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Ocular signs associated with a rhodopsin mutation (Cys-167→Arg) in a family with autosomal dominant retinitis pigmentosa
  1. FRANCESCA SIMONELLI,
  2. MARIO RINALDI,
  3. ANNA NESTI,
  4. FRANCESCO TESTA,
  5. ERNESTO RINALDI
  1. Eye Clinic, Second University of Naples
  2. International Institute of Genetics and Biophysics, CNR, Naples, Italy
  1. ALFREDO CICCODICOLA,
  2. LUISA FLAGIELLO,
  3. MARIA GIUSEPPINA MIANO,
  4. VALERIO VENTRUTO,
  5. MICHELE D’URSO
  1. Eye Clinic, Second University of Naples
  2. International Institute of Genetics and Biophysics, CNR, Naples, Italy
  1. Professor Ernesto Rinaldi, Eye Clinic, Second University of Naples, Via Pansini, 5-80131 Naples, Italy.

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Editor,—Retinitis pigmentosa (RP) comprises a group of hereditary progressive retinal degenerative conditions characterised by typical fundus alterations, loss in visual field, and severely reduced or unrecordable electroretinograms (ERG) The first reported disease related mutations in the human rhodopsin gene, described in 1990 by Dryja et al,1 was a heterozygous C→A tranversion in the second nucleotide of codon 23. Since than many further mutations has been identified to a current total of about 90.2

Here we describe, for the first time in the literature, the clinical phenotype associated with a Cys-167→Arg mutation (TGC→CGC in exon 2) in an Italian family affected by autosomal dominant retinitis pigmentosa (ADRP). The same mutation was noted by Dryja et al,3 but there has been no report of correlated clinical data.

CASE REPORT

Four patients (see Fig 1) of a family from the Campania region of southern Italy, have been studied.

Figure 1

SSCP analysis and pedigree of the family. To detect point mutations, the entire rhodopsin coding sequence, including the five exons and their exon-intron junctions, was amplified using a “multiplex-PCR”.3 Shaded symbols represent those affected.

Patient II-1

The patient, a 45 year old woman, had central visual acuity 20/50 in both eyes with −3 −3 × 180° in right eye and −4 −2.50 × 180° in left. Nascent posterior subcapsular cataract and vitreous corpuscles were present. Fundus examination revealed waxy optic disc pallor, attenuated retinal vessels, atrophic retinal pigment epithelium (RPE), and bone spicules in the middle periphery on 360° (Fig 2). Goldmann kinetic visual field examination showed a concentric isoptere shrinkage up to 10° in the centre in each eye (I,4 and II,4). No peripheral vision island was observed. Goldmann–Weekers adaptoperimetry showed a high depression of the photopic and scotopic curve in both eyes. Electroretinography showed no photopic and scotopic curve. Acromatopsy was found in the colour test.

Figure 2

Fluorescein angiogram of patient II-1.

Patient III-1

This patient, a 11 year old male had central visual acuity 20/25 in both eyes with +1 −3 × 180° in the right and left eye. Fundus examination showed a rose coloured optical disc, attenuated retinal vessels, an atrophic RPE area over 360°, and a very rare osteoblast pigment clusters in the peripheral. The Goldmann visual field examination using I and 4, II and 4 mires showed mild concentric shrinkage of the peripheral isoptres. Goldmann–Weekers adaptoperimetry showed a mild depression of the scotopic and photopic curve in both eyes. ERG gave microvoltage photopic graphs with implicit wave periodicity of 40.60 ms and implicit b wave periodicity of 58 ms; the differential width was 3.921 μV. The scotopic ERG was extinguished in both eyes. The colour test was normal.

Patient III-2

This patient, a 8 year old male showed a corrected visus 20/25 in both eyes with +1.50 × 100° in the right and left eye. The fundus, Goldmann visual field and the Goldmann–Weekers adaptoperimetry examination are similar to the patient III-1. ERG showed a microvoltage photopic graph with implicit time of the a wave equal to 32 ms and implicit time of the b wave equal to 52.20 ms, with a differential width of 10.75 μV. The scotopic graph was extinguished.

Patient III-3

This male patient was first examined at 16 months. Fundus examination showed atrophic RPE changes and bone spicules in mild periphery. At age 7, he was re-examined and found to have a corrected visus of 20/25 in both eyes with +1. Goldmann visual field examination showed a marked reduction in retinal sensitivity in both eyes, especially in the nasal sectors. ERG showed a microvoltage photopic graph with an implicit wave time of 32.40 ms and an implicit b wave time of 53.70 ms, with a differential width of 14.7 μV. The scotopic graph was extinguished.

COMMENT

This study has correlated a mutation Cys-167→Arg of the rhodopsin gene with phenotypic type I in an Italian family. The mutation segregated with the clinical disease, and all affected patients showed a similar phenotype. The disease has a very early onset: in the youngest subject the diagnosis was made at 16 months of age. The first symptoms in all subjects were night blindness and visual field shrinkage (restricted side vision). Examination of the fundus of the eye identified a typical RP form, with vessel narrowing and osteoblast-like pigmentation in the middle retinal peripheral area in four sectors.

Atrophic changes of the RPE in the macular region and in the middle periphery were identified only in the patient II-1. Electroretinography showed an early alteration of rod function, whereas cone function was not completely compromised until almost age 18. Clinical examination repeated yearly for up to 7 years in three subjects indicated that the disease progresses very slowly.

Furthermore, the exact mechanism involved in affecting the visual cycle is difficult to imagine. Cysteine at position 167 of the rhodopsin gene is highly conserved during the evolution of mammals, but its relation to early death of visual cells is unknown. Also, only rods express the rhodopsin gene, and the cones use different photopigments, so that it remains mysterious that both cones and rods are affected in RP. In many cases of retinal degeneration cells undergo apoptotic death; but it is not known whether apoptosis is involved in all the forms of induced or degenerative photoreceptor death.4 Such mechanisms are just coming under scrutiny.

Acknowledgments

The authors would like to thank the family for its contribution to these studies. The authors were also grateful to Professor G Imbucci, of ORAO association; A Terracciano for technical assistance, and to Servizio di Tecnologie Biomolecolari, Area di Ricerca CNR Naples, where the sequences were performed. This work was supported by Telethon-Italy, grant no E546 to AC and CNR grant no CTB.94.2863 to ER; MGM is a Telethon-Italy fellow.

References

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