Pedigree of a family with fundusalbipunctatus showing affected (solid symbols) and unaffected (open symbols)members. Individuals whose DNA was tested are indicated by X's. Squares indicatemen; circles, women; and slash through symbol, deceased. The parents of theaffected twin sisters are consanguineous.
Fundus photographs (A, B) andfluorescein angiograms (C, D) of the patients with a mutation of the 11-cis retinol dehydrogenase gene. A, Left eye of patientIV:3 showing multiple yellow-white lesions excluding the macula, as well ashigh myopic changes and retinal degeneration in the macula. B, Left eye ofpatient IV:2 showing multiple yellow-white punctate lesions and high myopicchanges. No degenerative changes are seen in the macular area. C, Fluoresceinangiogram of the left eye of patient IV:3 showing hyperfluorescence in themacula. D, Fluorescein angiogram of the left eye of patient IV:2 showing noabnormality in the macular area.
Full-field electroretinogramsof a normal subject and twin sisters with fundus albipunctatus associatedwith cone dystrophy. Those of a patient with typical fundus albipunctatuswithout cone dystrophy are also shown for comparison. In the twins, rod electroretinogramsand rod-cone mixed bright-white electroretinograms recorded after prolongeddark adaptation (DA) are also shown. The arrowheads indicate the stimulusonset.
Nucleotide sequences of the 11-cis retinol dehydrogenase gene determined with sense primersin the patients. A compound heterozygous mutation of G to A at nucleotide394 (Val132Met) and G to A at nucleotide 539 (Arg280His) in the gene was identifiedin the patients. Bars indicate the positions of the mutations.
Nakamura M, Lin J, Miyake Y. Young Monozygotic Twin Sisters With Fundus Albipunctatus and Cone Dystrophy. Arch Ophthalmol. 2004;122(8):1203-1207. doi:10.1001/archopht.122.8.1203
EDWIN M.STONEMD, PhD
Copyright 2004 American Medical Association. All Rights Reserved.Applicable FARS/DFARS Restrictions Apply to Government Use.2004
To describe young monozygotic twin sisters with fundus albipunctatus(a type of autosomal recessive stationary night blindness caused by mutationsof the 11-cis retinol dehydrogenase gene [RDH5]) associated with cone dystrophy, previously reported in elderlymen.
Ophthalmologic examinations were performed, and the RDH5 gene was analyzed by direct genomic sequencing.
Twin 23-year-old sisters with high myopic refractive errors of approximately−13 diopters were diagnosed as having fundus albipunctatus. Their photopicelectroretinographic responses were markedly reduced, and cone dystrophy wasdiagnosed. One twin had macular degeneration with reduced best-corrected visualacuity, while the other twin had normal maculae with good visual acuity. Acompound heterozygous mutation, Val132Met and Arg280His, in the RDH5 gene was found in both sisters.
Cone dystrophy can be present in patients with fundus albipunctatus,not only elderly men but also young women. The clinical severity differedbetween monozygotic twins with fundus albipunctatus and cone dystrophy.
The patient's sex is not critical for the presence of cone dystrophyin patients with fundus albipunctatus. The discordant findings in the twinsindicate that factors other than genetics influenced the phenotype.
Fundus albipunctatus (FA) is a type of congenital stationary night blindnesswith an autosomal recessive transmission. The fundi of patients with FA havea characteristic appearance with a large number of discrete, small, roundor elliptical, yellow-white lesions at the level of the retinal pigment epithelium.1- 3 The electrophysiologicresponses are also distinctive because unusually long dark-adaptation periodsare required to obtain the maximum scotopic responses.3 The11-cis retinol dehydrogenase gene, RDH5, has been identified as the mutated gene in patients with FA.4- 13
Patients with FA complain of night blindness from early childhood, andthe clinical course has been considered to be stationary with normal visualacuity, visual fields, and color vision. However, we have found that somepatients with FA develop cone dystrophy (CD), resulting in progressive visualloss.5,14 Cone dystrophy is characterizedby an initial degeneration of cone photoreceptor cells causing progressiveimpairment of central vision, central scotoma, and loss of color discriminationwith the appearance of atrophic retinal changes in the macula. The photopicelectroretinograms (ERGs) are reduced more than the scotopic ERGs. To ourknowledge, all of the reported cases of FA associated with CD and moleculardegeneration were in men older than 40 years.5,10,11,14 Thus,we believed that some patients with FA will develop CD, and that these patientswill be mainly men.5
In this report, we describe the characteristics of 23-year-old, monozygotictwin sisters who had FA and CD. One twin had bilateral macular degenerationwith unilateral reduction of corrected visual acuity, whereas the other twinhad normal maculae with good visual acuity in both eyes. The discordant findingsindicate that the severity of CD in FA is related to factors other than genetics.
