Electroretinographic alterations in the Laurence-Moon-Bardet-Biedl phenotype

- ACTA OPHTHALMOLOGICA SCANDINAVICA 1996

Electroretinographic alterations in the Laurence-Moon-Bardet- Biedl phenotype Alessandro Iannaccone, Enzo M. Vingolo, Eduardo Rispoli, Giampaolo De Propris, Paolo Tanzilli and Mario R. Pannarale

Chair of Ophthalmology, Department of Ocular Electrophysiology, Center for Inherited Degenerative Retinal Disorders, University ‘La Sapienza’, Rome, Italy

ABSTRACT. Maximal 0.5-Hz and cone 30-Hz ERG responses were recorded from 19 patients showing a Laurence-Moon-Bardet-Biedl (LMBB) phenotype. Off-line averaging of 80 to 100 iterations was routinely performed. When needed, our previously described low-noise techniques and off-line fast Fourier transform procedures were used. The maximal ERG response was non-detectable in 52.6% of cases. About half of the recordable signals were below 5% of the lower normal amplitudes. Cone 30-Hz ERGS were measurable in 64.7% of cases. Of these, 63% of tracings were below 5% of the lower normal range. In most cases no dystrophic pattern was definable, due to severe reduction of both signals. Statistical analyses showed no correlation between ERG amplitudes and residual visual field areas. Clinical and electroretinographic observations suggest that retinopathy in most LMBB patients is a widespread form of degeneration, initially affecting rods but rapidly involving cones as well. However, there are also cases with a clear-cut cone-rod pattern, with fairly well preserved maximal ERG responses. The lack of correlation between maximal ERG responses and visual field residual areas, different from non-syndromic retinitis pigmentosa (RP) patients, could be related either to a low reliability of visual field testing in LMBB patients or to mechanisms accounting for the ongoing retinal degeneration in LMBB syndrome that are different from those of pure Rp. Variable findings are in line with the documented genetic heterogeneity of the syndrome.

Key words: Laurence-Moon-Bardet-Biedl syndrome - electroretinogram - retinal dystrophy - cone-rod - rod-cone - visual field.

late ataxia (Laurence & Moon 1866, Hutchinson 1900).

While systemic signs are not always found in every patient in the same pro- portion, retinal degeneration can be invariably demonstrated in each case, either from ophthalmoscopic or electroretinographic findings, and it has been suggested that an alternative diagnosis be considered in cases where retinopathy cannot be demonstrated (Schachat & Maumenee 1982). Des- pite reports describing pigmentary retinopathy as the prevailing ophthalmoscopic feature, the actual type of retinal degeneration affecting LMBB patients has not been established yet. Pre- vious investigations reported different clinical forms of retinopathy, most often with atypical features and in several instances with prominent macular involvment (Campo & Aaberg 1982, Keith 1984, Katsumi et al. 1985, Ta- zawa & Kurosawa 1988, Osuski et al. 1991). Electroretinographic studies on large groups of LMBB subjects are few, and also in this case data from the literature are far from unequivocal. Both rod-cone (Klein &Amman 1969, Campo & Aaberg 1982, Cowan & Heckenlively 1986) and cone-rod (Rizzo 111 et al. 1986) types of degenerative pattern have been claimed as the typical one for the LMBB phenotype: in most instances, however, barely detectable or totally undetectable signals have been reported (Krill et al. 1961, Ehrenfeld et al. 1970, Campo &

Acta Ophthalmol. Scand. 1996: 74: 8-13

aurence-Moon-Bardet-Biedl (LMBB) generative retinopathy. Additional fea- L syndrome is an inherited condi- tures are kidney abnormalities, identi- tion characterized, in its complete fied in virtually all patients (Churchill form, by obesity, polydactyly, mental et al. 1981, Harnett et al. 1988), dental retardation, hypogenitalism, and de- abnormalities (Kobrin et al. 1990), and

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ACTA OPHTHALMOLOGICA SCANDINAVICA 1996 -

Aaberg 1982, Fraqois 1982, Keith 1984, Luz et al. 1985, Katsumi et al. 1985, Greenet al. 1989, Jacobsonetal. 1990, Fulton et al. 1993).

