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Blue cone monochromatism (BCM) is a rare X-linked colour vision disorder characterized by the absence of both red and green cone sensitivity. Most mutations leading to BCM fall into two classes of alterations in the red and green pigment gene array at Xq28. In one class the red and green pigment genes are inactivated by deletion in the locus control region. In the second class genetic rearrangements have created an isolated pigment gene that carries an inactivating point mutation. Here we describe a clinical case of BCM caused by a new mutation where exon 4 of an isolated red pigment gene has been deleted. The finding represents the first intragenic deletion yet described among red and green pigment genes.

Current pattern of blindness (i.e. visual acuityor = 6/60) in Denmark was studied based on 1585 application forms for new membership to the Danish Society of the Blind during 1993. Statistics on blindness are very sensitive to the definitions used. A change of blindness definition to visual acuity6/60 reduced the number of formally blind subjects with 32%, and by using the definition of WHO (visual acuity3/60) only 562 subjects (35%) would have been considered blind. The prevailing causes of blindness were age-related macular degeneration with 1132 cases (71.4%), followed by diabetic retinopathy 133 cases (8.4%), and glaucoma 80 cases (5.0%). Among the younger subjects (133 persons) aged 20-59 years diabetic retinopathy comprised 36% and lesions of the optic pathways 26%, while myopia and retinitis pigmentosa accounted for 5% each. The majority of the applicants (92%) wereor = 60 years old. In this group, age-related macular degeneration was the main cause of blindness in 78%. Figures from 1993 were compared with six similar studies on newly registered blindness from the last 35 years. The annual number of registrations was doubled during the last 25 years. The annual number of registered blind due to diabetic retinopathy fell during the 60's and 70's followed by a constant rate during the last decades. Glaucoma blindness fell with a factor two, and declined from a relative frequency of 15% among the causes of blindness to 5%. The impact of age related macular degeneration increased from 20% to 70% during the same period.

Sixty-two patients from three large Danish families with autosomal dominant optic atrophy were clinically examined, and retrospective follow-up was made on 30 patients. We found great inter-and intrafamiliar variation in visual acuity and visual decline. One hundred and seventy-five chromosomal markers were analyzed in 118 family members. Linkage was demonstrated between the disease gene (OPA1) and the microsatellite markers D3S1314, D3S1262, D3S1265 and D3S1601, with the highest Lod score to D3S1601 Z=11.75. All markers are located on chromosome 3q in the telomeric area, the most probable location for the OPA1 gene being D3S1601-OPA1-D3S1265. Using data from the Danish Family Register of Hereditary Eye Diseases, the minimum prevalence rate was estimated to 1:12.301, making DOA the most common hereditary optic atrophy.

A collaborative, population based, prospective register study on the incidence of visual impairment in children during the year 1993 was carried out in five Nordic countries with a total population of 17 million inhabitants. The child population was 3.8 million individuals aged 0-17 years. The following variables were taken into account: nationality, age, sex, diagnoses, aetiology, degree of visual impairment, and additional impairments. Classification routines from an earlier prevalence study were used. The present study included 304 children corresponding to an incidence of notification of 8/100,000 children, varying from 5.7 to 11.1 in the five countries. Fifty per cent of the visually impaired children were reported before they were 3 years of age. In approximately 45% of the children, visual impairment was due to various brain disorders, with cerebral amblyopia and secondary optic atrophy as the two leading causes. The relative impact of retinopathy of prematurity had decreased from the third most frequent cause (10%) in the prevalence study to seventh place (4%) in the incidence study. Two thirds of the children had additional impairments and these children also suffered from the most severe visual impairments. Among aetiological factors the majority (64%) were prenatal. The overall male:female ratio of 1.4:1 was identical to the sex ratio of the prevalence study.

The gene for retinitis pigmentosa 3 (RP3), the most frequent form of X-linked RP (XLRP), has been mapped previously to a chromosome interval of less than 1000 kbp between the DXS1110 marker and the OTC locus at Xp21.1-p11.4. Employing a novel technique, YAC Representation Hybridization (YRH)', we have recently identified a small XLRP associated microdeletion in this interval, as well as several putative exons including the 3' end of a gene that was truncated by the deletion. cDNA library screening and sequencing of a cosmid centromeric to the deletion has now enabled us to identify numerous additional exons and to detect several point mutations in patients with XLRP. The predicted gene product shows homology to RCC1, the guanine-nucleotide-exchange factor (GEF) of the Ras-like GTPase Ran. Our findings suggest that we have cloned the long-sought RP3 gene, and that it may encode the GEF of a retina-specific GTP-binding protein.

