C.B. Hoyng

The spectrum of retinal phenotypes caused by mutations in the ABCA4 gene.

BackgroundThe majority of studies on the retina-specific ATP-binding cassette transporter (ABCA4) gene have focussed on molecular genetic analysis; comparatively few studies have described the clinical aspects of ABCA4-associated retinal disorders. In this study, we demonstrate the spectrum of retinal dystrophies associated with ABCA4 gene mutations.MethodsNine well-documented patients representing distinct phenotypes in the continuum of ABCA4-related disorders were selected. All patients received an extensive ophthalmologic evaluation, including kinetic perimetry, fluorescein angiography, and electroretinography (ERG). Mutation analysis had been performed previously with the genotyping microarray (ABCR400 chip) and/or single-strand conformation polymorphism analysis in combination with direct DNA sequencing.ResultsIn all patients, at least one pathologic ABCA4 mutation was identified. Patient 10034 represented the mild end of the phenotypic spectrum, demonstrating exudative age-related macular degeneration (AMD). Patient 24481 received the diagnosis of late-onset fundus flavimaculatus (FFM), patient 15168 demonstrated the typical FFM phenotype, and patient 19504 had autosomal recessive Stargardt disease (STGD1). Patients 11302 and 7608 exhibited progression from FFM/STGD1 to cone–rod dystrophy (CRD). A more typical CRD phenotype was found in patients 15680 and 12608. Finally, the most severe ABCA4-associated phenotype was retinitis pigmentosa (RP) in patient 11366. This phenotype was characterised by extensive atrophy with almost complete loss of peripheral and central retinal functions.ConclusionWe describe nine patients during different stages of disease progression; together, these patients form a continuum of ABCA4-associated phenotypes. Besides characteristic disorders such as FFM/STGD1, CRD and RP, intermediate phenotypes may be encountered. Moreover, as the disease progresses, marked differences may be observed between initially comparable phenotypes. In contrast, distinctly different phenotypes may converge to a similar final stage, characterised by extensive chorioretinal atrophy and very low visual functions. The identified ABCA4 mutations in most, but not all, patients were compatible with the resulting phenotypes, as predicted by the genotype–phenotype model for ABCA4-associated disorders. With the advent of therapeutic options, recognition by the general ophthalmologist of the various retinal phenotypes associated with ABCA4 mutations is becoming increasingly important.

Phenotypic variations in a family with retinal dystrophy as result of different mutations in the ABCR gene

AIMS To describe two phenotypic variations of autosomal recessive retinal dystrophy occurring in a consanguineous family in a pseudodominant pattern, resulting from mutations in the ATP binding cassette transporter (ABCR) gene. METHODS Patients of this family underwent an extensive ophthalmic evaluation, including fundus photography, fluorescein angiography, and electroretinography (ERG). Genetic analysis comprised sequence analysis of the retina specific ABCR gene. RESULTS Five patients presented with decreased visual acuity in the second decade, central chorioretinal atrophy associated with a central scotoma, and severely decreased photopic and scotopic ERG responses. This clinical picture, which in our opinion resembles a cone-rod dystrophy (CRD), was associated with compound heterozygosity for IVS30+ 1g →t and IVS40+5g→a mutations in the ABCR gene. The four remaining patients presented with night blindness in the first decade because of a retinitis pigmentosa-like (RP-like) dystrophy. In addition to a pale “waxy” optic disc, attenuated retinal vessels and bone spicule deposits, a widespread chorioretinal atrophy was observed. The scotopic ERG was extinguished and the photopic ERG was severely diminished. Genetic analysis revealed a homozygous 5′ splice mutation IVS30+1g →t in the ABCRgene. CONCLUSION Mutations in the ABCR gene can cause clinical pictures resembling autosomal recessive RP and autosomal recessive CRD.

Clinical characterization, linkage analysis, and PRPC8 mutation analysis of a family with autosomal dominant retinitis pigmentosa type 13 (RP13).

A Dutch family with autosomal dominant retinitis pigmentosa (adRP) displayed a phenotype characterized by an early age of onset, a diffuse loss of rod and cone sensitivity, and constricted visual fields (type I). One male showed a mild progression of the disease. Linkage analysis showed cosegregation of the genetic defect with markers from chromosome 17p13.1-p13.3, a region overlapping the RP13 locus. The critical interval of the RP locus as defined in this family was flanked by D17S926 and D17S786, with a maximal lod score of 4.2 (? = 0.00) for marker D17S1529. Soon after the mapping of the underlying defect to the 17p13 region, a missense mutation (6970G>A; R2310K) was identified in exon 42 of the splicing factor gene PRPC8 in one patient of this family. Diagnostic restriction enzyme digestion of exon 42 amplified from genomic DNA of all family members revealed that the R2310K mutation segregated fully with the disease. The type I phenotype observed in this family is similar to that described for three other RP13 families with mutations in PRPC8 .

