Progression of retinal pigment epithelial alterations during long-term follow-up in female carriers of choroideremia and report of a novel CHM mutation.

OBJECTIVES: To report clinical and functional findings in 2 female carriers of choroideremia who were followed up for 11 and 17 years and who showed progression of fundus alterations; and to report a novel CHM mutation. METHODS: We performed follow-ups in 2 female carriers of choroideremia, including repeated clinical and electrophysiologic examinations and fundus autofluorescence. Molecular analysis of the CHM gene was done by direct sequencing of the coding exons. RESULTS: Follow-up of female carrier 327 took place during 17 years. A second female carrier (subject 869) with a novel gene mutation in CHM was followed up for 11 years. The 2 carriers showed marked pigmentary alterations in the periphery of the retina. At the initial visit, carrier 869 had multiple small, yellowish flecks in the macula. Both carriers developed subnormal 30-Hz flicker responses on full-field electroretinography during follow-up, whereas electrooculography responses were normal. In both carriers, progression of fundus alterations was noted. Fundus autofluorescence images showed multiple small flecks with reduced autofluorescence. CONCLUSIONS: Over time, fundus alterations in female carriers of choroideremia are visible, and mild cone dysfunction might develop. Multiple yellowish flecks can exist in the macula. The typical mottled irregularity in fundus autofluorescence is a valuable diagnostic criterion that facilitates specific genetic testing. Clinical Relevance Fundus alterations in female carriers of choroideremia can progress over time and a mild generalized cone dysfunction can develop. Characteristic irregularities are seen in fundus autofluorescence imaging, which is helpful in identifying female carriers of choroideremia.

Phenotypic variability and long-term follow-up of patients with known and novel PRPH2/RDS gene mutations.

PURPOSE: To describe the phenotypic variability in 22 patients with PRPH2 gene mutations and to report six novel mutations. DESIGN: Retrospective study. METHODS: Clinical examinations included color vision testing, perimetry, fundus autofluorescence (FAF), fluorescein angiography, optical coherence tomography (OCT), and full-field and multifocal electroretinography (International Society for Clinical Electrophysiology of Vision standards). Blood samples were taken for deoxyribonucleic acid (DNA) extraction and mutation screening was performed by direct sequencing of polymerase chain reaction amplicons. RESULTS: Eleven unrelated patients and four unrelated families each with two affected members as well as one family with three affected members were examined. Diagnoses included central areolar choroidal dystrophy (CACD; n = 9), autosomal dominant retinitis pigmentosa (adRP; n = 7), adult vitelliform macular dystrophy (n = 3), and cone-rod dystrophy (CRD; n = 3). FAF was abnormal in all patients and showed various retinal pigment epithelial alterations, in CACD with a speckled FAF pattern. OCT revealed reduced retinal thickness, mostly in CACD, subretinal lesions, macula edema, or was normal. Follow-up (n = 12; range, 1.3 to 26 years) showed a slow progression of the retinal dystrophies. DNA testing revealed previously reported PRPH2 mutations in two families and eight individuals of whom two carried the same mutation but had different phenotypes. Novel PRPH2 mutations were detected in two families with adRP, in identical twins with CACD, and in each of an individual with CACD, CRD, and adRP. CONCLUSIONS: This series describes the broad spectrum of phenotypes associated with PRPH2 mutations. FAF and OCT are helpful tools for diagnosis and evaluation of disease progression. We report novel PRPH2 mutations in patients with CACD, CRD, and adRP.

ERG variability in X-linked congenital retinoschisis patients with mutations in the RS1 gene and the diagnostic importance of fundus autofluorescence and OCT.

PURPOSE: X-linked congenital retinoschisis (RS) is a relatively frequent retinal dystrophy associated with RS1 gene mutations. A negative electroretinogram (ERG), i.e., a b/a wave ratio <1.0 in the standard combined response, is considered a key diagnostic feature of RS. Only a few cases without a negative ERG have been reported. METHODS: This study includes 24 RS patients with RS1 mutations. ERGs (according to ISCEV standards, n = 23), ON-OFF-responses (n = 9), fundus autofluorescence (FAF, n = 8), and optical coherence tomography (OCT, n = 6) were performed. RESULTS: The mean age at examination was 22.6 years (0.5-53.2 years), and median visual acuity was 0.3 (no light perception to 0.6). A negative ERG was found in 13 of 23 patients (56.5%), of whom one patient presented a negative ERG at the 2-year follow-up, with an initial b/a wave ratio >1.0. Another patient had a b/a wave ratio of 0.96 in one eye and 1.02 in the fellow eye. In 10 of 23 patients, the b/a wave ratio ranged from 1.03 to 1.34. Single-flash cone and 30 Hz flicker responses were always reduced. FAF and OCT were pathologic in all patients tested. FAF was increased in the fovea. OCT revealed foveal schisis to various degrees and thinning of the retina in an older patient. CONCLUSIONS: Although ERG abnormalities were detected in all patients tested, more than 40% of patients with RS1 mutations did not have a negative ERG. In clinically suspected RS a combination of ERG, FAF, OCT, and molecular-genetic testing is advised to verify the diagnosis.

