Early-onset severe rod-cone dystrophy in young children with RPE65 mutations.

PURPOSE: To describe the ocular phenotype of patients with RPE65 mutations in infancy and young childhood. METHODS: Four children from three families with severe early-onset visual impairment related to electrophysiologically detectable retinal dystrophy were screened for mutations in the RPE65 gene. Visual function from infancy to the age of 10 years was assessed with age-adapted methods. Clinical examinations and electroretinograms (ERGs) were also performed on the six parents. RESULTS: In all three families, patients were compound heterozygous for mutations of the RPE65 gene (ins144T/IVS1+5G-->A, R91W/Y368H, 1114delA+T457N/IVS1+5G-->A). Visual acuity was measurable in all patients at the age of 6 to 10 years, despite severe visual impairment noted during infancy and congenital nystagmus in three of the four patients. Photophobia was not a feature. Funduscopic changes were discrete, the most prominent finding being increased granularity in the macula and the periphery. Peripheral vision was well preserved, measured by Goldmann perimetry. Rod ERGs were not recordable, whereas cone ERGs were detectable in early childhood. All features taken together suggest a specific form of Leber congenital amaurosis (LCA) distinguishable on clinical grounds. ERGs were normal in five of the six parents. One father had an ERG compatible with congenital stationary night blindness unrelated to his heterozygous state for the RPE65 mutation. CONCLUSIONS: RPE65 mutations on both alleles may be associated with early-onset severe rod-cone dystrophy. Visual functions of the four patients were better than is usually seen in LCA, in particular in cases associated with retGC1 mutations. RPE65 mutations should be suspected in infants who appear to be blind in dim surroundings but react to objects in bright illumination and have nonrecordable rod ERGs and residual cone ERGs.

Mutations in the VMD2 gene are associated with juvenile-onset vitelliform macular dystrophy (Best disease) and adult vitelliform macular dystrophy but not age-related macular degeneration.

Recently, the VMD2 gene has been identified as the causative gene in juvenile-onset vitelliform macular dystrophy (Best disease), a central retinopathy primarily characterised by an impaired function of the retinal pigment epithelium. In this study we have further characterised the spectrum of VMD2 mutations in a series of 41 unrelated Best disease patients. Furthermore we expanded our analysis to include 32 unrelated patients with adult vitelliform macular dystrophy (AVMD) and 200 patients with age-related macular degeneration (AMD). Both AVMD and AMD share some phenotypic features with Best disease such as abnormal subretinal accumulation of lipofuscin material, progressive geographic atrophy and choroidal neovascularisation, and may be the consequence of a common pathogenic mechanism. In total, we have identified 23 distinct disease-associated mutations in Best disease and four different mutations in AVMD. Two of the mutations found in the AVMD patients were also seen in Best disease suggesting a considerable overlap in the aetiology of these two disorders. There were no mutations found in the AMD group. In addition, four frequent intragenic polymorphisms did not reveal allelic association of the VMD2 locus with AMD. These data exclude a direct role of VMD2 in the predisposition to AMD.

Assessment of RS1 in X-linked juvenile retinoschisis and sporadic senile retinoschisis.

The RS1 gene is the causative gene in X-linked juvenile retinoschisis (RS). We have screened this gene for mutations in 13 patients with RS and in 7 probands with senile retinoschisis, a sporadic, later-onset form of retinoschisis. Mutations were detected in all RS patients. Of the 11 different mutations identified, six have been reported previously and live are novel. We did not find mutations in any of the senile retinoschisis patients and conclude that senile retinoschisis is not the result of germline mutations in the RS1 gene.

A comparison of two multifocal ERG systems.

The First Order Kernel responses (FOK) from a group of 15 normal subjects aged 21-36 yrs were recorded under clinical conditions with the multifocal ERG (MERG) systems VERIS and RETIscan using system-specific software and hardware under various parameter settings. First, the multifocal ERG's of normal subjects were recorded with the standard-parameters of VERIS and RETIscan. Thereafter the VERIS system parameters were set as close as possible to the RETIscan-setup, and the recordings were repeated. The VERIS parameters changed were the luminance- and contrast-settings of the stimulus-monitor and m-sequence-timing. In addition, the effects of different sampling rates were also examined. The consequences of the parameter changes were analyzed by displaying the peak times of the First-Order-Kernel (P1). The parameter-combinations used for recording lead to system-specific results. By varying the luminance/contrast settings and/or the m-sequence-timing the results can be changed. The amplitude of the recorded results can be influenced by the luminance-settings of the stimulus-monitor, and the topography of the P1 peak times is affected by the m-/f-frame-combination of the recording stimulus. With their standard parameters, the two systems give different measures of the P1 peak times. By adjusting the recording parameters, these differences can be reduced significantly. The main parameter here is the m-sequence-timing, although the sampling rate must also be taken into account with regard to the accuracy of the recording results.

[Incomplete congenital stationary night blindness (CSNB). An important differential diagnosis of congenital nystagmus]. / Die inkomplette kongenitale stationäre Nachtblindheit (CSNB). Eine wichtige Differentialdiagnose des kongenitalen Nystagmus.

BACKGROUND: Classifying congenital nystagmus in the absence of biomicroscopically detectable abnormalities of the eye, and in an otherwise healthy child is difficult, especially early in life. At that age, nystagmus and visual loss may be the predominant symptoms of congenital stationary night-blindness. Unless night-blindness is specifically asked for or an ERG performed the correct diagnosis may be missed. PATIENTS AND METHODS: We present the clinical data of two families with X-linked incomplete CSNB previously undiagnosed. ERG recordings in both families were suggestive of CSNB. The ERG of the obligate carrier was normal. In an attempt to distinguish between the complete and the incomplete type, and to identify further carrier signs, scotopic perimetry and dark adaptation were performed in both affected males and carriers. Scotopic perimetry allows to test the rod-mediated visual pathway in its spatial distribution. RESULTS: In affected males with non-recordable ERGs scotopic perimetry and dark adaptation disclosed residual rod function indicating an incomplete type. In carriers, there was a sensitivity loss at 600 nm, which may be a new carrier sign. CONCLUSIONS: The correct diagnosis of the different forms of CSNB together with the identification of carriers is important for (1) genetic counselling and (2) linkage studies to identify the gene(s) for CSNB.