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Hum Genet (1990) 85 : 635-642

�9 Springer-Verlag 1990

Clinical and genetic heterogeneity in retinitis pigmentosa

Josseline Kaplan I, Dominique Bonneau I, Jean Fr~zal I, Arnold Munnich ~, and Jean-Louis Duffer 2

1Clinique de G6n6tique Mddicale and 2Consultation d'Ophtalmologie, Unit6 de Recherches sur les Handicaps G6ndtiques de l'Enfant, [NSERM U.12, H6pital des Enfants-Malades, 149, Rue de S6vres, F-75743 Paris Cedex 15, France

Received December 12, 1989 / Revised March 14, 1990

Summary. The clinical course of defective vision and blindness has been investigated in relation to different modes of genetic transmission in a large series of 93 families with retinitis pigmentosa (RP). For autosomal dominant RP, two clinical subtypes could be distinguished according to the delay in macular involvement. In the severe form, macular involvement occurred within 10 years, while in the mild form, macular involvement occurred after 20 years. Interestingly, a significant increase of mean paternal age (38.8 years, mean controls in France = 29.1 years, P<0.001) was found in this form of RP, a feature which is suggestive of new mutations. For autosomal recessive RP, four significantly different clinical subtypes could be recognized, according to both age of onset and the pattern of development (P < 0.001), namely cone-rod dystrophy and early-onset severe forms on the one hand (mean age of onset = 7.6 years), late-onset mild forms and senile forms on the other. Similarly, two significantly different clinical subtypes could be recognized in X-linked RP, according to both mode and age of onset, which were either myopia (mean age= 3.5 _+ 0.5 years) or night blindness (mean age = 10.6_+4.1 years, P<0.001). By contrast, no difference was noted regarding the clinical course of the disease, which was remarkably severe whatever the clinical subtype (blindness before 25 years). In addition, all obligate carriers in our series were found to have either severe myopia or pigment deposits in their peripheral retina. Finally, sporadic RP represented the majority of cases in our series (42%). There was a considerable heterogeneity in this group, and at least three clinical forms could be recognized, namely cone-rod dystrophy, early onset-severe forms and late onset moderate forms. At the beginning of the disease, the hereditary nature of the sporadic forms was very difficult to ascertain (especially between 7-10 years) and only the clinical course could possibly provide information regarding the mode of inheritance. However, the high level of consanguinity, and the high sex ratio in early onset and severe

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sporadic forms (including cone-rod dystrophy), was suggestive of an autosomal or X-linked recessive inheritance, while increased paternal age in late onset forms was suggestive of autosomal dominant mutations.

Introduction

Retinitis pigmentosa (RP) is one of the major causes of hereditary defective vision and blindness since it involves about 30% of patients with visual problems seen in spe- cialized establishments (Feingold et al. 1976; Boughman et al. 1980). The disorder involves heterogeneous de- generative lesions of one or several elements of the retina, affecting initially the photoreceptors and the pigmented epithelium and spreading progressively to all the retinal cells. The course leads inexorably, at a more or less advanced age, to blindness, though the rate of pro- gression of the disease is extremely variable from one family to another (Fishman 1978). In addition, RP pre- sents a multitude of clinical pictures differing one from another according to the exact diagnosis and the age of the subject examined (Heckenlively et al. 1988). The genetic heterogeneity of the disorder is also very marked since all modes of inheritance have been described and it is probable that several distinct genes are responsible for each form of inheritance (Berson et al. 1980; Boughman et al. 1980; Boughman and Caldwell 1982; Bundey and Crews 1984; Bunker et al. 1984; Jay 1982). Indeed, at least two loci on the X chromosome have been identified (Wirth et al. 1988; Wright et al. 1989) and an early dominant form of RP has been recently mapped on chromosome 3 (McWilliam et al. 1989). In order to contribute to gene mapping in RP, we tried to define clinically homogeneous samples of patients, especially stressing the different clinical patterns within each genetic subtype. This study will hopefully contribute to improve genetic counselling in each group, especially in the numerous sporadic cases of the disease.