Choroideremia: variability of clinical and electrophysiological characteristics and first report of a negative electroretinogram.

PURPOSE: To analyze the variability of clinical and electrophysiological characteristics in X-linked choroideremia and provide the first report of a negative electroretinogram in choroideremia. DESIGN: Retrospective study. PARTICIPANTS: The records of 18 male patients with choroideremia and 8 female carriers were evaluated. METHODS: The data were reviewed regarding visual acuity (VA), color vision, perimetry, fundus autofluorescence, and full-field electroretinography (according to standards of the International Society for Clinical Electrophysiology of Vision). MAIN OUTCOME MEASURES: Morphological and functional phenotype characteristics, fundus autofluorescence, electroretinography, and Rab escort protein 1 (REP-1) mutations. RESULTS: Four unrelated families with choroideremia (9 affected males, 7 carriers) and 10 unrelated individuals (9 affected males, 1 carrier) were included. Mutational analysis, performed in 2 families and 3 individual males, revealed REP-1 mutations in all except 1 male. The age of the males ranged from 5.9 to 63.0 years (mean, 33.9), and VA ranged from hand movements to 1.0 (median, 0.7). Fundus autofluorescence (n = 7) showed defects in the retinal pigment epithelium in all males. Electroretinography (n = 13) was almost undetectable in 6 males and reduced in 6, indicating a rod-cone dystrophy. A further male showed a negative electroretinogram, with a b:a wave ratio of 0.5. Visual acuity of the 8 carriers (age, 4.8-56.8 years [mean, 24.0]) ranged from light perception to 1.2 (median, 1.0). Light perception was present in 1 carrier manifesting choroideremia with distinct chorioretinal atrophy. Pigmentary stippling, seen in the other carriers, was seen in fundus autofluorescence (n = 1) with a distinct speckled pattern. Electroretinograms were normal in 6 of 7 and reduced in the manifesting carrier. Defects in color vision and visual field were found in affected males and in the female carriers. CONCLUSIONS: The phenotype of choroideremia presents with high variability. In addition to the previously reported findings, we observed a negative electroretinogram, indicating a postreceptoral retinal dysfunction, in 1 affected male; severe course of choroideremia with early blindness in 1 manifesting carrier; color vision deficits in the majority of affected males and carriers; and characteristic alterations in fundus autofluorescence.

Dysfunction of transmission in the inner retina: incidence and clinical causes of negative electroretinogram.

BACKGROUND: Only limited data exist on the incidence of negative electroretinograms (ERG) in clinical practice. The purpose of this study is therefore to determine the incidence and clinical causes of a negative ERG in a tertiary care centre focused on inherited and acquired retinal degenerations. METHODS: All ERGs recorded (in accordance with ISCEV standards) in our electrophysiological laboratory from 1992 to 2004 were retrospectively reviewed. The negative ERGs (criterion: ERG with b:a wave ratio1 (8 eyes) or ERG responses were not detectable (2 eyes). Photopic ON- and OFF-responses were recorded in 38 eyes of 29 patients and 32/38 eyes presented with a negative ERG. The ON-response was reduced in 25/32 eyes, whereas the OFF-response was reduced in only 11/32 eyes. CONCLUSIONS: The incidence of a negative ERG can differ between the laboratories depending on the causes for ERG recording and was in our laboratory 2.9% in a consecutive series of patients with inherited or acquired retinal degenerations. A disorder characteristically associated with negative ERG (e.g. XRS, CSNB, MAR) was diagnosed in 53% of these patients, whereas in 47% the negative ERG indicated an unexpected post-receptoral dysfunction, e.g. in cone (-rod) dystrophy or RP. The ON-bipolar pathway was affected in most cases.