A Mini-Review: Leber Congenital Amaurosis: Identification of Disease-Causing Variants and Personalised Therapies.

Leber congenital amaurosis (LCA) encompasses a group of severe inherited retinal dystrophies (IRDs) responsible for early childhood blindness. There are currently 25 genes implicated in the pathogenesis of these diseases, and identification of disease-causing variants will be required for personalised therapies. Whole exome and whole genome sequencing is informative for detecting novel disease-causing genes, whilst next-generation sequencing has excelled at detecting novel variants in known disease-causing genes.A global effort will be required to identify patient populations for early intervention. At the Australian Inherited Retinal Disease Registry and DNA Bank, we seek to identify genetic variants in individuals with IRDs in the Australian population to identify potential candidates for clinical trials, to inform clinical management of patients including reproductive options and to expand existing knowledge of IRDs.Due to the diversity of genes implicated, personalised strategies are likely to be the benchmark for treating these diseases, and a combined approach of different therapies may be optimal in treating some of these diseases.

Targeted deletion of 5'HS1 and 5'HS4 of the beta-globin locus control region reveals additive activity of the DNaseI hypersensitive sites.

The mammalian beta-globin locus is a multigenic, developmentally regulated, tissue-specific locus from which gene expression is regulated by a distal regulatory region, the locus control region (LCR). The functional mechanism by which the beta-globin LCR stimulates transcription of the linked beta-like globin genes remains unknown. The LCR is composed of a series of 5 DNaseI hypersensitive sites (5'HSs) that form in the nucleus of erythroid precursors. These HSs are conserved among mammals, bind transcription factors that also bind to other parts of the locus, and compose the functional components of the LCR. To test the hypothesis that individual HSs have unique properties, homologous recombination was used to construct 5 lines of mice with individual deletions of each of the 5'HSs of the endogenous murine beta-globin LCR. Here it is reported that deletion of 5'HS1 reduces expression of the linked genes by up to 24%, while deletion of 5'HS4 leads to reductions of up to 27%. These deletions do not perturb the normal stage-specific expression of genes from this multigenic locus. In conjunction with previous studies of deletions of the other HSs and studies of deletion of the entire LCR, it is concluded that (1) none of the 5'HSs is essential for nearly normal expression; (2) none of the HSs is required for proper developmental expression; and (3) the HSs do not appear to synergize either structurally or functionally, but rather form independently and appear to contribute additively to the overall expression from the locus.

Auditory P300 studies in schizophrenic subjects and their first degree relatives.

Nineteen subjects with schizophrenia, 6 subjects with related disorders (schizophrenic spectrum disorders (S.S.D.)), and 20 unaffected first degree relatives from a sample of schizophrenic pedigrees, together with 35 normal control subjects, had auditory P300 evoked responses measured, using the "odd-ball" paradigm for stimulation. Bipolar recording on the midline (CZOZ) and two contralateral sites (CZ-mastoid) was carried out. It was found that approximately 40% of schizophrenics/S.S.D.'s had abnormal P300 responses. Abnormalities were seen in latency, RMS response voltage and in the left side response--right side response cross correlation coefficient. Schizophrenics/S.S.D.s showed responses which were topographically different than those of normal controls. Significant left-side/right-side response voltage asymmetry was not observed. In our study, only 10% of unaffected relatives of schizophrenics/S.S.D.'s showed abnormal P300 responses.

Neural networks--an artificial intelligence approach to the analysis of clinical data.

This paper describes an approach to the pattern recognition problem of categorizing evoked response waveforms, using that branch of artificial intelligence known as neural networking. A total of 19 subjects (38 eyes) were exposed to a reversing chequerboard pattern, and the resulting Pattern electroretinogram (PERG) recorded. This was repeated for each of the subjects at contrast levels of 75%,50% and 25%, with the resulting response becoming less pronounced as the contrast level was decreased. The subjects were also given an Arden contrast sensitivity test, and the resulting scores recorded for each eye. The averaged responses from each of the 3 contrast levels for each of the 38 eyes tested were used as the input to a computer simulated 3-input per neuron cascaded neural network. The output and weighting parameters for the individual neurons were then varied until the network was able to optimally classify the PERG results on the basis of the Arden contrast sensitivity scores. The neural network was thus taught to recognize patterns in the PERG responses in much the same way that an experienced clinician might. A second neural network was similarly taught to classify the PERG responses on the basis of a clinician's subjective rating of each of the responses.

A detailed study of sequential saccadic eye movements for normal- and poor-reading children.

This paper presents the results of an in-depth study of parameters characterizing sequenced saccadic eye movements for a group of dyslexic children and a comparative normal control group with ages in the range greater than 8.0 yr. and less than 13.0 yr. No parameters were statistically different for the two groups, which supports the findings of Brown, et al. and contradicts the findings of Pavlidis. Our results indicate that sequenced saccadic eye movements are not diagnostically useful for early detection of dyslexia.

Smooth pursuit eye movements in normal and dyslexic children.

This paper describes a detailed study of horizontal eye movements associated with visual tracking of a smoothly moving target. Essentially all children, even at target velocities as low as 5 degrees/sec., show some saccadic eye movements superimposed on smooth tracking movements. Detailed analysis of pursuit eye-movements from a group of 26 poor readers and 34 normal controls (8 to 13 yr.) showed that about 25% of poor readers have an abnormally raised saccadic component in smooth pursuit. This suggests that studies of eye movements during tracking of smoothly moving targets at low velocity, combined with a quantitative approach to data analysis, may be useful for early detection of a significant proportion of poor-reading children.

Dyslexia: saccadic eye movements.

This paper describes an extensive study of the parameters of saccadic eye movement in a group of 28 poor-reading children and a comparative normally reading group of 31 children. Ages ranged from 6.0 to 16.9 yr. Poor readers had normal intelligence but were lagging by at least two years in reading ability as compared to their peer age group. Parameters studied in refixation eye movements included saccadic latency, accuracy, velocity, and acceleration, as well as differences in latency for abduct and adduct movements. Shapes of saccades were also studied. It was shown that eye-movement performance in simple saccadic refixation was not distinguishably different for poor readers and normal readers, even though in reading, which requires higher processing, eye-movement characteristics are quite different. Maturational changes for various saccadic eye-movement parameters were also examined for the normal and poor reading groups.