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Genetic and epidemiological investigations on pigmentary degeneration of the retina and allied disorders in Switzerland
JOURNAL OF THE NEUROLOGICALSCIENCES
183
Genetic and Epidemiological Investigations on Pigmentary Degeneration of the Retina and Allied Disorders in Switzerland F. A M M A N N , D. K L E I N AND A. F R A N C E S C H E T T I Institut de Gdndtique m~dicale and Clinique ophtalmologique, University of Geneva (Switzerland)
INTRODUCTION Pigmentary degeneration of the retina is an important clinical and genetic entity with serious social implications. Most patients have to give up their profession around the age of 30-40 because of progressive failure of their sight leading to blindness usually around the age of 50--60. As the group of tapeto--retinal degenerations has never been the subject of a systematic study, we have undertaken since 1959 a clinical, genetic and epidemiological investigation with the object of establishing the frequency, clinical variability, geographical distribution and modes of inheritance of the different types of these affections. WAYS OF GENETICTRANSMISSION Classical retinitis pigmentosa may be transmitted in the following three ways: (1) The autosomal recessive mode o f inheritance. This form is characterized by its familial occurrence: theoretically, 25% of the siblings should be affected and an elevated rate of consanguineous marriages among the parents of affected offspring is found. The recessive type of transmission is by far the most common. The estimated frequency of its occurrence in our case-material is about 90~/o. In some cases with successive transmission through two generations, we may likewise be dealing in fact with a recessive mode, in which there is union between a homozygous and a heterozygous individual. This would particularly hold true for highly inbred areas (family Ro, published by FRANCESCHETTI 1953; family H/i-Lii, Fig. 1). (2) The autosomal dominant mode o f inheritance. This form is considered to be present only when at least three successive generations are affected. Furthermore, sex-linked heredity may only be excluded in the presence of at least one case of direct After a communication at the XIth International Congress of Genetics, September 1963, The Hague (The Netherlands). J. neurol. Sci. 0965) 2:183-196
184
V. AMMANN, D. KLEIN, A. FRANCESCHETTI
transmission from father to son. According to our studies, approximately 9')i, o1: till our cases are autosomal dominant. The findings of other authors according to which the dominant, in opposition to the recessive form, is practically never associated with deaf-mutism, was also confirmed by us.
II
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II] IV
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= Retinitis pigmentosa with deaf-tourism
I ~
• (~
V1
= Retinitis pigmentosa = Epilepsy = 3 children, sex unknown
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= Twins = Died in infancy
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VII1
1
5"6c5d5
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IIII
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Fig. 1. Pedigree showing retirtitis pigmentosa combined with deaf-mutism.
(3) The sex-linkedrecessive mode of inheritance. This form must be considered as rare. We were able to find only one single family, and this only because our investigation includes the follow-up study of all Swiss cases of retinitis pigmentosa already published in the literature. Thus, we have searched for the offspring of a family published by a Swiss ophthalmologist (DIEM 1914). The subject of her publication was the alternating occurrence of typical retinitis pigmentosa in two half-brothers and a so-called "retinitis punctata albescens" in the daughter of one of them. It is not our intention to relate here in detail the numerous difficulties and obstacles which we had to overcome in order to locate the offspring of this woman with "retinitis punctata albescens". As a result of this long search, we were at last able to fred Dr. DIEM in a home for aged people. As might ~ expected, our colleague was scarcely able to recall anything tangible, due to her advanced age. We almost lost our family altogether. These details are mentioned for the purpose of illustrating the importance of a genetic centre in every country. Systematic registration of all hereditary affections at such centros, as at the Genetic Department, Geneva, makes it possible to trace the names, origins and addresses of all Swiss families that have been published. J. neuro/. Sci. (1965) 2:183-196
PIGMENTARYDEGENERATIONOF RETINAAND ALLIEDDISORDERSIN SWITZERLAND
185
Returning to our subject, we would like to mention that, despite the meagreness of clues furnished by our colleague, we were able to trace the offspring of the proposita published in 1914. The pedigree thus comprises a total of 6 persons examined belonging to 4 generations (Fig. 2). Our surprise was great when ophthalmoscopic examina-
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~ - - - - - 7 , F a m i y descr bed by M DIEM~ L - - - - _ d Kiln. Mbl. Augenheilk., 5...33,:371-379,1914.
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Fig. 2. Sex-linked type of retinitis pigmentosa with reversible tapetal reflex in the carriers. (After RICCI, AMMANNANDFRANCESCHETTI1963). tion revealed in the female descendants of the proposita (III-3) the famous "tapetallike reflex" as described by MANN (1937) and recognized by FALLS AND COTTERMAN (1948) as characteristic for heterozygous women in sex-linked retinitis pigmentosa.
