British3'ournal ofOphthalmology 1994; 78: 353-358

Ocular manifestations in autosomal dominantretinitis pigmentosa with a Lys-296-Glu rhodopsinmutation at the retinal binding site

Sarah L Owens, FrederickW Fitzke, Christopher F Inglehearn, Marcelle Jay, T Jeffrey Keen,Geoffrey B Arden, Shomi S Bhattacharya, Alan C Bird

Moorfields Eye Hospital,LondonS L OwensM JayG B ArdenA C Bird

Institute ofOphthalmology, LondonFW Fitzke

Molecular GeneticsUnit, Department ofHuman Genetics,University of Newcastleupon TyneC F InglehearnT J KeenS S BhattacharyaCorrespondence to:Professor A C Bird,Professorial Unit, MoorfieldsEye Hospital, City Road,London EC1V 2PD.Accepted for publication21 December 1993

Figure I Kindred -

Moorfields RP959. Circles:females. Squares: males.Filled symbols: affectedmembers. Arrow indicatespropositus. Single diagonalindicates death. Crossindicates death in infancy.Lozenge indicatesmiscarriage. V-6 has theabnormal genotype.

AbstractA lysine to glutamic acid substitution at codon2% in the rhodopsin gene has been reported ina family with autosomal dominant retinitispigmentosa. This mutation is of particularfunctional interest as this lysine molecule is thebinding site of 11-cis-retinal. The clinicalfeatures of a family with this mutation havenot been reported previously. We examined14 patients with autosomal dominant retinitispigmentosa and a lysine-296-glutamic acidrhodopsin mutation. Four had detailedpsychophysical and electrophysiological test-ing. Most affected subjects had severe diseasewith poor night vision from early life, andmarked reduction of visual acuity and visualfield by their early forties. Psychophysicaltesting showed no demonstrable rod functionand severely reduced cone function in allpatients tested.(BrJ Ophthalmol 1994; 78: 353-358)

Since the initial localisation ofa gene defect to thelong arm of chromosome 3 in a family withautosomal dominant retinitis pigmentosa,'numerous mutations in the rhodopsin gene havebeen described. The first was a cytosine toadenine transversion in codon 23 resulting in a

proline to histidine substitution.2 A large numberof different rhodopsin mutations have now beenidentified.`8To date, the clinical features of autosomal

dominant retinitis pigmentosa families with ninedifferent rhodopsin amino acid substitutions or

deletions have been reported.9'7 Both quantita-tive and qualitative differences have beenrecorded with different rhodopsin mutations. In1991, Keen and colleagues described a familywith autosomal dominant retinitis pigmentosadue to a lysine to glutamic acid substitution at the296 codon on the rhodopsin gene.7 The 296position is of interest as it is the binding site of1 1-cis-retinal,'8 which initiates the transduction

RP959 ADRP

IV iv 6b 6 66bVI

process. Predictions are possible concerning theeffect of such a mutation on photoreceptormetabolism.

In this report, the ocular features and results ofdetailed psychophysical and electrophysiologicaltests in patients with this disorder are described.

Materials and methods

SUBJECTSThe proband IV-7 was identified by a BritishRetinitis Pigmentosa Society questionnaire. Thecomplete kindred is shown in Figure 1. Sixgenerations were documented with approx-imately 50% of those at risk of having theabnormal gene being affected in each generation,males and females were affected equally, andthere was male to male transmission. Thesefindings implied autosomal dominant inheri-tance with complete penetrance.In August 1990 all available family members

were reviewed (Table 1). Each affected familymember had an ocular examination includingvisual acuity, confrontation visual fields, andindirect ophthalmoscopy. All affected membershad typical fundus features of retinitis pigmen-tosa: optic nerve pallor, retinal vascular attenua-tion, and peripheral neurosensory retinalpigmentation with macular sparing. After theexaminations were completed, 10 ml of peri-pheral blood were taken from each person andplaced in potassium ethylenediaminetetra-aceticacid. Blood samples were taken from 10 affectedand five unaffected family members, as well asone spouse. Details of the DNA analysis havebeen published in a separate report.7The functional loss was characterised in four

affected family members with a visual acuity of6/60 or better using the following techniques:

(1) Photopic visual Jields. Kinetic Goldmannvisual fields or Humphrey visual fields wereperformed in the standard fashion.