We had the opportunity to examine several LMBB patients in the last few years, and this has prompted a detailed evaluation of their ocular and systemic features to try to identify recurrent as- pects in this peculiar and genetically heterogeneous condition. In previous reports (Iannaccone et al. 1993, De Propris et al. 1993) we documented that retinopathy in the LMBB phenotype is most often morphologically diffuse, with invariable severe vascular at- tenuation, mild typical pigmentary de- posits, frequent macular involvment and an unusually high prevalence of atrophic changes of the optic disc. On this occasion, we focused more on the electroretinographic abnormalities observed in our case material, trying to define the extent of retinal impairment, potential correlations with visual field residual area and other functional parameters, and possibly the type of dystrophic pattern (rod-cone or cone- rod).

Case material and Methods Nineteen patients (M = 11; F = 8) from 15 unreleted pedigrees have been examined, aged 18.5 years on average (f 7.5 SD; range 10-42 years). The age distribution was: 13 patients below 20 years, 5 patients below 40 years, and 1 older than 40. All subjects met at least three of the standard criteria for LMBB syndrome diagnosis. The main historic and associated systemic features of our case material are sum- marized on Table 1. Further clinical and functional patient-by-patient details will be object for a separate report.

Maximal ERG responses and cone ERGs were recorded from every patient using Henkes-type monopolar corneal electrodes. Pupils were dilated with tropicamide 1% drops, while patients dark-adapted for 30 minutes. Electrodes were then placed on both eyes under dim red light, after corneal anesthesia with 2 drops of 0.4% oxibu- procaine chlorhydrate solution. One or more drops of 0.2% sodium hyalu-

ronate were added before lens inser- tion (Rispoli et al. 1991). The reference electrode was placed on one ear lobe and the ground electrode on the other one, after cleaning and addition of saline jelly. A 2 cd - m2/s-intensity, 0.5 Hz-frequency white flash placed out- side of the faradic cage was used to elicit the retinal signal. Full-field stimu- lation was achieved via a fiber optic system placed into a light-proof fold- able tube going through the walls of the faradic cage. Off-line averaging of 80 to 100 iterations was the standard procedure for maximal ERG response recording. In most instances it was necessary to use our low-noise techniques (differential derivation system), as described in detail elsewhere (Ian- naccone et al. 1992, Rispoli et al. 1994). For the present methods, an amplification of the signal of X 10.000 was used (Cone1 srl IS0 A2/92 differential amplifier, Rome, Italy), with a X 50 gain at the level of the pre-amplifier and of X200 at the successive steps. Tha bandpass used for ERG recording was between 0.1 and 400 Hz, without using the notch filter at 50 Hz. The common mode rejection ratio (CMRR) of the amplifier was 2120 dB. Blinks, eye movements and other disturbances were automatically re- jected by the system.

Following 0.5-Hz ERGs, 30-Hz cone ERGs were recorded with the same electrode setting and recording system. Off-line averaging of 80 to 100 iterations was routinely performed to determine the cone response. In most cases, a fast Fourier transform analysis of the signals was also needed to identify the residual 30 Hz component.

When measurable, ERG parameters - i.e., amplitude of the signal, a-wave and b-wave latencies - were determined according to the standard criteria for clinical electroretinography (Marmor et al. 1989). ERG amplitude was expressed in microvolts (pV), and latencies in milliseconds (ms). Signals were considered as ‘recordable’ when exceeding at least twice the noise value, measured as peak-to-peak value of a separate recording of the baseline potential (averaged iterations = loo), obtained with the electrodes in place in the absence of flash stimuli (Rispoli et al. 1994). Artifacts were handled as during signal recording.

Goldmann kinetic perimetry under low photopic conditions (12.4 asb) was used to measure visual fields. Periphe- ral isopters were determined with the I4e, III4e and V4e targets. Visual field areas were measured on a conven- tional perimetry chart with a light pen and expressed in square centimeters (cm’), according to our previously described technique (Vingolo et al. 1992, Iannaccone et al. 1995). Scotomata within each isopter were then sub- tracted from the total area.

Other clinical parameters have been also evaluated according to previously described classification criteria, elsewhere described in detail (Del Porto et al. 1993). In brief, numerical gradings have been used to describe all the ophthalmoscopic and biomicroscopic features. Macular involvment has been classified according to the clinical status (macular severity score) defined on the basis of the occurrence and extent of atrophic changes, edema (cys- toid or diffuse), or wrinkling of the vi- treoretinal interface (cellophane ma- culopathy). Details on these clinical findings have been object for a separate report (De Propris et al. 1993). All these data have been statistically pro- cessed, and frequency distributions and correlations have been evaluated. Significance levels were fixed at p values of 0.01 or less.