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Patients and methods

Patients

It is well known that cones and rods are involved in the functioning of the retina. Cones are largely found in the macula and are responsible for visual acuity, colour discrimination and tolerance to bright light. The electroretinographic expression of cone impairment is an alteration of the so-called "photopic response". Rods are found in all regions of the retina except the macula. They are responsible for night vision and the peripheral visual field. The electroretinographic expression of rod impairment is an alteration, or absence, of the so-called "scotopic response". During the course of RP, night blindness occurs with progressive narrowing of the visual field. Fundus examination shows the abnormal presence of dark pigments (bone spicule pigmentation) from which the name of the condition is derived. These lesions correspond to the primary impairment of rods, followed by depigmentation of the pigmented epithelium with displacement of small clumps of pigment towards the deepest layers of the retina (Pagon 1988).

A prospective study of subjects with a non-syndromic form of retinal degeneration was started on January 1st 1988 and con-

Table 1o Distribution of the 141 families ascertained from 1 January 1988 until 30 June 1989

Diagnosis n %

Isolated RP 93 65.96

Stargardt's disease 10 7.09

Cone dystrophy 6 4.26

Leber amaurosis 7 4.96

Congenital stationary night blindness 2 1.42

Choroideraemia 3 2.13

Usher disease 19 13.47

Senior-Loken syndrome 1 0.71

Total 141

Table 2. Genetic categories of RP

Mode of inheritance n %

Autosomal dominant 19 20.43

Autosomal recessive 20 21.50

X-linked recessive 12 12.90

Male sibships 3 3.23

Sporadic cases 39 41.94

Total 93

tinued for 18 months until June 30 1989. In all, 141 families were ascertained from two sources: the multidisciplinary ophthalmological and genetic consultation of H6pital La~nnec, Paris and the genetic counselling consultation of H6pital Necker-Enfants Malades, Paris.

Our diagnostic criteria for RP were those laid down by the 1982 International Symposium of Ophthalmology (Marmor et al. 1983): (1) bilateral involvement, (2) concentric depression of the visual field, (3) severe scotopic involvement on ERG, resulting from alteration of rods, or no E R G response, (4) progressive loss of photoreceptor function.

Most forms have a loss of rod function, as a mode of onset. The main clinical data were quantified, particularly the age of onset and the severity of the disorder. These were assessed as follows: (1) early-onset forms were defined as a decrease in visual acuity before the age of 15, as opposed to late-onset forms in which visual acuity declines later during adulthood; (2) severe forms were defined as a visual acuity equal, or inferior, to 1/10 before the age of 30, as opposed to moderate forms in which visual acuity is great- er than 1/10 after 30 years; (3) senile forms were defined as the late onset of a mild form of the disease.

According to previous criteria, we have decided to include cone-rod dystrophy in our series, especially as rod involvement rapidly follows the early impairment of central vision (cones) in this form. On the other hand, we have excluded cone dystrophy, the distinctive later macular degeneration of Stargardt's disease, and congenital stationary night blindness which is a specific disorder without any alteration of the fundus (Pagon 1988).

According to these criteria, we have selected 93 families of RP for our study and excluded 48 other diagnoses (Table 1).

Methods

The analysis of each family consisted of two parts:

�9 Ophthalmological examination of affected subjects and as many relatives as possible. The examination included: evaluation of visual acuity, measurement of refraction using an automatic refrac- tometer (TOPCON RM A 5000), recording of the visual field with the Goldman perimeter, evaluation of colour perception with the Farnsworth 25 H U E , a slit lamp examination of the lens, measurement of intraocular pressure, a fundus examination after dilation of the pupil, and an electroretinogram using the ophthalmological monitor. Fluorescein angiography was not performed systemati- cally.

