Ocular findings in the Laurence-Moon-Bardet-Biedl syndrome

- ACTA OPHTHALMOLOGICA SCANDINAVICA 1996

Ocular findings in the Laurence- Moon-Bardet-Biedl syndrome Ruth Riise', Sten Andr6asson2, Alan F. Wright3 and Kristina Tornqvist2

Department of Ophthalmology', Central Hospital of Hedmark, Hamar, Norway Department of Ophthalmology2, University Hospital of Lund, Sweden M.R.C.3, Human Genetics Unit, Western General Hospital, Edinburgh, Scotland

ABSTRACT. Purpose: To improve the description of the ocular part of the Laurence-Moon- Bardet-Biedl syndrome. Methods: We examined 44 Scandinavian individuals who all had retinal dystrophy plus at least 2 more of the traditional cardinal signs of the syndrome: obesity, hypogenitalism, polydactyly and mental retardation. Results: Full-field electroretinograms were obtained in 36 of the individuals and were abnormal in all. The dark adaptation thresholds were elevated by on average 3.5 log units. Symptoms of night blindness were observed at a mean age of 4 years and visual problems at daytime at 6-7 years. No one exceeding the age of 16 had a best corrected visual acuity of more than 0.1. In the fundus attenuated vessels were noted at all ages while macular pigmentations and a wax-pale optic disc appeared at age 6-7 years. Pigmentary changes in the midperiphery were noted at the earliest at 13 years of age and appeared mainly as bone spicules, however, in a minority of cases the pigmentations were atypical. Ten of the participants had been followed through a period of 9 years. Their visual acuity was reduced by on average 0.3 line (decimals) and the angle of visual fields by approximate 3 degrees (Goldmann standard object V: 4e) per year through the adolescence. Conclusion: The ocular disease in Laurence-Moon-Bardet-Biedl syndrome presents early, the prognosis for visual function is poor and the fundus features are atypical and varying.

Key words: Laurence-Moon-Bardet-Biedl syndrome - Bardet Biedl syndrome - retinitis pigmentosa - retinal dystrophy.

Acta Ophthalmol. Scand. 1996: 74: 612-617

aurence-Moon-Bardet-Biedl (LMBB) L syndrome is an autosomal recessive inherited disorder with a prevalence varying between 1/160.000 (Klein & Am- mann 1969), 1/128.000 (Lofterd et al. 1990), 1/59.000 (Haim 1992) and 1/17.500 (Green et al. 1989).

Traditionally, the LMBB syndrome has been described as having the follow- ing cardinal features: retinal dystrophy, obesity, hypogenitalism, mental retardation (Laurence & Moon 1866) and polydactyly (Bardet 1920; Biedl 1922). A variation of additional features has been identified: neurological disease (Hut- chinson 1900; Rizzo et al. 1986; Lavy et al. 1995), renal disease (Churchill et al. 1981; Harnett et al. 1988), diabetes mel-

litus (Alstrom et al. 1959; Escallon et al. 1989), nerve deafness (Burn 1950; Alstrom et al. 1959), cardiac anomalies (Elbedour 1994), liver disease (Pagon 1982), dental anomalies (Kobrin et al. 1990; Lofter~d et at. 1990; Borgstrom et al. 1996) and anomalies of hands and feet (Rudling et al. 1996).

Clinical and genetic heterogeneity has been documented (Green et al. 1989; Kwitek-Black et al. 1993; Leppert et al. 1994; Sheffield et al. 1994; Carmi et a]. 1995; Riise et al. 1995).

Retinal dystrophy is a sine qua non in the LMBB syndrome irrespective of whether the syndrome is separated into the subgroups Laurence-Moon, Bardet- Biedl and Alstrom syndromes (Schachat

& Maumenee 1982) or kept within a broadly based phenotype (Rizzo et al. 1986;Kobrinet al. 1990;Riiseet al. 1995).

Unfortunately, most LMBB cases remain undiagnosed until school age (Sku- seth 1985), a fact of concern since the retinal dystrophy gives clinical signs at an early age and has a poor visual prognosis (Riise 1987; Fulton et al. 1993).