Fig. 3. Tapetal reflex in a carrier of retinitis pigmentosa (V-3 of Fig. 2). (After R]ccI, AMMANNAND FRANCESCHETTI1963). J. neurol. Sci. (1965) 2:183-196
186
F. AMMANN, D. KLEIN, A. FRANCESCHETTI
On the other hand, the only son (IV-2) of the proposita showed retinitis pigmento,~a sine pigmento with a visual acuity of right 0. l (20/200); left: finger counting; important field defects and a completely abolished ERG. In retrospect, we may therefore assume that the proposita of DIEM'S publication had also been a heterozygote. Furthermore, we found a striking phenomenon in the two heterozygous descendants (IV-I, V-3L namely a reversibility of the tapetaMike reflex. As a matter of fact, the tapetal reflex disappeared in the course of prolonged fundoscopic examination and reappeared after the patient had remained about one hour inthe dark. This phenomenon recalls MIzuo's phenomenon in OGUCHI'S disease, but with the difference that, in the latter, the abnormal gray-white coloration of the fundus disappears after some time in a dark room. For this reason we have called the reappearance of the reflex in the dark m our cases an 'inverse MIzUO'S phenomenon' ( R I c c I , AMMANNAND FRANCESCHETTI, 1963). It is interesting to note that a similar reversibility had already been stated by DIEM (Fig. 3). FREQUENCY
We wish now to consider the frequency of autosomal recessive retinitis pigmentosa in Switzerland. Preliminary results of our investigation comprise 101 patients belonging to 93 families. The frequency can roughly be estimated at 14.8 affected for 100,000 inhabitants, i.e., 1: 7000. The gene frequency is therefore l / i ) 7 ~ -- ~ and ihe carrier frequency approximately 4~-It is interesting to note that the frequency estimations in the literature vary between 1 : 10,000 (KEMP 1951) and 1 " 5000 (FRANCOIS 1958). Out of the I01 cases, 27 (i.e., 26.7%) are offspring of consanguineous marriages. Ten cases (i.e., 9.9%) are offspring of marriages between first cousins. For statistical correction of our material, WEINBEgG'S Geschwistermethode as well as BEgNSTEIN and HOGBEN'S a priori method (BERNSTEIN 1929; HOGBEN 1931) were applied. Using the Geschwistermethode, we obtain for 98 affected individuals* belonging to 80 sibships with living propositi, and a total of 351 sibs, the corrected percentage for the affected individuals in the following way: X E x (x -- 1) 38 N
Z n (n - - 1)
353
X = 10.76 i l . 6 6 % where x be the n u m b e r of affected children per sibship; and n the n u m b e r of children per sibship. According to BERNSa'~tN and HO6BEN'S a priori method, we obtain the following corrected ratio
between affected and non-affected children: X Zx N
Y.(n • s) + ~(s" C)
98 351 q- 148 • 655
X - 19.61 I I . 7 8 % where s be the number of sibships; n the number of children per sibsbip; and x the number of affected
n- 3n children in each sibship group (sibships with 1, 2, 3, etc. sibs). C is the corrective figure: 4n_3,
Whereas the figure of 19.6% obtained with BERNSTE1N and HOGBEN'S method corresponds more or less with the expected theoretical 25% for the MENOELIAN recessive mode of inheritance, the figure of 10.8% according to WEINBERG'S Ge• We arbitrarily fixed the age of 10 years for patients to be included in our calculation. Three cases were excluded, either because they did not fulfil this requirement or for other reasons. J. neurol. Sci. (1965) 2 : 1 8 3 - 1 9 6
PIGMENTARY DEGENERATION OF RETINA AND ALLIED DISORDERS IN SWITZERLAND
187
schwistermethode is rather below this theoretical proportion. The only explanation
for the relatively low rate of affected individuals, as obtained from WEINBERG'S method, is the relatively high percentage of sporadic cases in our material. The sex ratio in the 80 sibships is 57 affected males to 41 affected females, and 133 non-affected males to 120 non-affected females. This difference is not significant (Z2 0.890). There is therefore no reason to assume that sex-linked cases could at least partially be responsible for the rather large number of affected males. In applying the statistical method to the material of BELL (1922), the sex-ratio between the affected individuals is 454 men to 363 women, and between the nonaffected individuals, 373 men to 362 women. This difference approximates to the threshold of significance (Z2 3.61; threshold of significance: Z2 3.841"). It is therefore possible that cases of sex-linked type of retinitis pigmentosa are included within BELL'S material.