(2) Dark adapted visual fields. The pupil wasdilated with phenylephrine 2 5% and cyclopen-tolate 1 0%, and the patient was dark adapted forat least 45 minutes. The Humphrey field analyser(Allergan Humphrey, Hertfordshire) was modi-fied for use in dark adapted conditions.'9 Aninfrared source illuminated the bowl, and aninfrared monitor (Phillips, Eindhoven, Holland)was used to detect eye movements. Fields wererecorded using programs central 30-2, peri-pheral 30/60-2, macula, and custom macula 49.The target size corresponded to Goldmann size

V for peripheral testing and to Goldmann size IIIfor macular programs. Each program was per-

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Table I Historical information

Onset Onset Onset Age atnight decreased decreased cataractblindness side vision reading extraction

Patient (years) (years) vision (years) (years)

III-5 Birth Unknown Unknown Unknown111-13 Birth Birth 33 54III-21* Birth 15 15 56IV-2* Birth 37 37 40IV-4 Birth 30 33 39IV-5 Birth 5 33 33III-18 Birth Birth Unknown UnknownIV-7 Birth 25 25 28IV-8 Birth 40 - -III-19 Birth Unknown Unknown UnknownIII-23 Birth Unknown 47 51IV-9 Birth 37 37 40IV-10 Birth 25 25 27V-6 Birth - - -

V-7 Birth - - -

IV-11 Birth 25 26 -

IV-12 Birth 17 17 -

*Information from telephone interview.

formed with both a red (predominant wavelength650 nm) and blue (predominant wavelength450 nm) filter in the stiumuls beam.

(3) Dark adaptometry. Results of the darkadapted blue central 30-2 fields were reviewed todetermine the most informative locations ofdarkadapted visual sensitivity. Ideally, test locationswere outside the central 90 with sensitivitieshigher than 20 dB. Ifno such point fulfilled thesecriteria, a location inside 9° was used. TheHumphrey field analyser was used for darkadaptometry, and it was controlled by a customprogram on an IBM PS/2 model 50 computer asdescribed.2021 Fully dark adapted rod thresholdswere measured at two coordinates with the bluefilter in the stimulus beam.

(4) Fundus reflectometty. Fundus reflectometrywas used to measure reflectance levels ofthe lightadapted eye compared with the dark adapted eyeusing published methods.22 This provided aquantitative estimate of rhodopsin regeneration.

(5) Electroretinography. In patients IV-8,IV- 1, and IV-12, the electroretinogram wasobtained with silver-silver chloride reference andground electrodes, a gold foil electrode placed inthe lower fornix, and a stroboscopic flash

Table 2 Results ofocular examination

CentralAge Visual Visual Pigment choroidal

Patient (years) Sex acuity fields deposits atrophy

III-5 70 Female LP 0 +++++III-13 70 Female NLP 0 +++ +IV-4 43 Female CF 0 + +IV-5 39 Female CF 5 +III-18 65 Female 6/24 2 + +IV-7 45 Female HM 0 +++ +++IV-8 44 Male 6/12 25 +III-19 69 Male 6/60 2 + + +III-23 68 Female 6/18 0 +IV-9 42 Female 6/12 2 +IV-10 40 Female 6/6 2 (*)+V-6§ 21 Female 6/9V-7 18 Male 6/9 75 (*)+IV-11 27 Female 6/12 25 +IV-12 22 Female 6/18 25

+++=severe.+ + =moderate.+=mild.- =absent.NLP=no light perception.LP=light perception.CF=count fingers.HM=hand movements.(*)=additional white subretinal deposits.S=Subject V-6 has declined to be examined further.

stimulus.23 Patient V-7's electroretinogram wasobtained with a Ganzfeld stimulator lined withgreen (550 nm) and red (660 nm) light emittingdiodes.24

(6) Colour vision testing. This was performedusing a television stimulator and computergraphics system.25 26

(7) Fundus photography. Colour fundus photo-graphy of the disc, macula, and periphery wasperformed with a Zeiss fundus camera.