�9 Genetic consultation consisted in elicitation of a detailed history and establishment of a pedigree chart. The clinical and genetic data for each family included were compared, and five groups could be distinguished according to the mode of inheritance (Table 2):

Autosomal dominant, when the disease affects several individuals of both sexes over at least two generations and especially when there is father-son transmission (Fig. 1). The penetrance of the condition was calculated by the ratio: affected subjects/affected subjects + obligate carriers of the clinically silent gene.

d

Fig. 1. Example of regular autosomal dominant RP

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Fig. 2. Example of regular autosomal recessive RP

e

()

Fig. 3. Autosomal recessive RP in which consanguinity can explain a false dominant phenomenon

Fig. 4, Example of X-linked recessive RP with night blindness as the mode of onset. 1,2 symptomatic; 11,2 bone spicule pigmentation in fundus

X-linked recessive, whenever the disease affects males over at least two generations with maternal transmission (Fig. 4). Families with one single generation of affected males but whose mothers had characteristic pigment deposits on the fundus were included in this group (Fig. 5).

Male sibships were distinguished from X-linked forms. This group consists of families where only males of the same generation are affected without any other familial element and notably where both parents are strictly normal on examination.

Sporadic cases, when the disease involves only one individual in a family where both parents have been examined by an ophthal- mologist.

Mean values~ paternal age and sex ratio were compared to a control sample (Field et al. 1982) using Student's t-test or the chi- square test.

Results

The clinical and epidemiological data recorded for the different forms of RP are listed below.

Autosomal dominant forms (ADRP)

- N u m b e r of families: 19 (20.43%) - N u m b e r of affected probands : 26 (17 males and 9

females) - N u m b e r of subjects examined at consul ta t ion: 38 - N u m b e r of affected subjects alive: 74 - Sex ratio: 1.05 (38 males and 36 females) - Pene t rance : 90/103 = 0.87 - Mode of onset always night b l indness (100%) - M e a n age at onse t 11.8 years (1 SD = 4.1)

It seemed to us that two types could be dis t inguished according to the delay in macular i nvo lvemen t after onset of the disease, es t imated by a decrease of visual acuity and/or fundus lesions:

- I n type I, macular i nvo lvemen t appears within 10 years after onset (2 families, 3 p robands , 10.5%)

I I I

2 S

Fig. 5. Example of X-linked recessive RP with severe myopia as the mode of onset 1,2; II,7; 111,2 and 5 severe myopia and bone spicule pigmentation in fundus

Autosomal recessive, when the disease affects several members of both sexes in the same sibship while ophthalmological examination shows their parents to be unaffected (Fig. 2). The case where several generations are affected was included in this group when well- established consanguinity explains the phenomenon of false domi- nance (Fig. 3). On the other hand, sporadic cases with parental consanguinity were excluded whatever the sex.

n I

n= 12

n = 6

n - -3

J 10 20 30 40

Years of na~ura[ developmeni"

Fig. 6. Distribution of ADRP according to the delay of macular involvement measured in years of natural development

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- In type II, macular involvement appears after 20 years after onset (17 families, 18 probands out of 21, i.e., 89.5%) (Fig. 6)

Along the same lines, the age of onset of concentric loss of the visual field was significantly different in the two groups (P < 0.001). In contrast, no significant difference was found for the age of onset among the two groups (Table 3).

Autosomal recessive forms (ARRP)

- Number of families: 20 (21.50%) - Number of probands affected: 21 (9 males, 12 females) - Number of subjects examined at consultation: 44 - Number of affected subjects alive: 51 - Sex ratio: 0.82 (23 males and 28 females) - Number of unaffected subjects within sibships: 44 (21 male and 23 female)

As a function of clinical data, these families were classed as follows:

- Cone-rod dystrophy - Early-onset and severe forms - Late-onset and mild forms - Senile forms

Table 4 shows that the age of onset, the mode of onset and the age at which visual acuity decreased varied ac-