This study conformed to the tenets of the Declaration of Helsinki, andinformed consent was obtained from the subjects after an explanation of thepurpose and procedures. The sisters were examined in the Department of Ophthalmology,Nagoya University, Nagoya, Japan. A complete ophthalmologic examination wasperformed, including best-corrected visual acuity, slitlamp and fundus examinations,fundus photography, fluorescein angiography, and ERG.
Genomic DNA was extracted from leukocytes of peripheral blood, and exons2, 3, 4, and 5 of the RDH5 gene were amplified bypolymerase chain reaction. The polymerase chain reaction conditions and theprocedures for direct sequencing have been described in detail elsewhere.4,5 To search for polymorphisms, 100 allelesfrom normal, unrelated Japanese individuals were also directly sequenced.
Standardized full-field ERGs, elicited by Ganzfeld stimulation, wererecorded after pupillary dilation with 0.5% tropicamide and 0.5% phenylephrinehydrochloride. The rod (scotopic) ERGs were recorded with a blue stimulusof a luminance of 5.2 × 10− 3 candela-seconds per squaremeter (cd-s/m2). The mixed rod-cone, single-flash (bright white)ERGs were elicited by a white stimulus of 44.2 cd-s/m2. They wererecorded after 20 minutes and also after 3 hours of dark adaptation. The photopic(cone) single-flash ERGs and 30-Hz flicker ERGs were elicited by white stimuliat an intensity of 4 cd-s/m2 and 0.9 cd-s/m2, respectively,on a white background of 68 cd/m2.
The 23-year-old twin sisters were referred to our hospital for a diagnosisfor their visual difficulties. They were considered to be monozygotic becausethey bore a close resemblance to each other. Both patients had noticed nightblindness from childhood, while only twin 1 (IV:3, Figure 1) had noticed a gradual reduction of vision during the previous5 years. Their paternal grandmother and maternal great-grandfather were siblings(Figure 1). The corrected visualacuity of twin 1 was 1.2 OD and 0.2 OS with refractive errors of −12.50−2.25 × 15° OD and −13.00 −1.25 × 175°OS, and that of twin 2 (IV:2, Figure 1)was 1.2 OU with refractive errors of −12.00 −2.50 × 175°OD and −13.00 −3.00 × 5° OS. They stated that theirhealthy mother was also highly myopic.
In both patients, numerous small, discrete yellow-white dots were observedat the level of retinal pigment epithelium with scarring of the macula inboth eyes (Figure 2A and B). Bothmaculae of twin 1 (IV:3) demonstrated macular degeneration (Figure 2A), and fluorescein angiography showed hyperfluorescencein the corresponding areas (Figure 2C).Twin 2 (IV:2) did not show any abnormality in the macula by either indirectophthalmoscopy (Figure 2B) or fluoresceinangiography (Figure 2D) in botheyes. The intraocular pressures and anterior segments were normal. Neithernystagmus nor strabismus was found in either patient.
The full-field rod ERGs elicited by Ganzfeld stimulation were significantlyreduced after 20 minutes of dark adaptation, and they improved but remainedsubnormal after prolonged dark adaptation in both patients (Figure 3). The amplitudes of the a and b waves of the bright-flash,mixed rod-cone ERG were reduced in both sisters (Figure 3). Although a bright-flash negative-type ERG (b wave <a wave) after 20 to 30 minutes of dark adaptation is a distinct characteristicin FA, it was not possible to use this diagnostic feature because of blinkartifacts (Figure 3).
The photopic a and b waves and 30-Hz flicker ERGs were significantlyreduced in both patients, indicating the presence of CD (Figure 3).