We have collected 44 patients with the LMBB syndrome in order to give a de- tailed ophthalmological description of the phenotype. Ten of our patients were followed through a 9-year prospective study of visual acuity and visual fields in order to quantify the visual prognosis.

Material and Methods Fourty-four Scandinavian (Denmark 11, Norway 20, Sweden 13) individuals with retinal dystrophy plus at least two more of the traditional cardinal signs of the LMBB syndrome attended a one-day outpatient ophthalmological examination at the University Eye Clinic in Lund, Sweden. The participants in the study were found and contacted through the Swedish and Danish W-registers, the Swedish Register of Visually Impaired Children and the Norwegian LMBB As- sociation.

The group investigated consists of 24 males and 20 females with a mean age of 24 years (range 3-57) belonging to 30 families. Eleven of the families have 2-3 affected members. All the participants could be classified into the Bardet-Biedl subgroup, however, five of these also had features (paraparesis or diabetes f deafness) typical for the Laurence-Moon or the Alstrom subgroup.

The study is part of a multidisciplinary project involving specialists in ophthalmology, electrophysiology, pediatrics,

612

ACTA OPHTHALMOLOGICA SCANDINAVICA 1996 - Visual acuity

1.0 r

0.5

. . , . . . . , . . -*- % Observed night blindness

-. 0 -. % Observed visual problems of daytime . . . . . .

L * --

4 * .

* *

0 1 2 3 4 5 6 7 8 9 1 0 1 1 1 2 1 3 1 4 1 5 1 6 1 7 Age

Fig. 1. The distribution of the age at time for first observation of night blindness and visual impairment during daytime in 44 individuals with the LMBB syndrome.

45 - 40 - 35 - 30 -

s 5 25- - r

g 20- ar

odontology, radiography and molecular genetics.

The ocular examination included as- sessment of corrected visual acuity of both eyes measured by optotypes or grat- ings and expressed in decimal fractions.

Refraction was measured by cyclo- plegic retinoscopy and expressed in spherical equivalents by adding one-half of the cylindrical correction.

Slit-lamp examination and ophthal- moscopy were supplemented by fundus photographs. Intraocular pressure was measured by applanation tonometry in those older than 45 years. Visual fields were evaluated by Goldmann kinetic per- imetry and expressed by the mean of horisontal and vertical angles from the fixaton points of the two eyes minus the angle of any scotomas for the isopter generated by the standard object V4e.

Dark adaptation threshold was measured by Goldmann-Weekers adapto- meter after 40 min dark adaptation and expressed in log units of deviation from the normal.

Colour vision was examined by the Farnsworth D-15 test. Full-field electroretinography was registered in a Ni-

Table l. The first clinical sign of retinal dystrophy in 44 individuals with the LMBB syndrome.

