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Retinal dystrophies caused by mutations inRPE65: assessment of visual functions
  1. Christian P Hamela,b,
  2. Jean-Michel Griffoinb,
  3. Laetitia Lasquelleca,
  4. Christian Bazalgettea,
  5. Bernard Arnauda
  1. aService d'ophtalmologie, Hôpital Gui de Chauliac, 80, avenue Augustin Fliche, 34295 Montpellier cedex 5, France, bInserm U 254, 71, rue de Navacelles, 34090 Montpellier, France
  1. Christian P Hamel, INSERM U 254, 71 rue de Navacelles, 34090 Montpellier, Francehamel{at}


AIMS To characterise the disease in patients with mutations inRPE65.

METHODS Individuals from two families were studied clinically.

RESULTS 13 and 20 year old compound heterozygote individuals from one family with R234X and 1121delA mutations showed nystagmus, macular dystrophy and low contrasted spots in the fundus. Some heterozygotes had macular drusen. A 40 year old compound heterozygote individual from another family with L22P and H68Y mutations had few bone spicule pigment deposits and macular atrophy.

CONCLUSION Compound heterozygote individuals had severe rod-cone dystrophies featuring few pigment deposits in the fundus, pigment epithelium atrophy, and early involvement of the macula, with variations in severity leading to the diagnosis of Leber's congenital amaurosis or retinitis pigmentosa. Macular drusen in heterozygotes carrying a null allele may reflect the decreased capacity in the RPE65 function.

  • Leber's congenital amaurosis
  • retinitis pigmentosa
  • RPE65
  • retinal pigment epithelium
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Recently, genetic defects in RPE65, the gene coding the retinal pigment epithelium (RPE) specific protein RPE65, have been found.1-6 There is evidence indicating that RPE65 is involved in the isomerisation from all-trans to 11-cis retinol that occurs in the RPE.7 Here, we describe the observations of three compound heterozygote individuals and of their relatives (heterozygotes and normal homozygotes) carrying RPE65mutations.

Patients and methods


In the three generation French family 1, 15 members, except II-1, were examined; in the two generation Italian family 2, only the propositus (II-2) was examined (Fig 1). Results of theRPE65 screening in both families has been reported previously.14

Figure 1

Pedigree of two families with members affected by either Leber's congenital amaurosis (family 1) or retinitis pigmentosa (family 2). Black symbols indicate clinically affected individuals, open symbols unaffected people. Individuals carrying age related macular degeneration are shown by an asterisk. Normal and disease allele carrier status is indicated for each family member.


Standard ophthalmological examination was performed as well as colour vision testing, Goldmann perimetry, and fluorescein angiography. Full field electroretinogram (ERG) was recorded using a ganzfeld apparatus (Metrovision, France) and dark adaptometry was performed with a Goldmann-Weekers apparatus using a test seen with an angle of 11° according to the standard protocol.



A 20 year old patient (III-2) from family 1 had nystagmus, night blindness, and inability to move alone since birth in the absence of systemic disease; her condition was reported as Leber's congenital amaurosis. She was emmetropic with 4/200 and 2/200 in right and left eyes, respectively. She showed numerous yellowish spots throughout the fundus, narrowing of retinal vessels, moderate pallor of the optic discs, and macular atrophy (Fig 2A, B). She could not discriminate any colour. Photopic and scotopic ERGs were unrecordable. Her 13 year old brother (III-3) showed a similar ocular history and symptoms, although he seemed to be slightly less severely affected (Fig 2C, D).

Figure 2

Fundus photographs (A, C, E) and fluorescein angiograms (B, D, F). Right eye of patient III-2 (A, B) and left (C) and right (D) eyes of patient III-3 from family 1, both affected with Leber's congenital amaurosis, exhibit yellowish spots, attenuation of retinal vessels, pallor of optic discs, either atrophy (B) or oedema (D) of the macula, and virtual absence of pigment deposits. Left eye of patient II-2 from family 2 (E, F) affected with retinitis pigmentosa shows rare pigment deposits, narrowing of retinal vessels, pallor of optic disc, and confluent patches of macular chorioretinal atrophy.