Molecular genetic examination disclosed a compound heterozygous mutationof G to A at nucleotide 394 (Val132Met) and G to A at nucleotide 539 (Arg280His)in the RDH5 gene (Figure 4). Their healthy mother was heterozygous, with a mutationat nucleotide 394 but normal findings at nucleotide 539. The same mutationsin the gene have been detected in other Japanese patients with FA.5,10,15 No such base substitutionswere found in 100 alleles from healthy individuals.5 Inaddition to the genotype of the RDH5 gene, the monozygosityof the twin was determined by totally concordant results of the polymerasechain reaction with fluorescent-labeled primers for 22 highly polymorphicloci including D1S249, D2S337, D3S1267, D4S402, D5S630,D6S257, D7S636, D8S550, D9S286, D10S1686, D11S4175, D12S78, D13S159, D14S68,D15S205, D16S520, D17S1852, D18S61, D19S220, D20S186, D21S1914, and D22S283.
We have examined the RDH5 gene in 6 cases ofFA associated with CD and in 8 cases without CD. A homozygous or compoundheterozygous mutation in the gene was detected in all of the patients.5 Because the CD was seen more frequently in older patients,and because some of those with CD had progressive macular degeneration withgradual decline of visual functions during a long follow-up period, we concludedthat mutations of the RDH5 gene led to a progressiveCD resulting in a severe loss of visual function with increasing age in somepatients with FA.5 All of these patients withCD were older than 50 years, and they began to notice a decrease in theirvision after 40 years of age.5,11,14 Only1 young patient (a 9-year-old) with FA has been reported to have reduced visualacuity and macular dystrophy.16 This boy hadcompound heterozygous mutations of Tyr281His and Leu310GluVal in the RDH5 gene and had symmetric atrophic lesions in the maculaof each eye. The amplitudes of his focal cone macular ERGs were significantlyreduced, indicating that he had macular dystrophy. However, he was not consideredto have CD because his full-field photopic ERGs were normal.16 Thus,to date, no young person with FA associated with CD has been described toour knowledge.
The present twin sisters were diagnosed as having CD despite their youngage (23 years) because their full-field photopic ERGs were significantly reduced.These results indicated that CD can be present not only in elderly patientsbut also in young patients with FA. The mutations found in these sisters havealready been found in other Japanese patients, including a 53-year-old womanwho had the same combination of compound heterozygous mutation of Val132Metand Arg280His.5 She maintained her good visualacuity of 1.2 in both eyes without macular degeneration, and her cone ERGresponses were within normal limits. These observations lead us to suggestthat other genetic or environmental factors might have induced the CD in thetwins.
One possibility may be that high myopia played a role in the developmentof the cone dystrophy in the twins. However, no other case with FA has beenreported to be associated with high myopia. In this case, it was presumedthat some other factors in addition to myopia or genetics had an influenceon the progress of cone dystrophy in the twins because one twin had bilateralmacular degeneration with unilateral reduction of best-corrected visual acuity,whereas the other twin had good vision without macular degeneration in botheyes.
We previously suggested that the sex of the patient would have someeffect on the presence of CD because all of the patients with FA associatedwith CD were men.5,14 However,the patients in the present report were women, indicating that the sex isnot a critical condition for the presence of CD.
The clinical phenotype of patients with FA is heterogeneous. Recently,we examined the RDH5 gene in a number of patientswith FA with or without macular dystrophy; however, we observed no clear correlationbetween genotype and phenotype.5,15 Thedetails of the factors affecting the progress of CD are still unknown, andadditional data must be gathered to help make this clear.
Correspondence: Makoto Nakamura, MD, Department of Ophthalmology,Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya466-8550, Japan (firstname.lastname@example.org).
Submitted for publication May 28, 2003; final revision received January15, 2004; accepted January 15, 2004.
This study was supported in part by Grants-in-Aid for Scientific ResearchB14370556 (Dr Nakamura) and A13307048 (Dr Miyake) from the Ministryof Education, Culture, Sports, Science, and Technology of Japan, and by theMinistry of Health, Labor, and Welfare of Japan, Tokyo, Japan.