Table 3. Clinical differences between the two subtypes of ADRP. Data are mean values in years (+ 1 SD) for 24 probands belonging to 19 families. NB, Night blindness; NS, not significant

Type I Type II Statistical tests

No. of patients 3 21 Mean age of onset 7.6 11.8 NS

+ 1 SD 0.5 4.3 Onset symptom NB NB Mean age of loss of peripheral

visual field 15 28.3 P < 0.001 +- 1 SD 8.6 4.7

Table 4. Distribution and clinical characteristics of ARRP. Data are mean values in years (+ 1 SD) for 21 probands belonging to 20 families. ~ VA, Visual acuity; VF, visual field; NB, night blindness

Clinical forms Cone-rod Early- Late- Senile dystrophy onset onset form

severe mild form form

% 22.2 38.9 33.3 5.6 Age of onset 6.8 7.6 17.1 50.0

+_4.6 +4.1 +_6.0 Onset symptom ~, VA NB NB NB Decrease of VA 6.8 13.7 36.6 -

+ 4.6 +_ 4.8 _+ 10.3 - Peripheral loss of VF 14.0 11.7 24.6 50.0

+-3.7 +-3.1 +6.7

Table 5. Cumulated frequencies of night blindness and decreased visual acuity in XLRRP. Data are given in % for 12 probands belonging to 12 families

Age of onset Night blindness Decreased visual acuity

Before 5 years 8.33 8.33 5-10 years 66.66 -

10-15 years 100.00 33.33 15-20 years 75.00 20-25 years 100.00

cording to the clinical-type, as did the age of onset of narrowing of the visual field. For example, in cone-rod dystrophy, onset was characterized by macular involvement and a decrease in visual acuity (7/7) while, in other forms, the initial symptom was always night blindness (14/14).

X-Linked recessive forms (XLRRP)

- Number of families: 12 (12.90%) - Number of affected probands: 12 - Number of subjects examined: 29 - Number of affected living males: 37 - Number of female carriers: 35

Onset symptoms were either an early myopia (4/12, mean age = 3.5 years, range = 3-4 years), or, later, a night blindness (8/12, mean age = 10.6 years, range = 5 - 15 years). Night blindness always developed before the age of 15, regardless of the mode of onset. In contrast, the age of onset of decrease in visual acuity ranged over a longer period of time (Table 5).

Finally, obligate carriers available for examination (10/35) were found to have either severe myopia (5/10) or pigment deposits in their peripheral retina (4/10). This observation could be related to the mode of onset of the disease, especially as 4/5 obligate carriers had severe myopia when the onset symptom in proband was myopia. Along the same lines, only 1/5 obligate carriers had severe myopia when the onset symptom was night blindness.

Male sibships

- Number of families: 3(3.2%) - Affected living males: 6 - Healthy male: 1 - Healthy female: 1 - Subjects examined: 6

According to our criteria, these three families were considered as having a late-onset mild form.

Sporadic cases

- Number of families: 39 (41.9%) - Number of affected probands: 39 - Sex ratio: 0.95 (19 males and 20 females) - Number of subjects examined: 76

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Table 6. Consanguinity analysis of RP

Consanguinity f = 1/16 total total

% n % n

AD 5.2 1/19 5.2 1/19 AR 35.0 7/20 20.0 4/20 XLR 0 0 Male sibships 33.0 1/3 33.0 1/3 Sporadic 7.6 3/39 7.6 3/39

Severe forms 21.4 3/14 21.4 3/14 Mild forms 0 0/20 -

Total 12.9 12/93 9.7 9/93

Table 7. Mean paternal age in the different genetic subtypes. Data are mean values given in years (_+ 1 SD). Statistical tests refer to the control sample. NS, Not significant

Father's Statistical Fathers older age test than 35 years

(%)

Control sample 376 29.1 __ 2.9 AD 5 38.8 + 4.7 P < 0.001 AR 11 27.3 _+ 4.5 NS Sporadic cases

Early-onset severe 13 26.9 + 6.0 NS

Late-onset mild 19 33.8 + 9.8 P < 0.001

16.0 80.0

7.7 31.5

Sporadic cases of RP fell into three clinical subtypes, namely early-onset severe forms (23%), cone-rod dys- t rophy (21%), and late-onset mild forms (56%).