First ocular symptom No. of patients

~~~~ _ _ _ ~ ~

Night blindness 26 Visual problems at daytime 6 Problems simultaneously night and day 10 No symptoms 2

I

0.05 O” i * *

* * * -- * HM/LP

0 10 20 30 40 50 60 HM = Hand Movements Age (years) LP = Light Perception

Fig. 2. Visual acuity in the right eye as function of age in 44 individuals with the LMBB syndrome.

I

.t! _ . . . LMBB . . _ . . . . . . . . . . . . . . . . . . . . .

X Reference

2.

-9.0 -8.0 -7.0 -6.0 -5.0 -4.0 -3.0 -2.0 -1.0 0 +1.0 +2.0 t3.0 +4.0 +5.0 +6.0 +7.0 +8.0

Spherical equivalent (D)

Fig. 3. The refraction of both eyes expressed in spherical equivalents in 44 individuals (from 30 families) with the LMBB syndrome and a reference curve based upon 2832 eyes in 1416 Danish individuals (Fledelius 1983).

colet Compact Four analysis system as described elsewhere (Riise et al. 1996).

The data were supplemented by information from the patients and their rela- tives and from hospital and school rec- ords.

Results Clinical signs Onset of symptoms: Information on the age of onset of night blindness and/or visual problems during daytime was obtained in all patients. Night blindness was the first ocular symptom or appeared simultaneously with visual impairment in bright light in 36 cases. However,,in 6 patients visual problems at daytime appeared first and in 2 children, 6 and 7 years old, no visual problems were observed. (Table 1). The mean age for the

first observation of night blindness was 4 years (SD 3.2, range 0-16) and for visual problems during daytime 6.4 years (SD 3.4, range 0-16) (Fig. 1).

Two siblings were extremely photo- phobic from the age of 2.

Visual acuity: The best corrected visual acuity of the best eye was better than 0.1 in only 14 persons, and the oldest in this group was 16 years. The degree of visual impairment was strongly related to age especially during adolescence as shown in Fig. 2.

Nystagmus: Nystagmus with both horisontal and vertical components was seen in 27 of the individuals with a mean age of 30 years, while those without nystagmus had a mean age of 14 years.

Refraction: The spherical equivalent of refraction of both right and left (N = 88)

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50- 45-

40- 35- 30- 2 5

The mean angle of 15.

10 - visual field of the two

5- 44 individuals with

Fig. 4. 20-

eyes related to age in

eyes is shown in Fig. 3 together with a reference curve for the general Danish population (Fledelius 1983). There is a significant (p = 0.02, Chi-square test) dominance of myopia defined as a spherical equivalent of - 1.0 or higher. If only one member (the oldest) from each family is included, in order to omit influence of other genetically determined causes of refractional errors, the same trend is seen, but the dominance of myopia is not significant (p = 0.2, Chi-square test).

Irztrnoculur pressure: IOP measured in

0 . . . .

. 0 .

0 . 0

. . .

. .

Fig. 5. Pale optic disc, attenuated vessels, macular pigmentation and a few bone corpuscles in an 11 year-old boy with the LMBB syndrome.

Fig. 7. Pale optic disc, macular pigmentations and bone spicuies in the mid-periphery in a 23 year-old female with the LMBB syndrome.

Fig. 6. Bull’s eye macular change in a 33 year old patient with the LMBB syndrome. There is a central island of darker coloured pigment epithelium surrounded by a circle of pigment epithelium atrophy.

Fig. 8. Tigroid fundus with peripapillary choroidal atrophy and atypical pigmentations in the midperiphery in a 33 year-old male with the LMBB syndrome.

- 614

ACTA OPHTHALMOLOGICA SCANDINAVICA 1996 -

Visual acuity

“O 1

HMiLP -I

0 10 20 30 40 50 60

HM = Hand Movements Age (years) LP = Light Perception

Fig. 9. Visual acuity of the right eye through 9 years in 10 individuals with the LMBB syndrome.

Angle of visual field

0 2 4 6 8 1 0 1 2 1 4 1 6 1 8 M 2 2 2 4 2 6 2 8 3 0 3 2 3 4 Age

Fig. 11. The mean angle of visual fields of right and left eye through 4-9 years in 9 individuals with the LMBB syndrome.

those, who were more than 45 years old, was normal.

individuals and only 2 patients, 9 and 10 years old, had a smaller difference.

Visual fields: Eighteen individuals with an average age of 16 (range 6-35) years could be tested with the standardized object V 4 e (Fig. 4), and 5 of these could also be tested with I:4e. Only 3 persons had visual fields for V:4e greater than 35 degrees.

Electroretinography: Full-field electroretinograms were obtained in 36 individuals and showed early loss of signals from both rods and cones, and the amplitudes were reduced in all who could be tested. The results in detail are being published separately (Riise et al. 1996).

