Geoffrey Woodruff

Mutations in LRP5 or FZD4 Underlie the Common Familial Exudative Vitreoretinopathy Locus on Chromosome 11q

Familial exudative vitreoretinopathy (FEVR) is an inherited blinding disorder of the retinal vascular system. Autosomal dominant FEVR is genetically heterogeneous, but its principal locus, EVR1, is on chromosome 11q13-q23. The gene encoding the Wnt receptor frizzled-4 (FZD4) was recently reported to be the EVR1 gene, but our mutation screen revealed fewer patients harboring mutations than expected. Here, we describe mutations in a second gene at the EVR1 locus, low-density-lipoprotein receptor-related protein 5 (LRP5), a Wnt coreceptor. This finding further underlines the significance of Wnt signaling in the vascularization of the eye and highlights the potential dangers of using multiple families to refine genetic intervals in gene-identification studies.

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

Idiopathic congenital nystagmus is characterized by involuntary, periodic, predominantly horizontal oscillations of both eyes. We identified 22 mutations in FRMD7 in 26 families with X-linked idiopathic congenital nystagmus. Screening of 42 singleton cases of idiopathic congenital nystagmus (28 male, 14 females) yielded three mutations (7%). We found restricted expression of FRMD7 in human embryonic brain and developing neural retina, suggesting a specific role in the control of eye movement and gaze stability.

FACTORS AFFECTING THE OUTCOME OF CHILDREN TREATED FOR AMBLYOPIA

The outcome of treatment for amblyopia and the factors that affect this are not well understood. A major reason for this has been the exclusion from previous large studies of a sometimes unknown number of patients because of failure to comply with treatment. This paper analyses the outcome of amblyopia treatment in a retrospective review of the orthoptic records of a cohort of 961 children treated for amblyopia at seven centres who first attended in 1983. The final visual acuity was recorded by Snellen or matching methods in 894 children (93 %). Of these, 48 % achieved 6/9 or better, 35 % less than 6/9 but better than or equal to 6/18, and 17 % achieved less than 6/18. The outcome was best for pure anisometropic amblyopia, intermediate for pure strabismic amblyopia and least good for mixed strabismic and anisometropic amblyopia with a final visual acuity of 6/10.2, 6/12.8 and 6/14.8 respectively. While the age at start of treatment did not correlate with final visual acuity both poor initial visual acuity and poor compliance were associated with poor outcome. The main factor affecting the outcome of amblyopia treatment is the initial visual acuity. Comparison with the literature suggests that the results of treatment in this country may be falling far short of what would be possible in ideal circumstances with unlimited resources.

Occlusion for amblyopia: A comprehensive survey of outcome

The results of a long term follow up of all patients from a single health district started on occlusion for amblyopia in 1983 are reported.Three hundred and sixty-eight patients started treatment, their average age was four years seven months, the average amount of daily occlusion was 1.5 hours and the average length of follow up was 31 months. 37% of cases achieved a final visual acuity of 6/9 or better and another 33% a visual acuity of 6/12 or 6/18. 23% did not achieve 6/18 and treatment of these patients was regarded as failure. Data for the remainder (7%) were incomplete.The success rate of occlusion treatment varied little with the age of starting treatment. The group with combined strabismus and anisometropia responded least well to treatment.

The Prevalence of Nystagmus: The Leicestershire Nystagmus Survey

PURPOSE Nystagmus, which can be infantile (congenital) or acquired, affects all ages. The prevalence of nystagmus in the general population is unknown. New genetic research and therapeutic modalities are emerging. Previous estimates have been based on wider ophthalmic epidemiologic studies within specific occupational or age groups. The authors carried out the first epidemiologic study to specifically establish the prevalence of nystagmus in Leicestershire and Rutland in the United Kingdom. METHODS Three independent data sources identified persons with nystagmus from the hospital and community. The first was a hospital-based questionnaire and clinical survey (n = 238). The visually impaired services (n = 414) and education services (n = 193) in Leicestershire provided the second and third separately obtained community-based sources of information. Capture-recapture statistical analysis was used to estimate prevalence. RESULTS The prevalence of nystagmus in the general population was estimated to be 24.0 per 10,000 population (95% confidence interval [CI], +/-5.3). The most common forms of nystagmus were neurologic nystagmus (6.8 per 10,000 population; 95% CI, +/-4.6), nystagmus associated with low vision such as congenital cataracts (4.2 per 10,000; 95% CI, +/-1.2), and nystagmus associated with retinal diseases such as achromatopsia (3.4 per 10,000 population; 95% CI, +/-2.1). Within ethnic groups, nystagmus was significantly more common in the white European population than in the Asian (Indian, Pakistani, other Asian backgrounds) population (P = 0.004). CONCLUSIONS The findings suggest that nystagmus is more common in the general population than previously thought. This may be of significance in resource allocation and health care planning.

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

Idiopathic congenital nystagmus is characterized by involuntary, periodic, predominantly horizontal oscillations of both eyes. We identified 22 mutations in FRMD7 in 26 families with X-linked idiopathic congenital nystagmus. Screening of 42 singleton cases of idiopathic congenital nystagmus (28 male, 14 females) yielded three mutations (7%). We found restricted expression of FRMD7 in human embryonic brain and developing neural retina, suggesting a specific role in the control of eye movement and gaze stability.

The incidence and prevalence of amblyopia detected in childhood

We present incidence estimates for amblyopia using data from a study of a cohort of 364 children from a single English county who were referred during 1983 for occlusion therapy. Using a criterion of a visual acuity of 6/12 or worse to define amblyopia, we estimate that 3.0% of the countys children develop the condition. Successful treatment of some of these children means that 1.9% will remain amblyopic as adults.

Factors Affecting Treatment Compliance in Amblyopia

Amblyopia is the most common form of visual disability in children. Successful treatment by patching depends on compliance, but evidence of factors affecting compliance is limited and contradictory. Because there is a well established relationship between social deprivation and access to health care, we hypothesized that social deprivation might be associated with noncompliance. Data from a historical cohort of 961 children from seven English orthoptic clinics starting treatment for amblyopia in 1983 were used to study factors affecting compliance with amblyopia treatment. Children were classified as noncompliant if they failed to attend all appointments prescribed during the first year of treatment. There was a significant difference in compliance between centers (P = .0001). Overall, children with anisometropic amblyopia were more compliant than those with strabismus but this varied significantly between centers. A relationship between social deprivation and compliance was also found (P = .00001). Only 41% of children from the most deprived wards were compliant compared with 61% in the least deprived wards. Compliance was not found to be related to age at starting treatment.

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

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

Ophthalmological Aspects of Pierson Syndrome

PURPOSE To study the ocular phenotype of Pierson syndrome and to increase awareness among ophthalmologists of the diagnostic features of this condition. DESIGN Retrospective, observational case series. METHODS A multicenter study of 17 patients with molecularly confirmed Pierson syndrome. The eye findings were reviewed and compared to pertinent findings from the literature. RESULTS The most characteristic ocular anomaly was microcoria. A wide range of additional abnormalities were found, including posterior embryotoxon, megalocornea, iris hypoplasia, cataract, abnormal lens shape, posterior lenticonus, persistent fetal vasculature, retinal detachment, variable axial lengths, and glaucoma. There was high interocular and intrafamilial variability. CONCLUSIONS Loss-of-function mutations in laminin beta2 (LAMB2) cause a broad range of ocular pathology, emphasizing the importance of laminin beta2 in eye development. Patients with Pierson syndrome can initially present with ocular signs alone. In newborns with marked bilateral microcoria, Pierson syndrome should be considered and renal function investigated.