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Retinitis pigmentosa with visual fluctuations and arrestin gene mutation
  1. YASUSHI ISASHIKI
  1. Center for Chronic Viral Diseases, Kagoshima University Faculty of Medicine, Kagoshima-shi, Japan
  2. Department of Ophthalmology, Kagoshima University Faculty of Medicine, Kagoshima-shi, Japan
  3. Yokohama Teishin Hospital, Yokohama, Japan
  1. NORIO OHBA,
  2. KATSUAKI KIMURA,
  3. SHOZO SONODA,
  4. TOMOKO KAKIUCHI
  1. Center for Chronic Viral Diseases, Kagoshima University Faculty of Medicine, Kagoshima-shi, Japan
  2. Department of Ophthalmology, Kagoshima University Faculty of Medicine, Kagoshima-shi, Japan
  3. Yokohama Teishin Hospital, Yokohama, Japan
  1. TETSUMA OZAWA
  1. Center for Chronic Viral Diseases, Kagoshima University Faculty of Medicine, Kagoshima-shi, Japan
  2. Department of Ophthalmology, Kagoshima University Faculty of Medicine, Kagoshima-shi, Japan
  3. Yokohama Teishin Hospital, Yokohama, Japan
  1. Norio Ohba, MD, Department of Ophthalmology, Kagoshima University Faculty of Medicine, Kagoshima-shi 890-8520, Japan.

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Editor,—We report a case of retinitis pigmentosa with day to day visual fluctuations and a mutation in the arrestin gene.

CASE REPORT

A 45 year old Japanese man first noticed night blindness at junior high school age, followed by a slowly progressive loss of visual acuities and fields. At presentation, the best visual acuity was 10/200 in each eye. Goldmann perimetries revealed generalised narrowing of the peripheral field and marked loss of central visual sensitivities. Bright flash electroretinogram (ERG) in a fully dark adapted state was not recordable in either eye. Ophthalmoscopies revealed advanced stage of retinitis pigmentosa (Fig l). There was no Mizuo’s phenomenon1 in the fundus. This patient reported that he had felt relatively better vision (“good day”) on every other day that alternated with worse vision (“bad day”).

Furthermore, he claimed that bad day was repeated after physical stress or alcohol drinking, followed by a good day to return to the ordinary cycle. In our 10 years’ observation, the profile of day to day variation was reproducible. To quantitatively assess the characteristic visual symptoms, perimetric tests were performed in both the centre and periphery using an automated perimeter on eight different days in a period of 2 months, half on a good day and the other half on a bad day; ERG examinations were also performed. Figures 2 and 3 illustrate the results, demonstrating that the visual sensitivity in the peripheral field varied in a manner consistent with the patient’s reports, although not obvious in the central field. In contrast with perimetries, ERG responses remained undetectable irrespective of visual fluctuations. His healthy parents were first cousins, and his elder brother had night blindness due to classic retinitis pigmentosa. Because of the mild mental retardation, the day to day visual fluctuations or other symptomatic variations could not be confirmed in his brother.

Figure 1

Fundus in the right (A) and left (B) eye of the patient. There are diffuse chorioretinal atrophies accompanied by numerous bone spicule pigments, attenuated retinal vessels, and pale optic discs.

Figure 2

Visual field sensitivity, determined by an automated perimeter (Interzeag Octopus 101, low vision program) on different days. Representative visual field charts (right eye) obtained on a “good day” (left chart) and a “bad day” (right chart).

Figure 3

Mean sensitivity (dB) at 76 locations; the value in normal individuals of the same age as the case is around 30 dB. Open symbols (circles, right eye; triangles, left eye) illustrate measurements on four good days and closed symbols on four bad days. Visual sensitivity on good days is significantly better than that on bad days (paired t test, p <0.002).

DNA was extracted from the peripheral blood after obtaining informed consent. Exon 11 of the arrestin gene was amplified using polymerase chain reaction.2 The amplified product was separated on polyacrylamide gel and revealed abnormally rapidly migrated signal suggesting a small deletion. Direct sequencing using an automated nucleotide sequencer (ALF Express, Pharmacia) disclosed a homozygous deletion of adenine at nucleotide 1147 (1147delA). This mutation was also found in our two independent patients with Oguchi’s disease, but not in 25 unrelated cases of autosomal recessive retinitis pigmentosa or 70 healthy individuals (Fig 4).

Figure 4

Direct sequencing results of exon 11 of the arrestin gene in the reported case, demonstrating a homozygous deletion of adenine at nucleotide 1147 (arrowhead).

COMMENT

Some patients with advanced retinitis pigmentosa report that their vision is “crystal clear” in the morning but soon becomes fuzzy, and some others announce on a particular visit that their visual field testing either went well or poorly depending on whether they are having a good or bad day.3 4 The patient described here had advanced retinitis pigmentosa and reported that he had experienced over the years alternating days of good and bad vision and that the day to day visual fluctuations had been modified by physical stress or alcohol drinking. Perimetric evaluations of this case demonstrated daily variability in visual sensitivities which corresponded to the subjective complaints. This form of visual fluctuation appears unusual, and it is remarkable that this patient had such a homozygous mutation in the arrestin gene that gives rise to a premature truncation of translation. The human arrestin, also known as S-antigen, has an inhibitory role in the activated phototransduction cascade. It should be mentioned that the arrestin gene is one of those expressed in the pineal gland that is considered to play a major role in the circadian rhythm.5 Thus, it is tempting to speculate that the mutation in the arrestin gene could have modified rhythmic activities to induce daily alternating visual fluctuations in the present retinitis pigmentosa patient. The full coding sequences of the rhodopsin gene were normal in the relevant patient (data not shown). However, we could not deny the association of different polymorphisms in related gene products, or different environmental influences on the daily alternating visual fluctuations.

Recent molecular assessments revealed families with diffuse retinitis pigmentosa with or without features of Oguchi’s disease harbouring 1147 delA in the arrestin gene.6-8 The patient described here provides additional evidence that the same arrestin gene mutation is causally related not only to Oguchi’s disease but also to autosomal recessive retinitis pigmentosa. It is emphasised that our patient had classic features of autosomal recessive retinitis pigmentosa with poor visual prognosis and showed unusual visual fluctuations. In view of a rare mutation of arrestin gene, the relevant retinitis pigmentosa might be extremely rare. In a large series of white patients with aetiology of undefined retinitis pigmentosa arrestin gene mutation was not detected.9

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