The gene for the most frequent from of X-linked retinitis pigmentosa (XLRP), RP3, has been assigned by genetic and physical mapping to a segment of less than 1000 kbp, which is flanked by the marker DXS1110 and the ornithine transcarbamylase (OTC) gene. In search of microdeletions, we have screened the DNA of 30 unrelated patients with XLRP by employing a representative set of YAC-derived DNA fragments that were generated by restriction enzyme digestion and PCR amplification. In one of these patients, a 6.4 kbp microdeletion was detected which was not present in the DNA of 444 male controls. A cosmid contig spanning the deletion was constructed and used to isolate cDNAs from retina-specific libraries. Exons corresponding to these expressed sequences as well as other putative exons were identified by sequencing more than 30 kbp of the critical region. So far, no point mutations in these putative exon sequences have been identified.

With the mapping of the locus CHM for choroideremia and the subsequent cloning of the gene, reliable carrier and prenatal diagnosis has become a possibility. We discuss our experience with prenatal diagnosis of choroideremia, an X-linked choroidoretinal dystrophy leading to blindness in otherwise healthy males. In the period 1987–1995, five prenatal diagnoses have been performed by either indirect linkage analysis or by direct detection of the disease-causing mutation, reflecting the impact of molecular biology in clinical genetic practice.

A family with an unusual association of retinitis pigmentosa, progressive and severe hearing impairment, vestibular dysfunction, and congenital zonular cataract is described. The disease had a rather uniform appearance in five affected individuals. Parental consanguinity was documented in all cases and a common ancestor born in 1702 was identified. Consequently, autosomal recessive inheritance seems to be the most likely mode of transmission. This disorder possibly represents a new clinical entity among combined retinal dystrophy and hearing impairment syndromes.

Congenital cataract, type Volkmann (McKusick no 115665, gene symbol CCV) is an autosomal dominant eye disease. The disease is characterized by a progressive, central and zonular cataract, with opacities both in the embryonic, fetal and juvenile nucleus and around the anterior and posterior Y-suture. We examined blood samples from 91 members of a Danish pedigree comprising 426 members, by using highly informative short tandem repeat polymorphisms and found the closest linkage of the disease gene (CCV) to a (CA)n dinucleotide repeat polymorphism at locus D1S243 (Zmax = 14.04 at theta M = 0.025 theta F = 0.000), at a penetrance of 0.90. Using two additional chromosome 1 markers, we were able to map the CCV gene in the sequence 1pter-(CCV, D1S243)-D1S468-D1S214. The (enolase 1) gene has been mapped to this area; however, a mutation described in this gene did not give eye disease.

Leber's hereditary optic neuropathy (LHON), which is associated with mutations in mitochondrial DNA (mtDNA), is commoner in males than females. A study of over 30 LHON families with a mutation at position 3460 of mtDNA demonstrates a significantly decreased male excess from that generally quoted, with evidence for a marked bias in the ascertainment of males over females. This has implications for the analysis of those factors which give rise to the male bias.

Objectives To evaluate comorbidity before and after the diagnosis of branch retinal vein occlusion to determine whether it is a consequence of arterial thickening and therefore could serve as a diagnostic marker for other comorbidities and to evaluate the risk factors for the development of such occlusion. Design Case-control study with prospective follow-up data from Danish national registries. Setting Four secondary referral centres covering about 80% of the Danish population (4.4 million). Participants 1168 patients with photographically verified branch retinal vein occlusion and 116 800 controls alive and aged ≥40 when the occlusion was diagnosed in the corresponding case. Main outcome measures The risk of comorbidity 10 years and 1 year before the diagnosis of branch retinal vein occlusion and the incident comorbidity in a mean period of seven years after the diagnosis, with odds ratios and incidence rate ratios adjusted for age, sex, and year of diagnosis. Results Risk factors present 10 years and 1 year before the diagnosis of branch retinal vein occlusion included peripheral artery disease (odds ratio 1.83, 95% confidence interval 1.14 to 2.95), diabetes (1.74, 1.40 to 2.17) and arterial hypertension (2.16, 1.86 to 2.51). After the diagnosis, patients had an increased risk of developing arterial hypertension (incidence rate ratio 1.37, 95% confidence interval 1.15 to 1.57), diabetes (1.51, 1.17 to 2.04), congestive heart failure (1.41, 1.12 to 1.68), and cerebrovascular disease (1.49, 1.27 to 1.76). Conclusion Diabetes, hypertension, and peripheral artery disease are associated with an increased risk of developing branch retinal vein occlusion up to a decade later. Branch retinal vein occlusion was associated with an increased risk of subsequently developing hypertension, diabetes, congestive heart failure, and cerebrovascular disease, emphasising the importance of preventive initiatives. These results fit the assumption that branch retinal vein occlusion is a consequence of arterial thickening and that the arteriovenous crossing signs that precede it are hallmarks of arterial disease.

