages are the main findings in patients with optic nerve atrophy. Such children are worst-case patients of any paediatric ophthalmology department with a high prevalence of severe visual impairment, mental retardation and multiple disability. Treatment in a specialised center is therefore necessary for an efficient therapy. In addition, the statistical survey shows that in children who survived the critical phases of prematurity secondary damages can lead to persistent impairment and to alterations of visual and general development.