Results Measures from both 0.5-Hz and 30- Hz ERGs for each patient are sum- marized in Table 1. Taking all findings together, maximal 0.5-Hz ERG responses were non-detectable in 52.6% of cases (10 of 19 patients). About half of the recordable signals were below 5% of the lower normal amplitudes (400 pV). B-waves averaged 78.13 p.Y spanning from 3 to 299 pV. Recor- dable ERGs showed severe delays in every instance compared to normal values. Average a-wave peak latency was 30.26 msec (k 9.34; normal range: 22.5 ms+1.5), and average b-wave peak latency was 64.34 ms (k 10.15; normal range: 44 ms f 2.5).

Cone 30-Hz ERGs were measurable in 64.7% of cases, averaging 2.18 pV (range 0.18-6.00 pV). Of these, 6 3 o/o of tracings were below 5 o/o of the

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Table 1. Summary of patients’ data: historical, functional and clinical systemic findings (N.R. = non recordable).

Case Sex Ageatex- Ageof Presenting ERG amplitude (kV) Main systemic signs and symptoms No. 30 Hz amination onset ocular symptoms 0.5 HZ

(years) (years)

1 C.O. F 42 10 night blindness

2 L.F. M 19 4 night blindness flight adversion

3 L.E. M 15 10 night blindness

4 PI. M 35 5 night blindness

5 S.A. M 18 From light aversion birth +low vision

flight adversion

N.R. N.R. N.R. N.R. N.R. N.R. N.R. N.R. 26.75 2.12 34.75 2.00 N.R. ,0.50 N.R. 1.10 N.R. N.R. N.R. N.R.

Obesity, dystrophic extremities, virilism, dysmenorrhea, microdontia, renal abnormalities Obesity, dystrophic extremities, cryptorchidism

Obesity, dystrophic extremities, mild mental retardation, cryptorchidism Obesity, dystrophic extremities, mild mental retardation, hypogonadism Obesity, dystrophic extremities, hypogonadism, renal abnormalities

6 PS. M 10 2 night blindness 163 not available Obesity, dystrophic extremities, hypogonadism

7 A.A. F 16 2 night blindness 18.0 1.30 Obesity, dystrophic extremities,

8 M.V. M 24 10 night blindness 58.7 6.0 Obesity, mild mental retardation, hypogonadism, +light adversion 52.5 5.0 cryptorchidism, microdontia, renal abnormalities

9 Z.A. M 19 2 night blindness N.R. 0.80 Obesity, dystrophic extremities, hypogonadism

207 not available

12.0 1.80 overt mental retardation, renal abnormalities

N.R. 0.40 10 L.A.

11 VF.

12 EG.

13 C.Cr.

14 C.C1.

15 B.M.

16 D.N.

17 D.V.

F 15

M 21

M 14

F 28

M 15

F 21

F 16

F 19

5

From birth 10

4

13

4

8

7

night blindness +light adversion night blindness +light adversion night blindness + side vision loss night blindness

night blindness

night blindness

light adversion

light adversion

N.R. N.R. N.R. N.R. 6.75 6.50 N.R. N.R. 6.0 7.70 N.R. N.R. 240 299 145 125

N.R. N.R. 0.60 2.00 0.70 0.35 3.16 4.32 4.60 5.80 1.25 0.50 3.50 4.00 N.R. N.R.

Obesity, dystrophic extremities, mild mental retardation, microdontia Obesity, dystrophic extremities, mild mental retardation, cryptorchidism Obesity, dystrophic extremities, mild mental retardation Obesity, virilism, dysmenorrhea, dental abnormalities Obesity, mild mental retardation, cryptorchidism

Obesity, dystrophic extremities, overt mental retardation, hypogonadism, dysmenorrhea Obesity, dystrophic extremities, mild mental retardation, renal abnormalities, late ataxia Obesity, dystrophic extremities, mild mental retardation, cardiac, renal and dental abnormalities, mild gait disturbances

18 M.F. M 11 6 low vision N.R. N.R. Obesity, dystrophic extremities, overt mental

19 D.D. F 18 3 night blindness 3.25 0.25 Obesity, dystrophic extremities, N.R. N.R. retardation, hypogonadism, cryptorchidism

+light adversion 3.0 0.18 overt mental retardation, renal abnormalities

lower normal range (50 pV). When measurable, also in this case b-wave peak latency was markedly delayed (52.14 f 5.55 ms) compared to standard reference values (32 ms f 2).