We appreciate the experiments and in silico studies of Kumar and Santhiya calling attention to the importance of addressing the risk of nonspecific amplification of the CRYBB2 pseudogene, CRYBB2-P1. 1 Likewise, we acknowledge their notice on errors in the list of primer pairs published as Supplementary Table S1 in our report on mutations in Danish families with congenital cataract. 2 We repeated the amplification of exon 5 of CRYBB2 in one individual from family CC00133 with the claimed mutations due to gene conversion, in one affected individual from each of four additional families with congenital cataract, and in one healthy individual. Amplifications were performed with the primer pair used originally for the analyses of the family, as well as the two primer pairs discussed in the letter by Kumar and Santhiya, 1 Weisschuh et al., 3 and Santhiya et al. 4 The original PCR primer pair designed for amplification of CRYBB2 exon5 was designed so that the forward primer (ex5fGTGTGCAAGTGTGGTGTGC) could not anneal to the pseudogene, CRYBB2-P1, whereas the reverse primer (ex5rGAAGCCAGAGGTCAGCAGAG) was unable to discriminate between the two genes. Only family CC00133 of the 12 CCfamilies investigated at that time showed the three DNA variations in cis. We were, however, unable to reproduce the results from the original study and our results were now in complete accordance with the results of Kumar and Santhiya. Unfortunately we have no explanation for the erroneous results obtained in the original study. 2 In conclusion, the three variations claimed to be located in cis in exon 5 of CRYBB2 in

PURPOSE: To estimate the prevalence, genotype, and clinical spectrum of Best vitelliform macular dystrophy (Best disease). DESIGN: Retrospective epidemiologic and clinical and molecular genetic observational study. METHODS: SETTING: National referral center. PARTICIPANTS: Forty-five individuals diagnosed with Best disease. OBSERVATION PROCEDURES: Retrospective review of patients diagnosed according to clinical findings and sequencing of BEST1. Patients with recently established molecular genetic diagnosis were followed up including multifocal electroretinography (mfERG), spectral-domain optical coherence tomography (SD-OCT), and fundus autofluorescence (FAF) imaging. MAIN OUTCOME MEASURES: BEST1 mutations, SD-OCT and FAF findings, mfERG amplitudes, prevalence estimate of Best disease. RESULTS: BEST1 mutations described previously in Danish patients with Best disease are reviewed. In addition, we identified a further 8 families and 1 sporadic case, in whom 6 BEST1 missense mutations were found, 4 of which are novel. The mutation c.904G>T (p.Asp302Asn) was identified in members of 4 unrelated families. Structural alterations ranged from precipitate-like alterations at the level of the photoreceptor outer segments (OS) to choroidal neovascularization. The extent of the former correlated with the reduction of retinal function. A prevalence estimate of Best disease in Denmark based on the number of diagnosed cases was 1.5 per 100 000 individuals. CONCLUSIONS: Our data expand the mutation spectrum of BEST1 in patients with Best disease. Alterations of the OS overlying lesions with subretinal fluid are similar to those seen in central serous retinopathy and may indicate impaired turnover of OS. Our frequency estimate confirms that Best disease is one of the most common causes of early macular degeneration. (Am J Ophthalmol 2012;154:403-412. (c) 2012 by Elsevier Inc. All rights reserved.) (Less)