ResultsThe majority of patients in this family had severevisual compromise at an early age. However,there were exceptions to this. Two familymembers (V-6 and V-7) denied that they wereaffected initially since they had less visual diffi-culty than other family members with thedisease. However, on repeated questioning it wasevident that their night vision was poor fromearly life but they had little trouble by day.Another family member was reported to havesufficient vision to repaint his house at the age of62 years.No patient remembered having good vision at

night. They noticed decreased side vision anddecreased daytime or reading vision at about theage of 30 years. Most had cataract extractions intheir thirties, but there was little if any post-operative improvement in visual acuity. Severereduction in central vision (count fingers, handmotions, light perception level) was typical intheir early forties (Tables 1 and 2).Four patients were evaluated at Moorfields

Eye Hospital. Testing revealed similar results inall four cases (Tables 3-4). Cases 3 and 4 arerepresentative and are presented in detail.

CASE 3Family member IV-12, age 22, never had nightvision. Loss of side vision was noticed by the ageof 17 years, associated with a mild decrease inreading vision. She had worn spectacle correc-tion since the age of 5 years.

Table 3 Light adapted visualfield size and dark adaptedsensitivities in decibels usingHumphrey visualfields, central30-2. Normal values: red, 25-35 dB; blue, 42-53 dB

Sensitivies

Visual Red Red Blue Blue Bluefield 30 90 30 90 >90

IV-8 250 10 0 4 0 0IV-11 250 15 0 13 0 0IV-12 250 26 13 13 3 0V-7 40° 20 8 10 0 0

Table 4 Dark adaptometry

Prebleach log intensity Vtarget (dB)

ConePoint Point Rod duration

Patient one two break (min) Comments

IV-8 31 32 No 30 Rapid decline toprebleach levels

IV-12 24 25 No 30 Typical contourof cone darkadaptation

V-7 45 45 No 40 Rapid decline toprebleach levels

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Figure 2 Dark adaptationcurve ofpatient IV-12(large symbols) after stronglight adaptation showingnormal cone adaptation butabsence ofany recorded rodadaptation. Small symbolsrepresent a normal recovery.The time constant, c, wasdetermined to be 2 3 minutesindicating a normal timecourse ofcone recovery. 17

50 60 70 80 90 100 110 120

Time (minutes)

With +3 50 correction visual acuity was 6/18with the right eye and 6/9 with the left. Thelenses were clear, and there were few vitreouscells. There was mild optic nerve pallor andretinal vascular attenuation. The peripheralretinal pigment epithelium had a mottled appear-ance without pigment migration into the retina.Cystoid macular oedema was present, which wasgreater in the right eye than the left. There wasno choroidal atrophy.Goldmann visual fields showed marked gener-

alised constriction and measured 25° with theV4e target (Table 3).Dark adapted sensitivities to red and blue in

the left eye central 30-2 program showed meanvalues of 26 dB and 13 dB, respectively, at the 30locations. (Normal values for red, 25-35 dB, andfor blue, 42-53 dB.) The 90 locations revealedmean values of 13 dB red, and 3 dB blue. Darkadapted red fields showed few functioning loca-tions outside 210. On dark adapted blue fieldtesting the target was not seen outside 90 (up toand including 600) at all standard points tested.There were no fixation losses, false positives, orfalse negatives (excellent reliability indices)(Table 3).Dark adaptometry was tested at coordinates

3,3 and 3,-3. Prebleach thresholds to the V

target were elevated to 24 dB and 25 dB,respectively. A normal cone portion of the darkadaptometry curve was found; prebleach thres-holds were reached in 10 minutes (Fig 2). Darkadaptometry was continued for 30 minutes.There was no cone-rod break and no identifiablerod portion (Table 3).The ERG showed no recordable response.

