Alterations of slow and fast rod ERG signals in patients with molecularly confirmed Stargardt disease type 1 (STGD1)

purpose. To investigate the slow and fast rod signals of the scotopic 15-Hz flicker ERG in patients with molecularly confirmed Stargardt disease type I (STGD1). There is evidence that these slow and the fast rod ERG signals can be attributed to the rod bipolar–AII cell pathway and the rod–cone coupling pathway, respectively. methods. Twenty-seven patients with STGD1 with mutations in both alleles of the ABCA4 gene were included. Scotopic ERG response amplitudes and phases to flicker intensities ranging from −3.37 to −0.57 log scotopic troland · sec (log scot td · sec) were measured at a flicker frequency of 15 Hz. In addition, scotopic standard ERGs were obtained. Twenty-two normal subjects served as controls. results. The amplitudes of both the slow and fast rod ERG signals were significantly reduced in the STGD1 group. The phases of the slow rod signals lagged significantly, whereas those of the fast rod signals did not. The standard scotopic ERG did not reveal significant alterations. conclusions. The results provide evidence that a defective ABCA4 transporter can functionally affect both the rod bipolar–AII cell pathway and the rod–cone coupling pathway. In STGD1, the scotopic 15-Hz flicker ERG may reveal subtle abnormalities at different sites within the rod system that remain undetected by standard ERG techniques

Clinical electrophysiology of two rod pathways: normative values and clinical application

Background: The scotopic 15-Hz flicker electroretinogram (ERG) has two limbs (slow and fast ERG rod signals), and these have been attributed to two retinal rod pathways (the ON rod bipolar and AII amacrine pathway and the rod-cone gap-junction pathway). The aim of this study was to provide normative values of the scotopic 15-Hz flicker ERG, to estimate the inter-individual variability, and to apply this method to a clinical setting. Methods: Twenty-two normal subjects, one patient with retinitis pigmentosa (RP), and two patients with Stargardt's macular dystrophy (SMD) participated in the study. The SMD patients were screened for mutations in the 50 exons of the ABCA4 (formerly ABCR) gene. We measured ERG response amplitudes and phases to flicker intensities ranging from –3.37 to –0.57 log scotopic trolands s at a flicker frequency of 15 Hz. Results: The normal scotopic 15-Hz flicker ERG showed a biphasic amplitude pattern with a minimum at about –1.57 log scotopic trolands s, where there was an abrupt phase shift of about 180 deg. The inter-individual variability in ERG amplitude ranged from 47% to 67% for the slow and from 41% to 64% for the fast rod signal. Both the RP patient and the SMD patients (who were compound heterozygotes for mutations in the ABCA4 gene) showed reduced amplitudes for the two rod ERG pathways. Conclusion: The inter-individual variability might be explained by anatomical differences between individual retinae. In the RP patient, the amplitude reductions corresponded well with the standard rod ERG. In the SMD patients, however, the scotopic 15-Hz flicker ERG revealed rod dysfunction, whereas the standard rod ERG was within normal limits. The scotopic 15-Hz flicker method may be more sensitive than the standard rod ERG

A second independent Tyr168Cys mutation in the tissue inhibitor of metalloproteinases-3 (TIMP3) in Sorsby's fundus dystrophy.

Sorsby's fundus dystrophy (SFD) is a rare autosomal dominant macular disorder with age of onset usually in the fourth decade. It is characterised by loss of central vision owing to subretinal neovascularisation and disciform macular degeneration. In an effort to identify the SFD gene, the disease locus was first mapped to chromosome 22q13-qter by genetic linkage analysis, the same chromosomal region as the gene encoding the tissue inhibitor of metalloproteinases-3 (TIMP3). Subsequently, two separate mutations in TIMP3 were found in affected members of two unrelated SFD pedigrees (Tyr168Cys and Ser181Cys). More recently, two additional SFD related mutations, Ser156Cys and Gly167Cys, have provided further confirmation that heterozygous mutations in TIMP3 are causally responsible for the SFD phenotype. We now report the occurrence of the Tyr168Cys mutation in an SFD patient of Austrian descent and show that this mutation found earlier in an American SFD family arose independently. The new findings add to an emerging pattern of SFD mutations which all seem to affect the C-terminal region of the mature TIMP3 protein. In addition, all known mutations cause a change of an amino acid to a cysteine residue. This suggests a critical role for the additional C-terminal free thiol group in SFD pathogenesis

Molecular basis of an inherited form of incomplete achromatopsia

Mutations in the genes encoding the CNGA3 and CNGB3 subunits of the cyclic nucleotide-gated (CNG) channel of cone photoreceptors have been associated with autosomal recessive achromatopsia. Here we analyze the molecular basis of achromatopsia in two siblings with residual cone function. Psychophysical and electroretinographic analyses show that the light sensitivity of the cone system is lowered, and the signal transfer from cones to secondary neurons is perturbed. Both siblings carry two mutant CNGA3 alleles that give rise to channel subunits with different single-amino acid substitutions. Heterologous expression revealed that only one mutant forms functional channels, albeit with grossly altered properties, including changes in Ca2+ blockage and permeation. Surprisingly, coexpression of this mutant subunit with CNGB3 rescues the channel phenotype, except for the Ca2+ interaction. We argue that these alterations are responsible for the perturbations in light sensitivity and synaptic transmission