Visual prognosis is a crucial theme in the counselling of individuals affected by a progressive retinal dystrophy. Unfortunately prognostic predictions are hampered by large interindividual differences in disease courses even within well defined nosological entities. Ten patients from 8 families affected by choroideremia were studied. The clinical signs in our patients were rather uniform. Deterioration of the peripheral visual fields typically began in the second decade of life, and progressed during the following one or two decades. Esterman transformation of peripheral visual field measurements was chosen as the best single indicator of visual impairment. Noticeable age differences in residual visual fields among patients were demonstrated. The age difference between the mildest and the severest cases amounted to 25 years. One of the expectations of the exploration of disease genes, is the potential predictive value of mutation identification with regard to phenotypic variability. Different presumed causative mutations were identified. Nevertheless, all the mutations are predicted to cause premature stops during translation, resulting in a non-functional or missing protein. Consequently, the observed age variation in the photopic visual field degradation must be due to still unrecognized factors, either constitutional and/or environmental.

The locus for autosomal dominant congenital stationary night blindness (adCSNB) has recently been assigned to distal chromosome 4p by linkage analysis in a large Danish family. Within the candidate gene encoding the beta-subunit of rod photoreceptor cGMP-specific phosphodiesterase (beta PDE), we have identified a heterozygous C to A transversion in exon 4, predicting a His258Asp change in the polypeptide. We found a perfect cosegregation (Zmax = 22.6 at theta = 0.00) of this mutation with the disease phenotype suggesting that this missense mutation is responsible for the disease in this pedigree. Homozygous nonsense mutations in the beta PDE gene have been found recently in patients with autosomal recessive retinitis pigmentosa, a common hereditary photoreceptor dystrophy.

Five patients, not related to each other, showed clinical signs, including electroretinograms, of a retinal dysfunction which mainly affected the cone system, but also involved the rod responses in a peculiar way. ERG b-wave threshold under dark adapted conditions was elevated. In contrast, rod b-wave sensitivity was enhanced with medium to high intensity flash stimulation. Furthermore, all patients had a severe reduction of the oscillatory potentials. The findings are discussed with special emphasis on a hypothetical disturbance in the cyclic guanosine monophosphate metabolism, involving both photoreceptors and cells of the inner plexiform layer responsible for retinal feedback mechanisms.

The registers of visually impaired children in Denmark, Finland, Iceland and Norway have been compiled into a common database by a Nordic study group of ophthalmologists, NORDSYN. The database contains information on 2527 children aged 0-17 years. The total number of children with visual impairment due to retinopathy of prematurity (ROP) is 247. ROP is the 3rd most common single diagnosis in the database. The age-specific national prevalence of registration (N/100 000) of visual impairment due to ROP varies from 12 in Denmark to 5 in Finland and Norway and 4 in Iceland. The differences can partly be explained by varying efficiency of registration. The age-distribution indicates that visual impairment due to ROP is not decreasing. Of the 247 children 175 had a visual acuity less than 1/60 and 58 had one or more additional impairments. Incidence studies on visual impairment in Nordic children are being prepared.

Purpose To describe the phenotype and genotype of patients with a diagnosis of oligocone trichromacy (OT). Methods Six unrelated patients had a detailed ophthalmic examination including color vision testing, a Goldmann visual field test, fundus photography, and full-field electroretinography (ffERG). Five patients also underwent multifocal (mf)ERG, autofluorescence recording, and optical coherence tomography (OCT). Genetic analysis included sequencing of all coding regions and flanking introns of CNGA3, CNGB3, GNAT2, KCNV2, and PDE6C. Results All patients had subnormal visual acuity, a history of congenital nystagmus, and subjectively normal or near-normal color vision; five patients reported photophobia. Clinical examinations revealed largely normal fundi, normal Goldmann visual field results with the IV/4e target, and normal color discrimination or mild color vision deficiency. Electrophysiological investigations showed either complete absence of recordable cone responses or severely reduced amplitudes. All retinal layers were identifiable by OCT, which also showed thinning of the peripheral retina. Genetic analysis revealed two causative CNGB3 mutations in one patient and single heterozygous mutations of unknown significance in CNGB3 and PDE6C in two other patients. Conclusions Oligocone trichromacy is a heterogeneous condition with respect to both phenotypic appearance and genetic background. The finding of mutations in genes known to be involved in complete and incomplete achromatopsia supports the notion that some forms of OT is an extreme form of incomplete achromatopsia with preferential loss of peripheral cones.

