Hereditary degenerations of the human retina are genetically heterogeneous, with well over 100 genes implicated so far. This Seminar focuses on the subset of diseases called retinitis pigmentosa, in which patients typically lose night vision in adolescence, side vision in young adulthood, and central vision in later life because of progressive loss of rod and cone photoreceptor cells. Measures of retinal function, such as the electroretinogram, show that photoreceptor function is diminished generally many years before symptomic night blindness, visual-field scotomas, or decreased visual acuity arise. More than 45 genes for retinitis pigmentosa have been identified. These genes account for only about 60% of all patients; the remainder have defects in as yet unidentified genes. Findings of controlled trials indicate that nutritional interventions, including vitamin A palmitate and omega-3-rich fish, slow progression of disease in many patients. Imminent treatments for retinitis pigmentosa are greatly anticipated, especially for genetically defined subsets of patients, because of newly identified genes, growing knowledge of affected biochemical pathways, and development of animal models.
We describe two families with retinitis pigmentosa (RP), a hereditary neurodegeneration of rod and cone photoreceptors in the retina, in which affected members were homozygotes for loss-of-function mutations in the IDH3B gene encoding the beta subunit of NAD-specific isocitrate dehydrogenase (NAD-IDH), the enzyme believed to catalyze the oxidation of isocitrate to α-ketoglutarate in the citric acid cycle. Cells from the affected family members had a substantial reduction of NAD-IDH activity with about a 300-fold increase in the Km for NAD. NADP-specific isocitrate dehydrogenase (NADP-IDH), an enzyme that can catalyze the same reaction, was normal. The patients had no health problems associated with the enzyme deficiency except for RP. The existence of these patients supports the hypothesis that mitochondrial NADP-specific IDH, rather than NAD-IDH, can serve as the major catalyst for this reaction in the citric acid cycle outside the retina, and that the retina has a particular requirement for NAD-IDH.Mutations in at least 34 genes have been identified as causes of nonsyndromic RP, including 15 dominant genes, 20 recessive genes, and 2 X-linked genes (RetNet website). The identified RP genes are estimated to account for about 60% of cases 1 . In addition, 11 unidentified genes have been mapped to specific chromosomal regions. It is estimated that there are dozens of still unmapped, unidentified recessive RP genes, each accounting for at most a few percent of cases 1, 2 .The approach we used to search for some of the unidentified recessive RP genes depends on the fact that recessive alleles are often deletions, frameshift mutations, or nonsense mutations that result in a scarcity of the disease gene's transcript either because the transcript is not made Correspondence to: Thaddeus P. Dryja, Massachusetts Eye and Ear Infirmary, 243 Charles Street, Boston, MA 02114; Thaddeus.dryja@novartis.com. * Current affiliation: University Medical Center Groningen, Groningen, The Netherlands § These authors contributed equally to the work AUTHOR CONTRIBUTIONS D.T.H., T.L.M., and T.P.D. designed and conducted the molecular genetic analyses. E.L.B. clinically evaluated, selected, and recruited patients and their family members, as well as helped in the design of the study. M.D. and R.F.C. designed and conducted the enzyme assays. All authors discussed and interpreted the results and wrote the manuscript. or is rapidly degraded due to nonsense-mediated decay 3 . The principle underlying this method has been previously described 4, 5, 6 , but, as far as we know, the method has never been used to identify a novel gene causing a hereditary disease. Using microarray techniques that simultaneously assay mRNA levels from tens of thousands of transcripts in individual patients, we searched for genes with absent or very low expression that may be due to two allelic diseasecausing mutations. While it would have been ideal to carry out the analysis with RNA derived from the retina prior to its degeneration, this tissue is not availa...
Using NVGs seems to improve nighttime mobility in dark outdoor conditions by decreasing unintended contacts with obstacles and increasing walking speed. Use of NVGs increased independent activities in these subjects and was generally positively evaluated for everyday outdoor use.
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