Dark adaptation: The thresholds, meas- urable in 23 individuals with a mean age of 21 years (range 6-38), wereelevated in all. The difference was 3-4 log units in 21

Colour vision: Colour vision could be tested in 7 persons and was normal in 5, all under the age of 9 years. The remaining 2 patients had elements of both tritan and deutan defects.

Iris, lens and vitreous: Iris was normal in all individuals. A posterior capsular star shaped cataract was noted in 23 persons, the youngest 16 years old. Synchisis scin- tillans, corpuscles or posterior vitreous detachment were registered in 14 individuals a11 above the age of 15 years.

Fundus: The ophthalmoscopic findings are listed in Table 2. We found attenuated retinal vessels in all. A wax-pale optic disc was noted in 38 persons, the youngest at the age of 7 years. Pigment in the macula was registered in 39 cases - the youngest at 6 years of age - appearing as ‘dust’ or

‘grains’ (Fig. 5). In the adult persons we saw examples of ‘bull’s eye’ (Fig. 6) and cases where the pigments were dispersed throughout the fundus with no possibility to separate the macular region. Bone spicules were registered in 27 cases (Fig. 7) - the youngest at 13 years of age. In 6 Danish and 2 Norwegian patients, however, the pigmentations were atypical round and ‘amorphous’ eventually combined with a tigroid fundus (Fig. 8). We found no differences between affected sibs when age was taken into consider- ation. Course of the disease The corrected visual acuity measured in 10 persons through 9 years is shown for the right eye as function of age in Fig. 9.

Six individuals, who were able to read optotypes through the whole observation period, lost on average one decimal line in 3 years.

The visual field of the right eye in the same patient at age 9 and age 18 is shown in Fig. 10. The visual fields for object V:4e measured in 9 persons through 4-9 years is shown related to age in Fig. 11. The loss of fields during adolescence was on average 3 (range 1-6) degrees per year. Two persons over the age of 20 years had mini- mal but stable fields during the observation period. ; Genetic linkage mapping Eleven families with 2-3 affected siblings were included in a study of linkage mapping in a larger material of LMBB syndrome families (Wright et al. 1995). The statistical significance of the result for the single family was, however, restrained by the small number of family members. A Lod score of 3 or more was obtained in only 2 families, both mapped with linkage

615 -


to the BBS4 locus in chromosome 15. We could not find any common characteris- tics separating the 4 LMBB cases in these 2 families from the remaining cases with respect to fundus morphology, refraction or the course of the disease. However, the fundus morphology was consistent in the affected members within the single family.

Discussion Although the patients in this study repre- sent a selection of the Scandinavian patients with the LMBB syndrome, it is our impression that they are representative of those patients who are diagnosed clini- cally. Our results are based upon adequ- ate cooperation of the patients with respect to both information and examination.

The diagnosis was made by other specialists before the patients attended our study. Twenty-five of our patients had four or more of the traditional cardinal symptoms. The individuals with less than four cardinal symptoms were nearly all women where no hypogenitalism or mental retardation was diagnosed. We pre- ferred the broadly based phenotype con- cept, the LMBB syndrome, since we found examples of overlapping between the Bardet-Biedl and the Alstrom or Laurence-Moon subgroups. Other auth- ors have described similar conditions (Rizzo et al. 1986; Escallon et al. 1989; Hauser et al. 1990; Nyska et al. 1991).

Our patients have an atypical retinal dystrophy defined by the initial sign of pigmentation of the macula in addition to attenuated vessels and vax pale optic discs (Newsome 1988) (Table 2). Fur- thermore, the later appearing pigments in the midperiphery are not always bone spicules but sometimes round aggrega- tions of pigment. Our documentation of the variations of the fundus morphology confirms the findings described by Klein & Ammann (1969), Green (1989) and

Table 2. The ophthalmoscopic findings in 44 individuals with the LMBB syndrome.

Features of fundus No.of Age patients range

Attenuated vessels 44 3-57 Pale optic disc 38 7-57 Macular pigmentations 39 6-57 No peripheral pigmentations 9 3- 10 0 - 10 bone spicules 3 13-15 > 10 bone spicules 24 11-57

Atypical peripheral pigmentations 8 20-39