Birdshot retinochoroidopathy is a rare ocular disorder which was named and delineated as a separate clinical entity by Ryan & Maumenee in 1980. We diagnosed birdshot retinochoroidopathy in a monozygotic pair of twins, who were affected with a time interval of 12 years, respectively. These are the first with birdshot retinochoroidopathy to be reported from the Nordic countries and the first report on this disorder in monozygotic twins. Due to night-blindness, visual field defects and a severely affected electroretinogram one of our cases initially was diagnosed as a choroidoretinal dystrophy. Birdshot retinochoroidopathy should be kept in mind as a differential diagnosis in retinitis pigmentosa-like disorders with widespread choroidal involvement. Our cases substantiated the evidence of a strong correlation with the presence of HLA-A29 antigen.

A Nordic study group of ophthalmologists, NORDSYN, has compiled registers in Denmark, Finland, Iceland and Norway of 2527 visually impaired children aged 0-17 years. This paper is concerned with the sex-distribution in the registers and has documented a statistically significant excess of males in two of the registers (Denmark and Finland). The dominance of males seems to be related to two main conditions: 1. Genetic factors. 2. Perinatal factors. The genetic factors are mainly concerned with X-linked inheritance. The fact that perinatal influences involve visual impairment in males more than in females is difficult to account for. It may be conjectured, that the basis for perinatal visual damage is determined by unknown prenatal, possibly genetic, factors.

A Nordic study group of ophthalmologists, NORDSYN, has compiled data from registers in Denmark, Finland, Iceland and Norway of 2527 visually impaired children. Each record contains the following information: sex, year of birth, year of registration, classification of visual impairment, ocular diagnosis, systemic diagnosis, aetiology and evt. additional impairments. The ocular diagnoses were compiled into groups, and coding systems for aetiology and additional impairment were developed. The sex distribution revealed a dominance of males compared to the general population at the same age. Cases with non-genetic aetiology showed — though to a lesser extent — the same relative preponderance of males. The diseases in males caused by x-linked genetic factors do, therefore, not fully explain the sex distribution observed in the study. The national prevalences for registration of childhood blindness (WHO-definition: best corrected visual acuity in the best eye less than 3/60 or visual field less than 10 degrees around fixation for the ages 0–15 years) are per 100 000 child-population aged 0–15 years: Denmark 41, Finland 15, Iceland 19 and Norway 15. The differences are primarily presumed to be due to varying efficiency in registration. The proportion of visually impaired children with an additional mobility, hearing or mental impairment is between one-third and one-half of the national materials, thus indicating the need for interdisciplinary tracing of and care for the visually impaired child. This study documents the need of uniform routines for data classification of visually impaired children. The quality of the data in the present study calls for caution in the interpretation of the prevalence estimates. Incidence studies are being prepared to obtain information on whether the amount and causes of visual impairment in children with or without multiple impairments are changing.

Careful clinical-aetiological assessment of visually impaired children is one of the prerequisites for prevention of future, 'unavoidable' cases of visual impairment of children in the industrialized part of the world. In a collaborative study (NORDSYN) between four Nordic national registers of visual impairment, we analysed and classified some of the factors considered to be essential components for the development of low vision or blindness in children. We discuss the conceptual basis for aetiological classification of eye disorders and visual impairment. An aetiological classification system, based on the type and debut of an essential causal factor is introduced. We present data on 2527 visually impaired children from the Nordic countries. In accordance with several other reports from the last twenty years it is demonstrated that prenatal factors, including genetic aetiologies, were involved in a large proportion (66%) of the cases. In children without additional impairments the corresponding fraction was 74%. Genetic factors accounted for a little over half of the prenatal cases, and in a substantial number of children (40%) with visual impairments of prenatal origin, the causes were obscure. In 1/5 of the material some peri-neonatal causal or modifying factor was identified. In 7% only, the presumed aetiological factor was introduced in the infantile-juvenile period of life. Further prevention of visual impairment among children of the industrialized countries would benefit most from a more comprehensive understanding of prenatal, nongenetic causal factors, further knowledge about regulating mechanisms responsible for gene expression, and additional improvements in perinatal care.