CASE 4Family member V-7, aged 18 years, was ofparticular interest to us. At the time ofthe familysurvey, he denied symptoms. On repeat ques-tioning he reported some difficulty at night but toa lesser degree than the rest of his family. Hedenied loss of side vision or daytime visualdifficulty. He had worn hyperopic spectaclecorrection since the age of6 years, and amblyopiaof the left eye was diagnosed aged 6 years whichhad been treated by patching of the right eye.On examination, visual acuity with +4 50

spectacles was 6/6 with the right eye and 6/9 withthe left. There was a variable 8° to 120 leftesotropia. No cataracts were present. There weremany vitreous cells. The fundus showed mildoptic nerve pallor and retinal vascular attenua-tion. There was limited pigment migration intothe retina and widespread white subretinaldeposits (Fig 3). No cystoid macular oedema orcentral choroidal atrophy was seen.

Light adapted central 30-2 and peripheral30/60-2 fields were performed in the right eyewith theV white target. They were relatively fullexcept for nasal depression between 400 and 600(Fig 4 A-D, Table 3).Right eye central 30-2 dark adapted red fields

showed wide-spread diffuse depression. Meansensitivity values obtained were 20 dB at 30 and 8dB at 90 (Fig 4 E, F). Central 30-2 and peripheral30/60-2 dark adapted blue field showed noresponse throughout, with the exception of thecentral 30 which showed a mean value of 10 dB(Fig 4 G H, Table 3). Reliability indices wereexcellent.

Pre-bleach dark adaptometry thresholds to theV target at points 3,-3 and -9,-9 were 45 dB at

Fig 3A Fig 3B

Figure 3 Fundus photographs, left eye, patient V-7 showing attenuation ofblood vessels (A) and pigment migration into theretina in the mtdperiphery (B).

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Figure 4 Humphrey visualfields, right eye, patient V-7. (A, B) Light adapted central 30-2. (C, D) Light adaptedperipheral 30160-2. (E, F) Dark adapted central 30-2 red. (G, H) Dark adapted central 30-2 blue. (A, C, E, G show grey

scale; B, D, F, H show numerical sensitivity values.)

both locations. Post-bleach values returned toprebleach levels in 10 minutes. Dark adaptome-try was continued for 40 minutes but there was

no identifiable rod portion (Table 3).Fundus reflectometry showed no measurable

rhodopsin; however, small amplitude nystagmushindered measurement.The ERG showed very attenuated responses

(Fig 5). With the green flashes, there was a

response peaking at about 175 ms, with an

amplitude graded with light intensity. The mini-mum response of 3 RV was obtained with an

intensity 300 times greater than that whichevokes a minimal b-wave in a normal eye. Noa-wave was seen. The red flash responses show a

small cornea negative response, beginning about75 ms following the flash, and the size of thisresponse is also graded with light intensity. Thenegativity is analogous to the threshold responsefor rods (the scotopic threshold response).27 Withred flashes, a cone generated response can berecorded, the photopic threshold response.24 Theflash intensity required to evoke this responsewas about 10 times greater than in normalsubjects. The most intense flash evoked a smallcone b-wave but this peaked at 150 ms, a very

delayed cone response. With a background light,no responses were recorded.Colour vision testing of the right eye showed

normal thresholds within the central 10; outsideI' the thresholds were elevated. Testing at 100showed absent tritan colour vision and grosschanges along other colour confusion lines.

DiscussionThe lysine-296-glutamic acid mutation in therhodopsin gene causes a severe form of retinitispigmentosa. All patients had a lifetime of poornight vision. There was relative sparing of day-time vision early in the disease, a feature charac-teristic of type I or diffuse retinitispigmentosa.2" By the fourth decade of life therewas reduction ofcentral vision, severe visual fieldconstriction, and lens opacification. Althoughthe visual prognosis was universally poor, some

variability ofdisease expression was detected as iscommon in autosomal dominant disease. Thedisease is more severe than that seen with themutations glutamic acid-344-stop, arginine-135-leucine and arginine-135-tryptophan, and lacksthe altitudinal distribution of disease seen with