GEOGRAPHICAL DISTRIBUTION
As far as the geographical distribution ofretinitis pigmentosa in Switzerland is concerned, its ubiquitous nature is evident. In a series of isolates, however, we were able to note a concentration of cases with considerably elevated rate of consanguineous marriages. In the Canton Glarus for instance, the rate of first-cousin marriages was 35.0~o, and for cousins until the 5th degree as high as 87.5~o. In order to illustrate the special demographic situation encountered in some regions, we present three typical examples of isolates where a particular accumulation of cases of retinitis pigmentosa was found. (1) The first example is a village (Saas) in the Canton Valais. It is situated in a narrow, rather remote valley. Its population is approximately 1560 inhabitants with a rate of 25.8 ~ of consanguineous marriages between cousins of the first to the third degree. In this village, we found a total of 7 cases of retinitis pigmentosa, 5 cases of macular dystrophy and 3 cases of fundus albipunctatus with hemeralopia. All of these, belonging to 9 different lines of descendants, could be traced back to one and the same ancestor who lived at the beginning of the 17th century (AMMANNAND MARTY 1962). We were recently able to trace a new case of macular dystrophy to this same common source (Ims, Alexander, born 1933, Pol. No. 6061/63). This alternation of three types of tapeto-retinal degeneration found in this pedigree suggests the possibility of different phenotypical manifestations of one and the same abiotrophic process. (2) A further example of an isolate is MoUens in the Canton Valais. The pedigree (Fig. 4) shows a series of consanguineous marriages giving rise to two families affected with retinitis pigmentosa, and a third family showing four sibs with heredoataxia of PIERRE MARIE'S type. This pedigree can be compared with that published by FRANCESCnETTI AND KLEIN (1947) with alternation of several forms of tapetoretinal degenerations and FRIEDREICH'S ataxia. (3) The third isolate with a high incidence of retinitis pigmentosa is the one already described by HANHART (1939). We had the opportunity to re-examine and complete his material. The isolate in question concerns the Wartau community in the St. Gallen Rhine-Valley, the population of which was approximately 3200 in J. neurol. Sci. (1965) 2:183-196
188
F. AMMANN, D. KLEIN, A. FRANCESCHETTI
1939. HANHART had found in this kindred 6 cases of retinitis pigmentosa belonging to 4 sibships. Noteworthy was the extremely benign character and slow progression of this form of retinitis pigmentosa. As a matter of fact, these patients had no notable visual defects, apart from pronounced night-blindness. Ophthalmoscopic findings were those of atypical retinitis pigmentosa.
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Fig. 4. Retini.tis pigmentosa and spino-cerebellar ataxia (PIERRE MARIE'S type) in the same family.
In 1962 we were able to confirm the benign and very slow progressive character of this form of retinitis pigmentosa in most of the original cases of HANr~ARr. Furthermore, we were able to expand HANHART'S pedigree by adding three new families with four affected cases (Fig. 5). The new cases of retinitis pigrnentosa added to the pedigree turned out, however, to be typical and progressive with reduction of visual acuity to perception of light (cases Su, Hans, 1920, XII-22; Ell, Edwin, 1898, XII-1 and Heinrich, 1901, XII-3). It is possible that the aggravated manifestation of the new cases is due to the exogenous source of one of the two alleles. Most of the families belonging to the Wartau isolate could be traced back to the J. neurol. Sci. (1965) 2:183--196
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190
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same ancestor living in the 17th century. Furthermore one of these families wit h retinitis pigmentosa (XII-31) is related to a sibship with three cases of BARDET-B1EDt. syndrome (XH-33, 34 and 35). This argues in favour of a certain relationship between the two entities.
ASSOCIATED AFFECTIONS
Deaf-mutism Deaf-mutism appears to be the most important affection associated with retinitis pigmentosa. A m o n g the 118 living individuals of our total material (dominant, recessive, etc.), 16 (i.e., 13.3%) have associated congenital deafness. This is in agreement with the findings in the literature (10.4% according to BELL 1922). In taking in consideration only typical recessive cases of retinitis pigmentosa, the following types of association were met with, each of which is illustrated by one example.
(1) Retinitis pigmentosa combined with deaf-mutism in two brothers (VI-5, 6), offspring of consanguineous parents (family Wy, Fig. 6). (2) Simple retinitis piguaentosa in the mother (IX-12) and retinitis pigmentosa complicated by deaf-mutism in two children (X-7, 8) (family H~i-Lii, Fig. 1).
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Fig. 6. Pedigree showing retinitis pigulentosa combined with deaf-mutism.