Patient II-2 from family 2, aged 40, had a medical history of retinitis pigmentosa. Although he reported night blindness since early childhood, he had no difficulty moving in daytime, and was reading fluently until aged 13. He had visual acuity of 6/200 with −2.00/−2.00 at 10° and 8/200 with −1.50/−1.25 at 130° in right and left eyes, respectively. Fundus examination showed markedly attenuated retinal vessels, waxy pallor of optic discs, rather sparse bone spicule-shaped pigment deposits in midperiphery, and extended atrophy of the macula with patches of retinal pigment epithelium/choriocapillaris atrophy (Fig 2E, F). Tritanopia and restriction of the V4e isoptre to 12° in each eye were also noted. ERG responses were undetectable.


Individuals with the R234X/+ genotype were unremarkable except for a few small macular drusen in I-1 who also had slightly diminished ERG rod responses. Dark adaptometry was within the normal range.

Six individuals carried the 1121delA/+ genotype. In the two heterozygotes from the first generation (I-3 and I-4), there were obvious signs of AMD with many large, soft drusen. By contrast, their normal homozygote sister (I-2) had no soft macular drusen. All three heterozygotes from the second generation had small macular drusen (Fig3) with ERG rod responses slightly diminished in two of them (II-3 and II-5). Their normal homozygote sisters had no or few scattered drusen and normal ERGs. The only heterozygote from the third generation (III-1) had a normal fundus and his ERG rod response was at the lower limit of the normal value. Dark adaptometry from individuals III-1, II-5, and II-3 were within the normal limits.

Figure 3

Right eye of 47 year old individual II-7 who is heterozygote (1121delA/+) shows many small macular drusen.


In patients with Leber's congenital amaurosis (LCA), visual acuity was still measurable, a feature recently described5that distinguishes LCA2 (due to mutations inRPE65, OMIM No 204100) from LCA1 (due to mutations in RETGC1, OMIM No 204000). Night blindness, the absence of hyperopia, and slow worsening of the visual outcome, also characteristic of LCA2, were noted. These features closely resemble those of childhood onset severe retinal dystrophy (CSRD) in which mutations in RPE65 have also been found.2 The RP phenotype found in one patient is infrequent in RPE65 mutations since it has been described in only five unrelated cases,348 while more than 30 unrelated patients have been diagnosed as LCA13569-12 or CSRD.21314Published cases of LCA and CSRD show that patients carry either translation terminating or missense mutations on both alleles, suggesting that in most cases a severe disease occurs, whatever the modification of the RPE65 protein (absence, truncation, or change in amino acid).

Mutations in other RPE expressed genes involved in the retinol metabolism have been described includingRLBP1, encoding cellular retinaldehyde binding protein (CRALBP), causing severe retinitis pigmentosa,15 retinitis punctata albescens,16and Bothnia dystrophy,17 andRDH5 encoding 11-cis retinol dehydrogenase, that leads to fundus albipunctatus.18 These conditions and those due toRPE65 mutations are characterised by night blindness, few or no pigment deposits, areas of pigment epithelium atrophy, involvement of the macula, and often dot-like deposits in the fundus. These features are also quite similar to vitamin A deprived retinal dysfunction syndrome19 and to hereditary defect in retinol binding protein,20 suggesting that impairment in the ocular metabolism of retinol predominantly affects rods. Macular involvement may reflect the greater density of rods over cones at the periphery of the macula.

We noted the presence of small macular drusen in individuals heterozygous for the 1121delA mutation, as found in heterozygous carriers with TULP1 translation terminating mutations that cause early onset severe retinal degeneration in the homozygous state.21 The presence of these drusen suggests that mutation in one allele may indeed cause a moderate dysfunction in the outer retina and lead to a time dependent accumulation of materials.


We thank the families, SOS Rétinite (Montpellier, France) which provided financial support for this work and to one of us (J-M G), IRRP (Bordezac, France), as well as Hervé and Monique Offret, Maryse Bélis (Service d'ophtalmologie, Kremlin-Bicêtre), Christian Billotte, and Mrs Labarrière, Montagne, and Noury (Service d'ophtalmologie, Caen) for their help.


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