In early-onset and severe forms (n = 9), the initial symptom was always night blindness. The mean age of onset was 5.5 years (1 SD = 2.8), the age of onset of decrease in visual acuity was 10 to 11 years (1 SD = 3.5), visual acuity became equal or inferior to 1/10 on average at 18 years (1 SD = 6.6) and the sex ratio in this category was 1.25 (5 males, 4 females).

In cone-rod dystrophy (n = 8), mean age at onset was 5.7 years (1 SD = 4.3), and the mode of onset was always a decrease in visual acuity + photophobia (8/8). Concen- tric loss of the visual field and night blindness occurred at 16 years (1 SD = 4.1), the sex ratio in this category was 3 (6 males, 2 females).

Finally, in late-onset and mild forms (n = 22), the mode of onset was always night blindness, mean age of onset was 18.6 years (1 SD = 5.3), and mean age at which visual acuity decreased was 32.7 years (1 SD = 7.7). The sex ratio in this category was 0.46 (7 males, 15 females).

Consanguinity

It is worth noting that 12/93 families were consanguineous (12.9%). For a consanguinity coefficient of 1/16 (first-relative consanguinity), this frequency was 9.7%. Table 6 shows different levels of consanguinity among the distinct genetic types.

Father's age

Paternal age was studied as a function of age at birth of the affected child and compared to a representative control sample of the French population (Briard et al. 1975). For dominant forms, and for the clinically related late onset-mild sporadic forms, the mean paternal age was significantly different from the mean age of fathers in the general population (38.8 years and 33.7 years, respec- tively, control = 29.1 years, P < 0.001; Table 7). Another line of evidence suggests a decisive effect of paternal age (but not of maternal age) in both forms. Indeed, when we compared the age difference of the parents in both dominant forms and in late-onset mild sporadic forms to our control sample (Table 7) we found a mild increase pointing to a consistent effect of paternal age (dominant forms = 5.6 years, late onset mild sporadic forms = 4.9 years, control -- 2.9 years). However, due to the scarcity of cases with fathers of probands beeing available (5), the statistical significance of these results must remain provisional. The paternal age was not significantly higher in other types than in controls (Table 7).

Discuss ion

Our study shows that two clinical forms of autosomal dominant RP can be recognized according to their clinical course. The difference does not lie in the age or type of the onset symptom (which is consistently night blindness in all patients) but rather in the clinical course of the disease. In fact, the course of type I is markedly acceler- ated for both concentric loss of the visual field and macular involvement. Indeed, macular involvement in type I occurs within 10 years while in type II it always occurs after 20 years of onset. This difference is highly significant and accounts for the severity of type I. Our results are also in agreement with other reports for both clinical heterogeneity and the frequencies of dominant RP (Massof and Finkelstein 1981; Farber and Fishman 1985; Lyness et al. 1985). Indeed the type II dominant form accounted for 76-78% in Lyness and Farber series re- spectively, while it accounted for 89.5% in our own series.

Our study is also in agreement with previous reports regarding the penetrance of RP. Indeed, we found a penetrance of 87% in dominant RP while in Boughman's series penetrance averages 40-60% (Boughman et al. 1980; Boughman and Fishman 1983). Along these lines, it should be kept in mind that a thorough examination (as reported in Methods) is required before ruling out the trait in a obligate carrier. For this reason, the generation skipping that we, and others (Boughman et al. 1980; Jay 1982), have observed should be considered with caution, especially as not all subjects were available for examination (three families of A D R P II, i.e., 15.8% of all dominant RP). On the other hand, one of the most interesting results of our study is the increase of both mean paternal age and age difference of the parents in

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dominant RP (38.8 + 4.7 years) as compared with the mean age of fathers in the general population (29.1 years in France, P < 0.001).