(3) Simple retinitis pigmentosa (IV-3) and retinitis pigmentosa combined with dcaf-muti~m (VI-3) in two branches of one family (family Hu-Bo, Fig, 7). (4) Alternation of simple retinitis pigmcaRosa (IX-11) and recessive deaf-mutism (X-10, 13; VIH-2, 3, 4) in different sibships and S~nerations of the same family (family Fa-13~, Fig. 8). The last-named pedigree comes from the famous isolate Ayent (Canton Valais), a villag~ with 2400 inhabitants, where HANHARTin 1955 found 70 living deaf-mutes (42 males and 28 females) o r 2 . 9 ~ o (see HANHART1962). Most of the families have been examined otolngically by S~CS]~TnN (1954).
J. neurol. Sci. (1965) 2:183-196
PIGMENTARYDEGENERATIONOF RETINAAND ALLIEDDISORDERS IN SWITZERLAND
191
These examples support the assumption that retinitis pigmentosa and congenital deafness are due to the same autosomal recessive gene with variable expressivity. Our findings are therefore in agreement with the conclusions of LINDENOV (1945) and HALLGREN (1959).
0 II [ ] = Male
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Fig. 7. Retinitis pigmentosa sine pigmento combined with deaf-mutism, and typical retinitis pigmentosa without deafness, in the same family.
Mental abnormalities and heredo-ataxia
Other affections described in the literature as associated with retinitis pigmentosa, are mental abnormalities and heredo-ataxia (BELL 1922; HALLGREN 1959). Our pedigrees indeed show a certain tendency for the retinitis pigmentosa-families to develop neurological and psychical disorders (see Figs. 9 and 10; see also Figs. 1, 4, 6, 7, 8 and 11), but they do not yet permit us to estimate the frequency of these associations. Bardet-Biedl syndrome
A particular association is the BARDET-BIEDL syndrome. So far, we have encountered 8 cases belonging to 5 families. Two of these families are of special interest. (1) The family Sch-Je - - originally published by JEr~qe (1953) and completed by us (see Fig. 9 of AMMANNet aL 1961) - - shows an alternation of the BARDET-BIEoLsyndrome with a FR6HUCH type of adiposo-genital dystrophy in another branch. (2) The family Ad, published by WILL1(1931) shows an alternation of the BARDET-BmOLsyndrome (XII-33, 34, 35) with simple retinitis pigmentosa in 7 branches from the Wartau isolate (see Fig. 5). Leber's congenital tapeto--retinal amaurosis We were able to establish a genealogical connection between a family affected J. neurol. Sci. (1965) 2:183-196
192
F. A M M A N N
D . K L E I N , A. F R A N C E S C H E T T I
with LEBER'S type of congenital tapeto-retinal degeneration published in 1957 by J/SHR (VI-3, 4, 7, 9), and a family showing 3 cases of typical retinitis pigmentosa (V-3, 5, 7; Fig. 11). The patients belonging to these two sibships were cousins of 3rd to 4th degree. This suggests a certain relationship between LEBER'Scongenital tapetoretinal amaurosis and typical juvenile retinitis pigmentosa. In this connection, we
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Fig. 8. Retinitis pigmentosa in an isolate with deaf-tourism (Ayent, Canton Valais).
would like to mention that the cases published by JOHR (VI-3, 4, 7, 9) were initially considered as examples of congenital optic atrophy, and that it was only owing to electro-retinography that the correct diagnosis could be established (see JtiHR 1957). J. neurol. Sci.
(1965) 2:183-196
PIGMENTARY DEGENERATION OF RETINA A N D ALLIED IN DISORDERS SWITZERLAND
193
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= Died in infancy II = Consanguineous marriage
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= Retinitis pigmentosa? (became blind, hemeralopia, pronounced obesity) : Total bilateral cataract
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Fig. 9. Retinitis pigmentosa combined with mental disorder.
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Fig. 10. Retinitis pigmentosa in association with mental disorder. J. neurol. Sci. (1965) 2:183-196
194
F. AMMANN, D. KLEIN, A. FRANCESCHETTI
Re,
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Fig. 11. Typical retinitis pigmentosa and congenital tapeto-retinal amaurosis (Leber) occurring in the same family.
