In 1992, Moller pointed out that the survey on causes of blindness in children reported by Fraser and Friedmann in 19677 and the review over 18 years of registration of visually impaired Danish children did not mention any recessive form of simple optic atrophy and concluded that "a clear-cut, well-documented pedigree had yet to be published".4 Here, we describe a family with an unambiguous isolated ROA. In contrast to the few cases formerly reported with a very early and severe form of isolated ROA, the four patients of this family were affected with an early-onset but moderately progressive form of the disease. The clinical phenotype was strikingly different from AOD (no central scotoma, red-green dyschromatopsia).
A genome-wide search for homozygosity led to the identification of a single homozygous region on chromosome 8q21-q22 (ROA1 locus). This result excluded linkage and thus allelism of ROA1 with all known syndromic ROA (see OMIM).
Among the genes of the [D8S1702-D8S1794] 12 Mb physical interval, CNGB3 was first considered. Indeed, although the phenotype of all patients was strikingly different from that described in total colour blindness, the report of severe dyschromatopsia close to achromatopsia in the few known cases of isolated ROA2,3 prompted us to search for mutations in this gene but no mutation was found.
Subsequently, we screened all genes encoding mitochondrial proteins owing to the view that known hereditary optic neuropathies genes are either mitochondrial (LHON) or encode proteins with high mitochondrial targeting (OPA1, OPA3, TIMM8A [MIM 300356]). Thus we first decided to screen genes known to encode mitochondrial protein such as DECR1 and PDP and proteins potentially targeted to the mitochondria, using the prediction programs MITOPROT and PSORT. The exclusion of these candidate genes prompted us to screen all known genes lying within the interval and subsequently several hypothetical genes. Since no mutation was found, we decided to screen several genes lying within the haploidenticial region defined by the D8S1794 and D8S1699 loci following the hypothesis that, in this family, the common ancestor might be affected with ROA and could carry two different mutations segregating through each branch of the family. No mutation was found and further studies are now required i) to identify the causative gene in this family and ii) to delineate the role of this locus in small non-consanguineous families affected with ROA in which linkage analysis can not be conclusive.
Finally, one can expect that the identification of the ROA1 gene and other genes involved in ROA will allow the dissection of molecular mechanisms underlying optic neuropathies to aid genetic counselling and to develop rational therapeutic tools.
Was this article helpful?