Fundus albipunctatus (FA) is a type of congenital stationary night blindness with an autosomal recessive inheritance pattern. The fundus of affected patients has a characteristic appearance of numerous small yellow-white dotlike lesions at the level of the retinal pigment epithelium (RPE). Marmor1 reported that the dotlike lesions increase in number over the years. Because his study had been carried out before mutations in the gene encoding retinal dehydrogenase type 5 (RDH5) were identified in patients with FA, 2 the molecular genetic abnormalities of his patients had not been studied. In the present study, we identified a novel compound heterozygous mutation in the RDH5 gene in a patient with FA and investigated medical records to identify changes in fundus findings during a long-term follow-up period.
A 21-year-old woman was first seen at age 6 years, when she was aware of night blindness. Her corrected visual acuity was 20/15 OU, and her visual fields were full. Numerous yellow-white dotlike lesions were observed at the level of the RPE in her fundus bilaterally. Since then, she had undergone periodic examinations for 15 years. Although the basic pattern of dotlike lesions did not change, there was subtle variation in their distribution and particularly in their density. For example, in the inferonasal area, the numbers of dotlike lesions appeared to have increased (Figure 1). Conversely, in the nasal area, they appeared to have decreased. No abnormality had been noted in the macular area during the 15 years of observation. Results of molecular genetic analysis revealed novel compound heterozygous mutations with nucleotide 928C to GAAG (Leu310 to Glu Val)and Arg167His (CAC to CGC) in the RDH5 gene (Figure 2). For the molecular genetic study, proceedings followed the tenets of the Declaration of Helsinki and were approved by the Ethical Committee for Medical Research of Hirosaki University School of Medicine, Hirosaki, Japan.
Fundus photographs of the nasal area of the patient at ages 6 (A), 13 (B), and 21 (C) years. Note that the numbers of dotlike lesions shown in the yellow squares have decreased with age (38, 26, and 5, respectively), whereas those in the white squares have increased (92, 105, and 112, respectively).
A novel compound heterozygous mutation of nucleotide 928C to GAAG (Leu310 to Glu Val) and Arg167His (CAC to CGC) in the RDH5 gene was found in our patient by molecular genetic analysis. The bidirectional sequencing data showed the novel Arg167His (CAC to CGC) missense mutation in both forward (A) and reverse(B) strands.
One of the 2 mutations that this patient harbors is a 4–base pair(GAAG) replacement of a single nucleotide (C), such that the leucine at amino acid 310 is replaced by glutamate and valine. A homozygous pattern of this mutation has been known to be the most common cause of FA in Japan.3,4 Therefore, it seems likely that this novel combination of the mutations as a compound heterozygous pattern is also a primary cause of FA.
Although the origin of the yellow-white dotlike lesions is still uncertain, it has been speculated that abnormal materials were produced as the result of the deficiency of RDH5.2 Although the number and density of lesions are known to gradually increase with age, 1 no one has previously reported on the decreasing number of lesions during a long time period, as was shown in our patient. These findings may suggest important clues for understanding the chemical properties, formation and degradation, and distribution of yellow-white dotlike lesions in FA. It is also interesting that dotlike lesions are not usually seen in the macular area, where particularly high lysosomal enzyme activity has been reported.5
The authors have no relevant financial interest in this article.
This study was supported in part by grants B-12557145 and B-11470361(Dr Nakazawa) from Grants-in-Aid for Scientific Research, Ministry of Education, Culture, Sports, Science, and Technology, and the Research Committee on Chorioretinal Degenerations and Optic Atrophy, the Ministry of Health, Welfare, and Labor of the Japanese Government (Dr Nakazawa), Tokyo.
Corresponding author and reprints: Mitsuru Nakazawa, MD, Department of Ophthalmology, Hirosaki University School of Medicine, Hirosaki, 036-8562 Japan (e-mail: firstname.lastname@example.org).
MF Long-term follow-up of the physiologic abnormalities and fundus change in fundus albipunctatus. Ophthalmology.
1990;97380- 384PubMedGoogle ScholarCrossref
TP Mutations in the gene encoding 11-cis
retinol dehydrogenase cause delayed dark adaptation and fundus albipunctatus. Nat Genet.
1999;22188- 191PubMedGoogle ScholarCrossref
M A frequent 1085del C/ins GAAG mutation in the RDH5 gene in Japanese patients with fundus albipunctatus. Invest Ophthalmol Vis Sci.
2000;411894- 1897PubMedGoogle Scholar
et al. Mutations in the 11-cis
retinol dehydrogenase gene in Japanese patients with fundus albipunctatus. Invest Ophthalmol Vis Sci.
2000;413933- 3935PubMedGoogle Scholar
K Regional distribution of lysosomal enzymes in the retina and choroids of human eyes. Albrecht von Graefes Arch Klin Exp Ophthalmol.
1981;216269- 273PubMedGoogle ScholarCrossref