Establishment of the concept of new clinical entities--complete and incomplete form of congenital stationary night blindness

摘要

I summarized our long-term study to prove that the complete and incomplete types of congenital stationary night blindness (CSNB) are different clinical entities and that the latter is a newly identified disease which has never been reported in the past. CSNB with normal fundi and negative electroretinogram (ERG) showing selective reduction of the b-wave was previously known as the "Schubert-Bornschein type". For the sake of convenience, we classified the disease into two types according to the absence or the presence of rod function: complete CSNB and incomplete CSNB. The hereditary mode of the former is X-linked recessive and autosomal recessive, while that of the latter is X-linked recessive. They are never found together in a single family. We found several additional differences between the two types, including ERG oscillatory potentials, cone mediated ERG, and refractive errors, all leading us to hypothesize that the two types are not variants of a single disease but are the sum of two different clinical entities. Our hypothesis has recently been proven true by molecular genetical analysis. Namely, the mutated gene in X-linked recessive complete CSNB was found in the nyctalopin (NYX) gene, while that in incomplete CSNB was found in the calcium channel (CANCA1F) gene which encodes the retina-specific calcium channel alpha 1-subunit. These results proved that complete and incomplete CSNB are different clinical entities and that the latter is the first disease of the eye which discloses mutation of this region. We classified 90 patients to include 49 complete and 41 incomplete types. Fifteen incomplete CSNB patients underwent gene analysis and they all showed mutation of the CACNA1F gene. We also examined for gene mutation in several patients who had progressive retinal disease and negative ERG and found two siblings with CANA1F gene mutation. This finding indicates that the mutation of the CACNA1F gene can also cause progressive retinal disease in addition to incomplete CSNB. Gene analysis of 11 patients with complete CSNB was performed and 6 revealed mutation of the NYX gene. The remaining 5 patients showed neither NYX nor CACNA1F gene mutation, suggesting they are of autosomal recessive complete CSNB where gene mutation has not been identified. The comparison of our phenotype and genotype diagnosis indicated that a precise ERG analysis can provide correct differentiation between complete and incomplete types. Other clinical findings include moderately low visual acuity in both types, high or moderate myopia in complete CSNB, and wide distribution from myopia to hyperopia in incomplete CSNB. Pathophysiology studies using clinical patients and animal models suggested that complete CSNB has a complete defect of the ON-bipolar cells or their synapses in the rod and cone visual pathways, leaving the OFF pathway intact (OFF-retina). On the other hand, the incomplete CSNB has an incomplete defect of the ON and OFF bipolar cells or their synapses in the rod and cone visual pathways. The macular function isrelatively well preserved in both types, which was shown by focal macular ERG. The incomplete CSNB patients seldom complain of night blindness, which causes us to overlook this disease because we then tend not to perform ERG testing. This disease is not so rare and clinicians should be more aware of its existence. The incomplete CSNB is a new hereditary retinal disease detected by Japanese investigators just like the Oguchi disease, and it has much unknown pathophysiology which needs to be identified in the future. Since the namings of complete and incomplete CSNB may be misunderstood as indicating functional classification of one disease, it has been proposed internationally to change the name "complete type" to CSNB1 and that of "incomplete type" to CSNB2.