PURPOSE. Identification of the causal mutations in 28 unrelated families and individuals with hereditary congenital cataract identified from a national Danish register of hereditary eye diseases. Seven families have been published previously, and the data of the remaining 21 families are presented together with an overview of the results in all families. METHODS. A combined screening approach of linkage analysis and sequencing of 17 cataract genes were applied to mutation analyses of total 28 families. RESULTS. The study revealed a disease locus in seven of eight families that were amenable to linkage analysis. All loci represented known genes, and subsequent sequencing identified the mutations. Mutations were found in eight genes, among them crystallins (36%), connexins (22%), and the transcription factors HSF4 and MAF (15%). One family carried a complex CRYBB2 allele of three DNA variants, and a gene conversion is the most likely mutational event causing this variant. Ten families had microcornea cataract, and a mutation was identified in eight of those. Most families displayed mixed phenotypes with nuclear, lamellar, and polar opacities and no apparent genotype―phenotype correlation emerged. CONCLUSIONS. In total, 28 families were analyzed, and mutations were identified in 20 (71%) of them. Despite considerable locus heterogeneity, a high mutation identification rate was achieved by sequencing a limited number of major cataract genes. Provided these results are representative of Western European populations, the applied sequencing strategy seems to be suitable for the exploration of the large group of isolated cataracts with unknown etiology.

purpose. Several nonsyndromic high-grade myopia loci have been mapped primarily by microsatellite markers and a limited number of pedigrees. In this study, whole-genome linkage scans were performed for high-grade myopia, using single nucleotide polymorphisms (SNPs) in 254 families from five independent sites. methods. Genomic DNA samples from 1411 subjects were genotyped (Linkage Panel IVb; Illumina, San Diego, CA). Linkage analyses were performed on 1201 samples from 10 Asian, 12 African-American, and 221 Caucasian families, screening for 5744 SNPs after quality-control exclusions. Two disease states defined by sphere (SPH) and spherical equivalence (SE; sphere+cylinder/2) were analyzed. Parametric and nonparametric two-point and multipoint linkage analyses were performed using the FASTLINK, HOMOG, and MERLIN programs. Multiple stratified datasets were examined, including overall, center-specific, and race-specific. Linkage regions were declared suggestive if they had a peak LOD score ? 1.5. results. The MYP1, MYP3, MYP6, MYP11, MYP12, and MYP14 loci were replicated. The novel region q34.11 on chromosome 9 (max NPL= 2.07 at rs913275) was identified. Chromosome 12, region q21.2-24.12 (36.59 cM, MYP3 locus) showed significant linkage (peak HLOD = 3.48) at rs337663 in the overall dataset by SPH and was detected by the Duke, Asian, and Caucasian subsets as well. Potential shared interval was race dependent—a 9.4-cM region (rs163016–rs1520724) driven by the Asian subset and a 13.43-cM region (rs163016–rs1520724) driven by the Caucasian subset. conclusions. The present study is the largest linkage scan to date for familial high-grade myopia. The outcomes will facilitate the identification of genes implicated in myopic refractive error development and ocular growth.

A large Danish family with Aland Island eye disease (AIED) was studied by linkage analysis using 16 polymorphic DNA markers covering the whole X chromosome. Positive lod scores were found for marker loci at the proximal part of the short arm of the X chromosome, DXS255 and TIMP ( Z max = 3.93 and 3.18 at θ = 0.0), suggesting an assignment of the locus for AIED to this part of the X chromosome. Recombination was observed with the locus DXS7 as well as with other loci distal to DXS7. These results are not in agreement with the deletion presented previously by D-A. M. Pillers et al. (1990, Am. J. Med. Genet. 36: 23–28), which mapped AIED to Xp21.

An assay was designed that allows detection, by PCR alone, of the mutation of base pair no. 11,778 in human mitochondrial DNA, causing Leber's hereditary optic neuropathy. This was obtained by using a 20-mer primer with the mutation-specific base in the 3′-position, plus a deliberately introduced C C -mismatch at base no. four from the 3′-end. The latter mismatch was necessary, and sufficient, to prevent amplification of the normal allele.