As far as we know, paternal age was not studied in the other series, and the fact that it was increased is in line with data from other autosomal dominant diseases, such as neurofibromatosis and achondroplasia (Penrose 1955). This result assumes more importance when it is compared to the paternal age of sporadic RP which has a clinical course similar to that of ADRP (see below).

Our study also shows that four clinical forms can be distinguished in autosomal recessive RP, namely cone- rod dystrophy, early-onset severe form, lat-onset mild form and senile form.

Cone-rod dystrophy has an early-onset before 10 years. In contrast with all other RP, this form is characterized by impairment of central vision (cones). This symptom, which is readily noted by the family, leads to an early diagnosis. The other three types of ARRP all originate with night-blindness (rods) but can be clinically distinguished by their age of onset and course. In the early-onset and severe form, which corresponds to the classical description, the onset is early (mean = 7.6 years) and not significantly different from that found in cone-rod dystrophy (P>0.5). The clinical course is rapid and severe. In the late-onset and moderate form, the clinical presentation is closely similar to ADRP II. Because of the irregular penetrance of the gene, con- fusion is always possible. However, out of our six families of this type, there were three marriages between relatives, which strengthens our conviction that this is indeed an autosomal recessive form. Such a percentage of consanguineous marriages (50%) also suggest the great rarity of this gene. Moreover, our results clearly show that the early and late-onset recessive forms of RP are indeed two different diseases with respect to both age of onset and mode of development (P < 0.01, see Table 4). Finally, we observed one family with a very late onset (55 years) and a moderate course. This presentation is similar to that reported by Grondhal as the "senile" form (Grondahl 1987). Its autosomal recessive character is confirmed by the existence of a first-relative consanguinity in the family described here.

The X-linked forms of RP are the most infrequent in our series (13%). As a function of mode of onset, we consider it possible to distinguish two significantly different forms: the first originates very early with myopia

(mean age of onset: 3.5 + 0.5 years), the second originates a little later with night blindness (mean age of onset: 10.6 + 4.1 years; P<0.01). Both forms lead to night blindness, on average before 15 years, which is in agreement with Fishman's data (Fishman et al. 1988).

The most important feature in all series of X-linked RP, whatever the subtype, is the severity of their clinical course after the onset of the first symptom (blindness before 25 years). However, in contrast with other reports, we have not been able to find any difference in age of onset between X-linked recessive RP, severe forms of ARRP and even ADRP I (P>0.9). The question of whether this clinical heterogeneity can be accounted for by the existence of two different loci on the X chromosome (RP 2 and RP 3) is of course very interesting and still open to discussion.

As far as heterozygotes are concerned, we were not able to observe the abnormal metallic sheen frequently reported in obligate carriers (Fishman et al. 1986; Wirth et al. 1988). It is important to emphasize, however, that the obligate carriers available for examination in our series were found to have either severe myopia or pigment deposits in their peripheral retina. To our knowl- edge, this feature has not been reported to date and deserves particular attention for carrier detection and genetic counselling.

Sporadic forms represent the majority of cases in our sample (42%) as well as in the other published series (Table 8). There is a considerable clinical heterogeneity in this group and at least three clinical forms can be distinguished, namely cone-rod dystrophy, early-onset severe form and late-onset moderate form. At the beginning of the disease, the hereditary nature of the sporadic forms is very difficult to ascertain, especially between 7 and 10 years of age. In fact, the age of onset of night blindness in the severe sporadic forms of our series did not differ either from that of the early-onset autosomal recessive forms (P>0.5) , from that of the X-linked recessive forms ( P > 0.05), or from that of the type ! dominant form (P > 0.5). Thus, all modes of transmission are encountered in this range (Fig. 7) and only the clinical course of the disease may provide information regarding the mode of inheritance. However, if the disorder starts before seven, we can reasonably rule out a dominant form of the disease (Fig. 7). Similarly, if the disease starts after 20, we can certainly rule out an X- linked form.