CONCLUSION
In conclusion, we would like to stress the importance of the investigation of isolates (see KLErNANDAMMA~rN1964). A high concentration of heredo-degenerative affections such as retinitis pigmentosa, FRmm'.EICn'Sataxia and deaf-mutism, in these isolates, are fated to be lost for investigations because of the improvement of means of communication. At the present time, these isolates still constitute suitable subjects for a clinical and genetic study of abiotrophies. In fact, such investigations are of particular value, because they afford information as to modes of irtheritance, clinical variability, evolution and associations of heredo--degenerative affections, and thus afford a more adequate classification of abiotrophic diseases. SUMMARY
The authors describe the results of a genetic and epidemiological investigation of pigmentary degeneration of the retina and allied diseases (Bardet-Biedl syndrome, congenital tapeto-retinal amaurosis of Leber, retinitis punctata albeseens, fundus albipunctatus cum hemeralopia, etc.) in Switzerland. About 90% of all cases of pigmentary degeneration of the retina are transmitted by the recessive mode, and 9% by the dominant mode of inheritance. One family alone presents a recessive sex-linked transmission of retinitis pigmentosa. In this family, the female heterozygotes show the typical tapetal reflex as described by FALLS AND COIII~RMAN in 1948. The frequency of pigmentary degeneration of the retina in Switzerland can be estimated at 1 : 7000, the gene frequency at 1 : 84, and the frequency of heterozygotes at 1 : 42. About 10% of all cases are offspring of marriages between first cousins. J. neurol. Sci. (1965) 2:183-196
PIGMENTARY DEGENERATIONOF RETINA AND ALLIED DISORDERS IN SWITZERLAND
195
There are some isolates in Switzerland with a high incidence of retinitis pigmentosa. O n e isolate, in particular, i n the C a n t o n of Valais, allowed us to d e m o n s t r a t e a p h e n o t y p i c a l a l t e r n a t i o n between different types of p i g m e n t a r y degeneration within several branches of a large family originating from a c o m m o n ancestor. A m o n g the hereditary affections associated with t a p e t o - r e t i n a l degenerations, congenital deafness is the most frequent (being associated with retinitis pigmentosa in 13 ~o). The Bardet-Biedl s y n d r o m e was observed in 4 patients out of a p o p u l a t i o n of 700,000 i n h a b i t a n t s (1 : 175,000). Finally, the a u t h o r s stress the i m p o r t a n c e of a n investigation of isolates, since they permit a more satisfactory classification of abiotrophic diseases.
ACKNOWLEDGEMENTS This study was supported by grants of the F o n d s N a t i o n a l Suisse de la Recherche Scientifique (No. 2729) a n d of the Public Health Service, Bethesda, Md. (grant NB 04590-01).
REFERENCES AMMANN,F. AND F. MARTY (1962) Une grande famille valaisanne avec plusieurs branches atteintes de formes diff6rentes de d6g6n6rescence tap6to-r6tinienne remontant au m6me couple ancestral, J. G~ndt. hum., ! 1 : 221-230. AMMANN, F., O. KLEIN AND H. R. BOHRINGER(1961) R6sultats pr61iminaires d'une enqu~te sur la fr6quence et la distribution g6ographique des d6g6n6rescences tap6to-r6tiniennes en Suisse (6tude de cinq cantons), J. Gdndt. hum., 10: 99-127. BELL, J. (1922) Retinitis pigmentosa and allied diseases, in: The Treasury of Human Inheritance, Vol. 2, Part l, University Press, London, Cambridge. BERr~STEiN, F. (1929) Variations- und Erblichkeitstatistik, in: Handbuch der Vererbungswissenschaften, Borntrfiger, Berlin. DIEM, M. (1914) Retinitis punctata albescens et pigmentosa, Klin. MbL Augenheilk., 53: 371-379. FALLS,H. F. ANDC. W. COTTERMAN(1948) Chorioretinal degeneration. A sex-linked form in which heterozygous women exhibit a tapetal-like retinal reflex, Arch. Ophthal. (Chic.), 40: 685-703. FRANCESCHETTI, A. (1953) R6tinite pigmentaire r6cessive dans deux g6n6rations cons6cutives ("pseudo-dominance"), J. Gdndt. hum., 2: 145-146. FRANCESCHETTI,A. AND D.-K.I~tN (1947) Weiterer Beitrag zur Frage der genetischen Beziehungen zwischen der Friedreichschen Ataxie und den verschiedenen Formen der tapeto-retinalen Degenerationen (Retinitis pigmentosa und Retinitis punctata albescens in zwei Verwandtengruppen der Friedreich-Sippe "Glaser"), Arch. Klaus-Stift. Vererb.-Forsch., 22: 93-121. FRAN(~OIS,J. (1958) L'Hdrddit~ en Ophtalmologie, Masson, Paris. HALLGREN, B. (1959) Retinitis pigmentosa combined with congenital deafness; with vestibulocerebellar ataxia and mental abnormality in a proportion of cases, Acta psychiat, scand., Suppl. 