Purpose To examine the age- and gender-specific prevalence and describe the common phenotype of early age-related maculopathy (ARM) and late-stage age-related macular degeneration (AMD) among the Inuit in Greenland. Design Population-based cross-sectional study. Participants All ≥60-year-olds born in Greenland and living in the communities of Nuuk and Sisimiut, Greenland. Methods The presence and form of early (ARM) and late age-related macular disease (AMD) were determined by grading color fundus photographs using the international classification and grading system for ARM and AMD. Main Outcome Measures Prevalences of ARM and AMD were assessed by masked grading of fundus photographs. Results Overall, 695 persons were included in the study (response rate, 74.8%). Prevalence of any ARM was 52.3%. Age-related maculopathy was present in the worse eye in 50.0%, 58.8%, and 44.7% of age groups 60 to 69, 70 to 79, and ≥80, respectively. Prevalence of any AMD was 9.5%. Any AMD was present in the worse eye in 3.9%, 14.6%, and 43.2% of age groups 60 to 69, 70 to 79, and ≥80. Prevalences of pure geographic atrophy (GA) in one or both eyes, exudative degeneration in one or both eyes, and GA in one eye and exudative degeneration in the other eye were 2.3%, 6.1%, and 1.1%, respectively. Conclusions The prevalence of ARM is higher than in most other populations studied, and the prevalence of AMD in the oldest age group is higher than in most other populations studied. The prevalence of exudative degeneration is higher than the prevalence of GA, in contrast to findings in some of the Nordic countries—particularly Iceland—and earlier observations in Greenland.

Usher syndrome type II (USH2) is an autosomal recessive disorder, characterised by moderate to severe high-frequency hearing impairment, normal balance function and progressive visual impairment due to retinitis pigmentosa. Usher syndrome type IIa, the most common subtype, is defined by mutations in the USH2A gene encoding a short and a recently discovered long usherin isoform comprising 21 and 73 exons, respectively. More than 120 different disease-causing mutations have been reported, however, most of the previous reports concern mutations restricted to exons 1-21 of the USH2A gene. To explore the spectrum of USH2A disease-causing mutations among Scandinavian USH2 cases, patients from 118 unrelated families of which 27 previously had been found to carry mutations in exons 1-21 were subjected to extensive DNA sequence analysis of the full size USH2A gene. Altogether, 122 USH2A DNA sequence alterations were identified of which 57 were predicted to be disease-causing, 7 were considered to be of uncertain pathogenicity and 58 were predicted to be benign variants. Of 36 novel pathogenic USH2A mutations 31 were located in exons 22-73, specific to the long isoform. USH2A mutations were identified in 89/118 (75.4%) families. In 79/89 (88.8%) of these families two pathogenic mutations were identified whereas in 10/89 (11.2%) families the second mutation remained unidentified. In 5/118 (4.2%) families the USH phenotype could be explained by mutations in the USH3A gene. The results presented here provide a comprehensive picture of the genetic aetiology of Usher syndrome type IIA in Scandinavia as it is known to date.

PURPOSE. To unravel the molecular genetic background in families with congenital cataract in association with microcornea (CCMC, OMIM 116150). METHODS. CCMC families were recruited from a national database on hereditary eye diseases; DNA was procured from a national gene bank on hereditary eye diseases and by blood sampling from one large family. Genomewide linkage analysis, fine mapping, and direct genomic DNA sequencing of nine cataract candidate genes were applied. Restriction enzyme digests confirmed identified mutations. RESULTS. Analyses of 10 Danish families with hereditary congenital cataract and microcornea revealed five novel mutations. Three of these affected the crystallin, -A gene (CRYAA), including two mutations (R12C and R21W) in the crystallin domain and one mutation (R116H) in the small heat shock domain. One mutation (P189L) affected the gap junction protein 8( GJA8), and one mutation (Y134X) was detected in crystallin -D (CRYGD). CONCLUSIONS. The identification of a CRYGD mutation adds another gene to those that may be mutated in CCMC and underscores the genetic heterogeneity of this condition. Three CRYAA mutations at the R116 position, in association with CCMC, suggest that R116 represents a CCMC-mutational hotspot. The CCMC phenotype demonstrates variable expression with regard to cataract morphology and age of appearance. Clinical heterogeneity, including additional malformation of the anterior segment of the eye, confirm that dedicated cataract genes may be involved in the largely unknown developmental molecular mechanisms involved in lens-anterior segment interactions. (Invest Ophthalmol Vis Sci. 2007;48: 3937‐3944) DOI:10.1167/iovs.07-0013