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threonine-58-arginine, glycine-106-arginine,threonine-17-methionine, and glycine-182-serine. 1317

Psychophysical and electrophysiological testscorroborated the severity of disease. Darkadapted Humphrey visual fields with the bluetarget, a test specific for rod function, showedthreshold elevations ofmore than 4 log units andno measurable rod function even in the patientwho claimed some residual night vision. Conethresholds were also elevated in all patientsexcept in the central 3°. Patient V-7 had a nearlynormal central light adapted cone sensitivity, but'with dark adaptation the cone thresholds were

elevated 1-2 log units. This is explained bypersistence of cone mediated contrast detectionin the light adapted state, but a loss of absolutecone sensitivity in the dark adapted state. Theelectroretinogram showed no rod or coneresponse in three patients, and a severely attenu-ated and delayed cone and rod response in thefourth. Despite the severity of rod and conephotoreceptor dysfunction in this disease, thereis some evidence in case 4 that rods are affectedprimarily.The metabolic disturbance at the cellular level

caused by the presence of a mutant gene may bedue to two possible mechanisms. Ifthe abnormalprotein does not pass through the rough endo-plasmic reticulum to the outer segment, any loss

of function of rhodopsin would be caused byreduced availability of rhodopsin during discmembrane formation. If the mutant rhodopsindoes not reach the outer segment, the consequentdisease is likely to be identical, regardless of thespecific rhodopsin mutation. A secondmechanism of cellular dysfunction would beconsequent upon the abnormal rhodopsin pass-ing into the outer segment, its presence disrupt-ing outer segment metabolism.3' In general, thelatter appears to be a much more likely given thevariability of disease from one family to anotherwith different mutations in the rhodopsin gene.

If the abnormal protein were incorporated intothe outer segment disc membrane it would bepossible to construct a hypothesis concerning theeffect this may have on cell function. In theheterozygous state, the outer segment wouldcontain two different rhodopsin populations:normal rhodopsin from the normal gene andmutant rhodopsin. It might be assumed that a

rhodopsin mutation involving the 1 1-cis-retinalbinding site might effectively stop transduction.However, an experimental membrane assay withthe lysine-296-glutamic acid rhodopsin mutationhas shown that abnormal protein will not bind1 l-cis-retinal, and that it reacts constantly withtransducin [D Oprian, personal communica-tion]. If the mutant rhodopsin behaved in thisway-i-nthe outer segment,. it is predictable that

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Figure 5 (A) Electroretinogram, right eye, patient V-7 usinggreenflash showing progressive increase in b-wave with increaseflash intensity. B-wave is small compared with normal, and is markedly delayed. Lowest trace: 0;1*second trace: 0 3; thirdtrace: I 0; fourth trace: 3-3;fifth trace: 33 0 quanta absorbed/receptorlflash. Vertical divisions equal 10 [tV; horizontaldivisions equal 25 ms. (B) Electroretinogram using redflash, the photopic and scotopic threshold responses are seen at highintensity implying marked desensitisation to red light. Lowest trace: 0 47; second trace: 2-83; third trace: 8S50 quantaabsorbedlreceptorlflash. Vertical divisions equal S lV; horizontal divisions equal to 25 MS.24

the retina would act as if it were in constant lightand would not dark adapt. This would result in a

markedly reduced scotopic sensitivity owing tothe presence of the mutant protein, and yet thenormal rhodopsin would bleach and regenerate.This would be measurable if there were notextensive loss of rod outer segment volume ormassive photoreceptor cell death.Fundus reflectometry, an indirect assessment

of rhodopsin levels, showed no measurablerhodopsin in one patient. This may have beendue to the confounding factors of reduced reflec-tance and the small amplitude nystagmus hinder-ing measurement. Examination of a less severelyaffected individual may resolve the question offunctional implications ofthe Lys-296'Glu muta-tion.

Supported in part of grants from British Retinitis PigmentosaSociety, National Retinitis Pigmentosa Foundation FightingBlindness USA, and Wellcome Trust. Dr Owens was supported asa Wolfson fellow.

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