Table 8. Review of literature on the genetic study of RP

Jay Jay British RP (1982a) (1982b) (1982)

Boughman Bundey Bunker et al. Our study and Fishman and Crews (1984) (1989) (1983) (1984)

AD 24.4 14.9 23.4

A R 13.4 5.9 14.6 XRL 15.7 3.8 4.8 Male sibships 4.5 4.2 4.3

Sporadic 41.1 70.3 52.7 Unordered 0.9 0.9 0.2 No. of families 426 289 555

21.7 26.3 19 20.4 16.0 12.3 19 21.5

9.0 16.7 8 12.9 3.2

50.0 44.7 46 42.0 3.3 8

300 114 85 93

AR (early onset severe form) XLR

AR (cone-rod AOI XLRO~ 3 7 10 15 20 30

Age of onset in years

Fig. 7. Distribution of AR Isenite form) clinical and genetic subtypes ~ / ~ / / / / / ~ with respect to the age of , , , onset in RP

45 50 55

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Table 9. Distribution of genetic subtypes of RP with regard to clinical heterogeneity

Onset with night blindness Onset with

Early-onset Late-onset ~ VA, cone-rod severe form mild form (%) (%) dystrophy (%)

Autosomal dominant - 100 - Autosomal recessive 22 39 39 X-linked recessive 67 - 33 Sporadic 23 57 20

Morever , sex-ratio, paternal age and consanguinity should be considered as well. Indeed, the excess of males, already noted by Jay 1982, and the high level of consanguinity in severe sporadic cases (cone-rod dys- t rophy and early-onset severe form), are suggestive of an X-linked or an autosomal recessive mode of inheritance. On the other hand, increased paternal age in mild forms is suggestive of autosomal dominant mutations.

As far as we know, only Bundey and Crews (1984) give the age of fathers in sporadic forms; unfortunately, they make no distinction between clinical categories and report a mean age of 30.7 years, no different from that of the British control sample. We also found the same paternal age (30.3 years) for the whole of the sporadic RP group.

Finally, one should keep in mind that the genetic ori- gin of sporadic RP is not obvious: phenocopies may also exist, a feature which considerably hampers the analysis of isolated cases of RP.

Several conclusions can be drawn from our study on non-syndromic RP. First, we confirm that two clinical forms of A D R P can be recognized, and homogeneous groups of families can be constituted for subsequent gene mapping studies. Second, we show that at least four forms of R P A R exist: a classical early-onset severe form, cone-rod dystrophy, and two modera te forms with a much later onset (Table 9); this differs from the classical conception of recessive RP. Third, the question of whether the clinical heterogeneity that we have observed in X-linked RP can be accounted for by the existence of two different loci (RP2, RP3; Bhat tacharya et al. 1984, 1985; Chen et al, 1989) on the X chromosome remains open to debate. However , prudence demands that mark- ers for both the RP2 and RP3 loci should be used when an antenatal diagnosis is proposed to families.

Finally, the great clinical heterogeneity that exists in sporadic cases seems important to us. The high level of

consanguinity of early-onset and severe forms, including cone-rod dystrophy, suggests a high proport ion of autosomal recessive forms. In this same clinical subgroup, the much higher sex ratio than that observed in moderate forms raises the possibility of mutat ions of a gene on the X chromosome. In late-onset forms, the increased paternal age suggests a large number of autosomal dominant mutations.

These findings and reflections resulting from our sample should hopefully contribute to genetic counselling in sporadic cases and facilate the task of gene mapping.

Acknowledgements. We are thankful to Gis61e Gal and Alan Strickland for their help in preparing the manuscript. The present study was supported by the Association Franqaise Retinitis Pig- mentosa.

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