PURPOSE. To perform a nation-wide elucidation of the prevalence and the mutation spectrum in X-linked retinitis pigmentosa (XLRP), and to make genotype-phenotype comparisons. METHODS. The study comprised 96 affected males and 149 female carriers from 42 families representing all identified XLRP individuals in the Danish population (5.4 million inhabitants). RPGR and RP2 were screened for mutations in 34 families, the medical files of the patients were scrutinized, and phenotype data were extracted. RESULTS. The prevalence of affected males was estimated to be 1:26,200 and 1:18,000 of female carriers. A rough estimate, however, indicates that the real prevalence of affected males was approximately 1:15,000. The cumulated life risk of development of XLRP in carriers was strongly age dependent and included one third of the carriers older than 60 years. Molecular analysis of RP2 and RPGR uncovered 28 different mutations in 33 of 34 index cases analyzed. Twelve patients carried a mutation in RP2, 12 in exons 1 to 14, and 9 in open reading frame (ORF) 15 of RPGR. Males with RP2 mutations tended to have higher degrees of myopia, lower visual acuities, and more preserved visual fields than did males with RPGR mutations at the same age. No significant differences in phenotype were found in age of onset and type of mutation in either RP2 or RPGR. CONCLUSIONS. A very high mutation detection rate in familial cases makes genetic testing a valuable clinical tool for genetic counseling and prenatal testing. The proportion of RP2-mediated XLRP in the Danish population is higher and the proportion of RPGR-ORF15 is lower than reported in other studies. Thus, strategies for diagnostic procedures should take into account the population-specific mutation spectrum.

PURPOSE. The present study was designed to elucidate the molecular genetic basis of a congenital stationary cone dysfunction characterized by congenital nystagmus, moderate visual impairment, and markedly disparate color vision deficiencies between two affected cousins. METHODS. Ophthalmic examinations with emphasis on color vision and electrophysiology. Molecular genetic analysis of the X-linked cone opsin genes, mutation screening of the CNGA3, CNGB3, and GNAT2 genes, and heterologous splicing experiments. RESULTS. Whereas the proband was found to carry a homozygous frameshift mutation (Tyr95fs) in GNAT2, her cousin was compound heterozygous for the Tyr95fs and a new intronic mutation c.46124G3A. Heterologous expression in COS7 cells showed that the latter causes a splicing defect that results in early translation termination. Yet, this mutation is leaky, giving rise to small amounts of correctly spliced transcripts and offer an explanation for the diverging clinical findings in the cousins, one best described as incomplete achromatopsia and the other with oligocone trichromacy. CONCLUSIONS. The cases presented broaden the phenotypic spectrum of GNAT2 mutations and underline the increasing importance of molecular genetics in the clinical diagnosis of atypical ophthalmic phenotypes. (Invest Ophthalmol Vis Sci. 2004;45:4256‐4262) DOI:10.1167/iovs.04-0317

Objective Bornholm eye disease (BED) consists of X-linked high myopia, high cylinder,optic nerve hypoplasia, reduced electroretinographic flicker with abnormalphotopic responses, and deuteranopia. The disease maps to chromosome Xq28and is the first designated high-grade myopia locus (MYP1). We studied a second family from Minnesota with a similar X-linkedphenotype, also of Danish descent. All affected males had protanopia insteadof deuteranopia. Methods X chromosome genotyping, fine-point mapping, and haplotype analysisof the DNA from 22 Minnesota family individuals (8 affected males and 5 carrierfemales) and 6 members of the original family with BED were performed. Haplotypecomparisons and mutation screening of the red-green cone pigment gene arraywere performed on DNA from both kindreds. Results Significant maximum logarithm of odds scores of 3.38 and 3.11 at thetas;= 0.0 were obtained with polymorphic microsatellite markersDXS8106andDXYS154,respectively, in theMinnesota family. Haplotype analysis defined an interval of 34.4 cM at chromosomeXq27.3-Xq28. Affected males had a red-green pigment hybrid gene consistentwith protanopia. We genotyped Xq27-28 polymorphic markers of the family withBED, and narrowed the critical interval to 6.8 cM. The haplotypes of the affectedindividuals were different from those of the Minnesota pedigree. Bornholmeye disease–affected individuals showed the presence of a green-redhybrid gene consistent with deuteranopia. Conclusions Because of the close geographic origin of the 2 families, we expectedaffected individuals to have the same haplotype in the vicinity of the samemutation. Mapping studies, however, suggested independent mutations of thesame gene. The red-green and green-red hybrid genes are common X-linked colorvision defects, and thus are unrelated to the high myopia and other eye abnormalitiesin these 2 families. Clinical Relevance X-linked high myopia with possible cone dysfunction has been mappedto chromosome Xq28 with intervals of 34.4 and 6.8 centimorgan for 2 familiesof Danish origin.