In most cases no dystrophic pattern was definable, due to extreme reduction of both signals. Only two patients (cases 16 and 17, sisters with a superimposable ocular and systemic phenotype) showed a cone-rod type of retinal dystrophy, with well preserved maxi-

mal ERG responses and absent or barely detectable 30 Hz ERGS.

Statistical analyses showed no correlation between ERG and clinico- functional parameters. Particularly, ERG amplitudes were unrelated to either one of the tested isopters of the residual visual field areas; no correlation was found between either 30-Hz amplitude or b-wave latency and, re- spectively, visual acuity, optic disc conditions, and macular clinical severity

score. The amplitude of the maximal ERG response (mean interocular amplitude for each patient) showed a weak inverse correlation with age (R = 0.313 considering all patients together, R = 0.356 if the two cone-rod cases were excluded from the analysis), not supported by statistical significance (p>0.1). No correlation at all was observed for the 30-Hz responses. Conversely, flicker cone responses tended to correlate with the age of

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onset of the symptoms (R = 0.359 for all patients, R = 0.41 excluding cone- rod patients), i.e. the earlier the onset the smaller the residual amplitude of the signal, a relation that was not observed for 0.5-Hz responses. Again, however, this trend was not supported by statistical relevance (p > 0.1).

Discussion Electroretinographic measurements revealed a very high incidence of undetectable ERGs (52.6% of 0.5-Hz responses, and 35.3% of 30-Hz signals). These figures are much higher than what we found in a study on non-syndromic RP patients with our low-noise techniques (Iannaccone et al. 1992, Rispoli et al. 1994). Thls confirmed the peculiar severity of the retinal disease in LMBB patients and precluded the definition of either a rod-cone or a cone-rod pattern of degeneration in the vast majority of cases, substantially demonstrating an equal rod and cone involvment.

In two sisters from our series we demonstrated a cone-rod pattern. However, they also showed other pe- culiarities such as central scotomas on visual field testing, generalized dys- chromatopsia, and light adversion as presenting symptom, all consistent with the observed type of retinal dis- function. A systemic distinctive feature of these two young girls was also progressive ataxia due to late-onset spastic paraparesis in one and mild gait abnormalities in the other, signs believed to be more typical of the Laurence-Moon original phenotype (Laurence & Moon 1866).

As to the type of dystrophic pattern possibly specific for LMBB subjects, data from the literature are equally non conclusive, in that most investigators found both types of ERGs already ex- tinguished at the time of examination (Krill et al. 1961, Ehrenfeld et al. 1970, FranCois 1982, Keith 1984, Luz et al. 1985, Katsumi et al. 1985, Green et al. 1989, Jacobson et al. 1990). Fulton and coworkers (1993) had 19 recordable ERGs out of 21 cases, though they were unable to define either a preferential rod or cone involvment. In fact, 58% of cases showed a rod-cone

pattern, and 26% a cone-rod type of dysfunction. A rod-cone pattern was suggested by some authors, also in view of other associated clinical features (Klein & Amman 1969, Cowan & Heckenlively 1986, Jacobson et al. 1990). Rizzo 111 et al. (1986), instead, documented an earlier impairment of cone function, followed by severe rod dysfunction as well, eventually determining nondetectable responses. These findings were interpreted as a widespread progressive retinal degeneration of the cone-rod type, consistent with the early and severe visual acuity and color vision disturbances. However, their case had other ocular and systemic features superimposable to those of cases 16 and 17 of our case material, which suggests caution in considering these hallmarks as general ones for all LMBB patients. Most probably, they represent a possible va- riant within the phenotype, and might predict the late occurrence of other severe neurologic disturbances, an as- pect shared both by Rizzo I11 et al.’s and our cases. In view of the recog- nized genetic heterogeneity of the LMBB syndrome (Sheffield et al. 1994a,b, Leppert et al. 1994, Carmi et al. 1995), cases 16 and 17 might reflect genetic bases peculiar to their phenotype, that are currently under investi- gation.