138, 34: 1-101. HANI-IART,E. (1939) Atypische "Retinitis pigmentosa" infolge einer mindestens 350 Jahre zuriickliegenden einfach-rezessiven Mutation, Schweiz. reed. Wschr., 69: 573-581. HANHART, E. (1962) Die genealogische und otologische Erforschung des grossen Walliser Herdes von rezessiver Taubheit und Schwerh6rigkeit ina Laufe der letzten 30 Jahre (1933-1962), Arch. Klaus-Stift. Vererb.-Forsch., 37: 199--402. HO~BEN, L. (1931) The genetic analysis of familial traits. I. Single gene substitutions, J. Genet., 25: 97-112, 211-240, 293-314. JENNY, R. (1953) Familiiires Auftreten yon cerebraler Adipositas mit Hypogenitalismus bei Blutsverwandtschaft der Eltern, Thesis, Geneva. J6HR, P. (1957) Apropos de 4 cas d'amaurose tap6to-r6tinienne (type Leber) dans une famille de 9 enfants issus de parents sains (forme cong6nitale?), Mad. Probl. Ophthal. (Basel), 1: 559-569. KEMP, T. (1951) Genetics and Disease, 2nd edit., E. Munksgaard, Copenhagen. J. neurol. Sci. (1965) 2:183-196
196
F. AMMANN, D. KLEIN~ A. FRANCESCHETTI
KLEIN, D. AND F. AMMANN (1964) Geographical distribution of some isolates with neuro-genettc affections in Switzerland, J. Gdndt. hum., 13: l (in print). LENZ, F. (1929) Methoden der menschlichen Erblichkeitsforschung, in: E. Go'rscHLICH (Ed.L Handbuch der hygienischen Untersuchungsmethoden, G. Fischer, Jena. LINDENOV, H. (1945) The etiology of deaf-mutism, with special reference to heredity, Op. ex. domo biol. hered, ham. Univ. Hafniensis, 8: 1-268. MANN, I. (1937) Developmental Abnormalities of the Eye, Cambridge University Press, London, Fig. 105; 2nd edit. (1957) Brit. med. Ass., London, p. 150. RICCI, A., F. AMMANN AND A. FRANCESCHETTI (1963) Reflet tap6toide r6versible (ph6nom6ne de Mizuo inverse) chez des conductrices de r6tinopathie pigmentaire r6cessive li6e au sexe, Bull. Soc. Franc. Ophtal., 76: 31-35. SECRI~TAN, J.-P. "(1954) De la surdi-mutit6 recessive et de ses rapports avec les autres formes de surdimutit6, Arch. Klaus-Stifit. Vererb.-Forsch., 29: 1-134. WILLI, H. (1931) Ueber dieangeborene sogenannte cerebrale Form der Dystrophia adiposo-genitalis (Laurence-Biedlsches Syndrom), Jb. Kinderheilk., 133 : 12-25.
J. neurol. Sci. (1965) 2:183-196
183
Genetic and Epidemiological Investigations on Pigmentary Degeneration of the Retina and Allied Disorders in Switzerland F. A M M A N N , D. K L E I N AND A. F R A N C E S C H E T T I Institut de Gdndtique m~dicale and Clinique ophtalmologique, University of Geneva (Switzerland)
INTRODUCTION Pigmentary degeneration of the retina is an important clinical and genetic entity with serious social implications. Most patients have to give up their profession around the age of 30-40 because of progressive failure of their sight leading to blindness usually around the age of 50--60. As the group of tapeto--retinal degenerations has never been the subject of a systematic study, we have undertaken since 1959 a clinical, genetic and epidemiological investigation with the object of establishing the frequency, clinical variability, geographical distribution and modes of inheritance of the different types of these affections. WAYS OF GENETICTRANSMISSION Classical retinitis pigmentosa may be transmitted in the following three ways: (1) The autosomal recessive mode o f inheritance. This form is characterized by its familial occurrence: theoretically, 25% of the siblings should be affected and an elevated rate of consanguineous marriages among the parents of affected offspring is found. The recessive type of transmission is by far the most common. The estimated frequency of its occurrence in our case-material is about 90~/o. In some cases with successive transmission through two generations, we may likewise be dealing in fact with a recessive mode, in which there is union between a homozygous and a heterozygous individual. This would particularly hold true for highly inbred areas (family Ro, published by FRANCESCHETTI 1953; family H/i-Lii, Fig. 1). (2) The autosomal dominant mode o f inheritance. This form is considered to be present only when at least three successive generations are affected. Furthermore, sex-linked heredity may only be excluded in the presence of at least one case of direct After a communication at the XIth International Congress of Genetics, September 1963, The Hague (The Netherlands). J. neurol. Sci. 0965) 2:183-196
184
V. AMMANN, D. KLEIN, A. FRANCESCHETTI
transmission from father to son. According to our studies, approximately 9')i, o1: till our cases are autosomal dominant. The findings of other authors according to which the dominant, in opposition to the recessive form, is practically never associated with deaf-mutism, was also confirmed by us.