Genetic fine mapping of the gene for recessive Stargardt disease.

Abstract Stargardt disease (STGD) is one of the most frequent causes of macular degeneration in childhood. Linkage analysis in families with recessive STGD has recently shown genetic homogeneity and a location of the underlying gene at 1p22-p21 in a 4-cM interval. Haplotype analysis in seven Dutch STGD families with 11 highly polymorphic markers spanning the critical region has enabled us to refine the location of the underlying gene to a 2-cM region flanked by the loci D1S406 and D1S236. We have identified one 45-year-old nonpenetrant individual who carries two disease alleles. In another family, an affected individual inherited the paternal but not the maternal disease chromosome, suggesting genetic heterogeneity or a different mechanism leading to the disease in this family.

Nonsyndromic Hearing Loss Caused by USH1G Mutations: Widening the USH1G Disease Spectrum

Objective: Currently, six genes are known to be associated with Usher syndrome type I, and mutations in most of these genes can also cause nonsyndromic hearing loss. The one exception is USH1G, which is currently only known to be involved in Usher syndrome type I and atypical Usher syndrome. Design: A Dutch family with autosomal recessively inherited hearing loss was examined. Audiometric, ophthalmic, and vestibular evaluations were performed besides the genetic analysis. Results: The hearing loss had an early onset with a downsloping audiogram configuration. Slight progression of the hearing loss was seen in both affected individuals. Compound heterozygous mutations in USH1G were found to segregate with the hearing loss in this family, a missense (c.310A>G, p.Met104Val) and a frameshift mutation (c.780insGCAC, p.Tyr261Alafs*96). Extensive ophthalmic and vestibular examinations demonstrated no abnormalities that are usually associated with Usher syndrome type I. Conclusions: This is the first family presented with nonsyndromic hearing loss caused by mutations in USH1G. Our findings expand the phenotypic spectrum of mutations in USH1G.

Identification of novel locus for autosomal dominant butterfly shaped macular dystrophy on 5q21.2-q33.2.

Butterfly shaped macular dystrophy was first described by Deutman et al. in 1970.1 It is characterised by bilateral accumulation of pigmented or yellowish material at the level of the retinal pigment epithelium. Lesions consist of 3–5 “wings,” which resemble the wings of a butterfly. Affected patients present with a subnormal electrooculogram and normal or slightly diminished visual acuity. The disease is relatively benign, but it can progress with age to chorioretinal atrophy in the parafoveal and peripapillary regions.2 Butterfly shaped macular dystrophy shares important similarities with age related macular degeneration—the most common cause of blindness in older patients.3,4 In both diseases, abnormal deposition of lipofuscin like material at the level of the retinal pigment epithelium is found, which results in loss of the overlying photoreceptors.2 Butterfly shaped macular dystrophy has an autosomal dominant inheritance pattern. To date, it has been associated only with mutations in the peripherin / RDS gene.5–12 We ascertained members of the family with butterfly shaped macular dystrophy that was described originally by Deutman et al. in 1970,1 and we excluded peripherin / RDS as the causative gene in this family.2 In addition, we excluded the ROM-1 gene; four genes expressed in cone photoreceptors; all known non-syndromic macular, retinal pigment epithelium, and choroidal dystrophy loci; all known Leber congenital amaurosis loci; and all known non-syndromic congenital and stationary retinal disease loci.2 This study aimed to identify the locus responsible for butterfly shaped macular dystrophy in this family with a genomewide linkage scan. ### Patients and ophthalmic examination We previously ascertained 13 members (eight affected and five unaffected) of a Dutch family with butterfly shaped macular dystrophy that was first described in 1970 by Deutman et al.1,2 Ophthalmic examination of the participating family members included best corrected Snellen visual acuity, slit …

Sensitive and fast determination of Y402H variants of complement factor H

Using these antibodies, we have developed a robust and sensitive assay to measure the CFH variants at position 402 of the protein. Anti-CFH, anti-CFH-Y402 and anti-CFH-H402 antibodies were coated on different strips using Nunc Maxisorp plates (Fig.1). Samples were diluted 500x and measured in duplo. Simultaneously, HRP-labeled anti-CFH was added and incubated for 1 hr at RT. TMB-substrate was added. After 20 min. reaction was stopped by adding oxalic acid Introduction Age-related macular degeneration (AMD) is the most common cause of irreversible loss of central vision in elderly people in developed countries. Recent studies using genetic approaches have confirmed the role of complement factor H (CFH), composed of 20 short consensus folding domain repeats (SCR). A polymorphism, Y402H, is strongly associated with AMD: homozygosity for the H402 isoform of CFH (10% of Caucasians) increases risk for AMD 3to 12-fold compared to those homozygous for the CFH-Y402 variant. Current methods for identifying the CFH-Y402H status of a patient require extraction of DNA followed by sequencing analysis.