Our clinical observation of night blindness as the prevailing presenting symptom often associated to light adversion, low visual acuity and dyschro- matopsia, along with our ERG findings, suggest that retinopathy in most LMBB patients is a widespread form of degeneration, initially affecting rods but rapidly involving cones as well. This hypothesis is in line with Jacob- son et al.3 data (1990). This severe condition is worsened by the observed co-existence of severe optic nerve abnormalities in most instances (Iannac- cone et al. 1993, De Propris et al. 1993), that have been confirmed by preliminary observations on flash visual evoked potentials (unpublished data). However, it seems likely that more than one phenotype can be observed, which is again consistent with genetic heterogeneity (Sheffield et al. 1994a,b, Leppert et al. 1994, Carmi et al. 1995).

Statistical analyses showed that

both types of ERG responses are unrelated to other clinical and functional parameters in patients with this phenotype. Particularly, no clear-cut statistical correlation was found between residual maximal ERG responses and visual field areas. This finding is different from what we found on a large population of non-syndromic Rp patients (Iannaccone et al. 1995). This lack of correlation could be due to different - probably co-occurring - fac- tors. A low reliability of visual field testing in LMBB patients could be claimed, related to difficulties in keep- ing fixation due to nystagmus or low visual acuity. Also poor cooperation in mentally retarded subjects might be another crucial factor in determining visual field reliability, although this was not a major issue in our series.

However, the absence of correlation could also suggest that the underlying mechanisms accounting for the ongoing retinal degeneration in LMBB syndrome might be different from those of pure W. Different from typical FW cases, Runge et al. (1986) demonstrated histologically that both periph- eral and central phatoreceptors are severely affected in LMBB retinas. In addition, Harrison & Van Heuven (1985) observed in one LMBB patient absent electroretinographic responses with white flashes in dark-adapted conditions and at 30 Hz, while an ERG was detectable in the light adapted state. Harrison and Van Heuven suggested that this behaviour was compatible with abnormal rod-cone interactions, i.e. the presence of functioning rods re- sponsive to light adaptation, unable to generate an ERG, but possibly exert- ing a tonic inhibitory influence on the cone response. Alternatively, they also claimed post-photoreceptoral mutual phasic interactions between rods and blue cones, accounting for a subtrac- tive effect in dark-adapted conditions. It is possible that a similar mechanism could have played a role in determining the high rate of undectable maximal ERG responses found in our series. However, four of our patients were tested also in light adapted conditions, with no evidence of such unusual beha- vior (unpublished data). Additional electroretinographic and histopatho- logic investigations might provide a better understanding of these find-

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ACTA OPHTHALMOLOGICA SCANDINAVICA 1996

ings, and will be object for investiga- tion in the next future.

When cone-rod cases were excluded from statistical analyses, some degree of correlation was observed between maximal ERG responses and age at the time of examination, and between 30-Hz cone ERGs and age of onset of the disease as assessed on historical grounds. Despite absence of statistical significance, this suggests that retinal function as a whole is not congenitally absent - or nearly so - in most LMBB patients (which would have show no possible correlation with age), and that deterioration of retinal responses could progress further over time. The fact that only the 30-Hz responses tends to be correlated to the age of onset could imply that rods might actually be the ones to be congenitally non-functioning, while cones might be degenerating shortly after. This might happen as a secondary phe- nomenon, or due to genetic defects affecting both photoreceptor popula- tions but phenotypically expressed earlier in rods. Unfortunately, pure rod responses were not recorded in this study, and therefore we are unable to tell whether rods alone might still be contributing to ERG responses in some instances (e.g., cases 3,6 or S), or if recorded signals were invariably generated solely by severely diseased cones.

As genetics of LMBB syndrome will be progressively clarified, better defined genotype-phenotype correlations will be possible both at the ophthalmological and systemic level. These informations, along with early longitudinal observations on patients with detectable ERGs, will allow a better classification of this condition and a more precise identification of reliable prognostic criteria.

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Received on November 28th, 1994.

Corresponding author: Alessandro Iannaccone, M D Via Arturo Graf 40 1-00137 Rome, Italy. Temporary address (August 1995-96): University of Pennsylvania Scheie Eye Institute (6th floor) 51 N. 39th Street (Myrin Circle) Philadelphia, PA 19104, USA.

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Electroretinographic alterations in the Laurence-Moon-Bardet-Biedl phenotype