II
'
II] IV
[ ] = Idale
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•
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= Retinitis pigmentosa with deaf-tourism
I ~
• (~
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= Retinitis pigmentosa = Epilepsy = 3 children, sex unknown
( ~
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= Twins = Died in infancy
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1
5"6c5d5
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IIII
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Fig. 1. Pedigree showing retirtitis pigmentosa combined with deaf-mutism.
(3) The sex-linkedrecessive mode of inheritance. This form must be considered as rare. We were able to find only one single family, and this only because our investigation includes the follow-up study of all Swiss cases of retinitis pigmentosa already published in the literature. Thus, we have searched for the offspring of a family published by a Swiss ophthalmologist (DIEM 1914). The subject of her publication was the alternating occurrence of typical retinitis pigmentosa in two half-brothers and a so-called "retinitis punctata albescens" in the daughter of one of them. It is not our intention to relate here in detail the numerous difficulties and obstacles which we had to overcome in order to locate the offspring of this woman with "retinitis punctata albescens". As a result of this long search, we were at last able to fred Dr. DIEM in a home for aged people. As might ~ expected, our colleague was scarcely able to recall anything tangible, due to her advanced age. We almost lost our family altogether. These details are mentioned for the purpose of illustrating the importance of a genetic centre in every country. Systematic registration of all hereditary affections at such centros, as at the Genetic Department, Geneva, makes it possible to trace the names, origins and addresses of all Swiss families that have been published. J. neuro/. Sci. (1965) 2:183-196
PIGMENTARYDEGENERATIONOF RETINAAND ALLIEDDISORDERSIN SWITZERLAND
185
Returning to our subject, we would like to mention that, despite the meagreness of clues furnished by our colleague, we were able to trace the offspring of the proposita published in 1914. The pedigree thus comprises a total of 6 persons examined belonging to 4 generations (Fig. 2). Our surprise was great when ophthalmoscopic examina-
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Fig. 2. Sex-linked type of retinitis pigmentosa with reversible tapetal reflex in the carriers. (After RICCI, AMMANNANDFRANCESCHETTI1963). tion revealed in the female descendants of the proposita (III-3) the famous "tapetallike reflex" as described by MANN (1937) and recognized by FALLS AND COTTERMAN (1948) as characteristic for heterozygous women in sex-linked retinitis pigmentosa.
Fig. 3. Tapetal reflex in a carrier of retinitis pigmentosa (V-3 of Fig. 2). (After R]ccI, AMMANNAND FRANCESCHETTI1963). J. neurol. Sci. (1965) 2:183-196
186
F. AMMANN, D. KLEIN, A. FRANCESCHETTI
On the other hand, the only son (IV-2) of the proposita showed retinitis pigmento,~a sine pigmento with a visual acuity of right 0. l (20/200); left: finger counting; important field defects and a completely abolished ERG. In retrospect, we may therefore assume that the proposita of DIEM'S publication had also been a heterozygote. Furthermore, we found a striking phenomenon in the two heterozygous descendants (IV-I, V-3L namely a reversibility of the tapetaMike reflex. As a matter of fact, the tapetal reflex disappeared in the course of prolonged fundoscopic examination and reappeared after the patient had remained about one hour inthe dark. This phenomenon recalls MIzuo's phenomenon in OGUCHI'S disease, but with the difference that, in the latter, the abnormal gray-white coloration of the fundus disappears after some time in a dark room. For this reason we have called the reappearance of the reflex in the dark m our cases an 'inverse MIzUO'S phenomenon' ( R I c c I , AMMANNAND FRANCESCHETTI, 1963). It is interesting to note that a similar reversibility had already been stated by DIEM (Fig. 3). FREQUENCY
We wish now to consider the frequency of autosomal recessive retinitis pigmentosa in Switzerland. Preliminary results of our investigation comprise 101 patients belonging to 93 families. The frequency can roughly be estimated at 14.8 affected for 100,000 inhabitants, i.e., 1: 7000. The gene frequency is therefore l / i ) 7 ~ -- ~ and ihe carrier frequency approximately 4~-It is interesting to note that the frequency estimations in the literature vary between 1 : 10,000 (KEMP 1951) and 1 " 5000 (FRANCOIS 1958). Out of the I01 cases, 27 (i.e., 26.7%) are offspring of consanguineous marriages. Ten cases (i.e., 9.9%) are offspring of marriages between first cousins. For statistical correction of our material, WEINBEgG'S Geschwistermethode as well as BEgNSTEIN and HOGBEN'S a priori method (BERNSTEIN 1929; HOGBEN 1931) were applied. Using the Geschwistermethode, we obtain for 98 affected individuals* belonging to 80 sibships with living propositi, and a total of 351 sibs, the corrected percentage for the affected individuals in the following way: X E x (x -- 1) 38 N