Haim & Rosenberg (1993). It has been claimed that the fundus shows choroidal atrophy in the Laurence-Moon subgroup (Campo & Aaberg 1982), however, in our study the most striking examples of choroidal atrophy (Fig. 8) were found in Bardet-Biedl patients without any signs of paraplegia typical for the Laurence- Moon subgroup.

The natural course of visual function in the LMBB syndrome has been described by Fultonet a1.(1993).Theyfound that reduction of acuity and dark adapted sensi- tivity occurred over about the same period of age in each individual patient and that the differences between right and left eyeweresmal1.h our study thefirst reported ocular symptom was mostly night blindness, typically detected in the first years of life and in general precisely observed by both parents and patients because of the severe social consequences of not being able to find toys in dark places or to play outside during the evening. Visual problems during day-time followed a few years later. The routine testing of visual acuity at school start is likely to be the rea- son for the high number of visual impairments registered at the age of 7 years.

The early appearance and the order of onset of these impairments are in accord- ance with ERGfindings (Lavy et al. 1995, Riise et al. 1996) and indicates that the rods are generally affected first.

Nystagmus in LMBB syndrome has been reported earlier (Rizzo et al. 1986). The abnormal eye movements noticed in our patients were correlated to increasing age and could either be connected to a progressive neurological disease (Lavy et al. 1995) or loss of vision (Leigh & Zee 1980).

The poor prognosis for the retinal dystrophy in the LMBB syndrome (Riise 1987; Green et al. 1989; Haim 1992; Fulton et al. 1993) has been related to early destruction of the photoreceptors (Runge et al. 1986) with degeneration in all areas of the retina and choroid in ad- vanced cases (Bek & Rosenberg 1995). Our study shows that visual acuity in LMBB syndrome declines to 0.1 during adolescence to reach a rather stable acuity of hand movements or perception of light in the second decade of life (Fig. 9). The reduction of central vision is more pronounced than in most other cases of recessive retinal dystrophy (except X-linked cases), where patients may re- tain central vision until they are 45-60 years old (Berson et al. 1985).

The visual fields were hard to evaluate because of the poor fixation of the patients. We therefore modified the method

of calculating the fields described by Weleber and Eisner (1988), and just measured the average of the vertical and horizontal angles from the fixation point minus any scotomas for isopter of Gold- mann standardised object V:4e. We were able to demonstrate a yearly loss of fields of 3 degrees during adolescence with very small visual fields in addition to low visual acuity towards the end of second decade (Fig. 11). To our knowledge this is the first time the decline of visual fields has been measured in several patients with the LMBB syndrome. Like Fulton et al. (1993) we could not find any correlation between retinal morphology and the course of the disease.

Our study confirms the dominance of myopia in cases with the LMBB syndrome (Green et al. 1989; Riise 1987). This is consistent with the finding of myopia in other forms of retinitis pigmentosa (Sieving & Fishman 1978).

Conclusion 1. The retinal dystrophy in the LMBB syndrome typically presents in the first years of life with night blindness followed by visual problems at daylight a few years later.

2. The fundus features are atypical with the finding of macular pigmentations together with attenuated vessels and a wax pale optic disc several years earlier than the observation of pigments in the midperiphery. The pigments in the periphery are not always the typical bone spicules.

3. The visual prognosis is poor with se- verely restricted visual fields and reduction of visual acuity to 0.1 or less during the second decade.

Acknowledgments This study was supported by grants from Hed- mark County Council, Norway, The Nor- wegian Association of the Blind, The Nor- wegian LMBB Association, The Norwegian Ophthalmological Society, The Nycomed- Pharma Award, The Danish Association of the Blind, The Danish Society for Prevention of Blindn$ss, The International Retinitis Pig- mentosa Association, The University and The University Hospital of Lund, Sweden and The Swedish Medical Research Council (project 14X 2321).

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Received on February 16th, 1996.

Corresponding author: Ruth Riise Department of Ophthalmology Central Hospital of Hedmark N-2300 Hamar, Norway. Tel47-625-16242. Fax 47-625-23892.

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Ocular findings in the Laurence-Moon-Bardet-Biedl syndrome