Z n (n - - 1)
353
X = 10.76 i l . 6 6 % where x be the n u m b e r of affected children per sibship; and n the n u m b e r of children per sibship. According to BERNSa'~tN and HO6BEN'S a priori method, we obtain the following corrected ratio
between affected and non-affected children: X Zx N
Y.(n • s) + ~(s" C)
98 351 q- 148 • 655
X - 19.61 I I . 7 8 % where s be the number of sibships; n the number of children per sibsbip; and x the number of affected
n- 3n children in each sibship group (sibships with 1, 2, 3, etc. sibs). C is the corrective figure: 4n_3,
Whereas the figure of 19.6% obtained with BERNSTE1N and HOGBEN'S method corresponds more or less with the expected theoretical 25% for the MENOELIAN recessive mode of inheritance, the figure of 10.8% according to WEINBERG'S Ge• We arbitrarily fixed the age of 10 years for patients to be included in our calculation. Three cases were excluded, either because they did not fulfil this requirement or for other reasons. J. neurol. Sci. (1965) 2 : 1 8 3 - 1 9 6
PIGMENTARY DEGENERATION OF RETINA AND ALLIED DISORDERS IN SWITZERLAND
187
schwistermethode is rather below this theoretical proportion. The only explanation
for the relatively low rate of affected individuals, as obtained from WEINBERG'S method, is the relatively high percentage of sporadic cases in our material. The sex ratio in the 80 sibships is 57 affected males to 41 affected females, and 133 non-affected males to 120 non-affected females. This difference is not significant (Z2 0.890). There is therefore no reason to assume that sex-linked cases could at least partially be responsible for the rather large number of affected males. In applying the statistical method to the material of BELL (1922), the sex-ratio between the affected individuals is 454 men to 363 women, and between the nonaffected individuals, 373 men to 362 women. This difference approximates to the threshold of significance (Z2 3.61; threshold of significance: Z2 3.841"). It is therefore possible that cases of sex-linked type of retinitis pigmentosa are included within BELL'S material.
GEOGRAPHICAL DISTRIBUTION
As far as the geographical distribution ofretinitis pigmentosa in Switzerland is concerned, its ubiquitous nature is evident. In a series of isolates, however, we were able to note a concentration of cases with considerably elevated rate of consanguineous marriages. In the Canton Glarus for instance, the rate of first-cousin marriages was 35.0~o, and for cousins until the 5th degree as high as 87.5~o. In order to illustrate the special demographic situation encountered in some regions, we present three typical examples of isolates where a particular accumulation of cases of retinitis pigmentosa was found. (1) The first example is a village (Saas) in the Canton Valais. It is situated in a narrow, rather remote valley. Its population is approximately 1560 inhabitants with a rate of 25.8 ~ of consanguineous marriages between cousins of the first to the third degree. In this village, we found a total of 7 cases of retinitis pigmentosa, 5 cases of macular dystrophy and 3 cases of fundus albipunctatus with hemeralopia. All of these, belonging to 9 different lines of descendants, could be traced back to one and the same ancestor who lived at the beginning of the 17th century (AMMANNAND MARTY 1962). We were recently able to trace a new case of macular dystrophy to this same common source (Ims, Alexander, born 1933, Pol. No. 6061/63). This alternation of three types of tapeto-retinal degeneration found in this pedigree suggests the possibility of different phenotypical manifestations of one and the same abiotrophic process. (2) A further example of an isolate is MoUens in the Canton Valais. The pedigree (Fig. 4) shows a series of consanguineous marriages giving rise to two families affected with retinitis pigmentosa, and a third family showing four sibs with heredoataxia of PIERRE MARIE'S type. This pedigree can be compared with that published by FRANCESCnETTI AND KLEIN (1947) with alternation of several forms of tapetoretinal degenerations and FRIEDREICH'S ataxia. (3) The third isolate with a high incidence of retinitis pigmentosa is the one already described by HANHART (1939). We had the opportunity to re-examine and complete his material. The isolate in question concerns the Wartau community in the St. Gallen Rhine-Valley, the population of which was approximately 3200 in J. neurol. Sci. (1965) 2:183-196
188
F. AMMANN, D. KLEIN, A. FRANCESCHETTI
1939. HANHART had found in this kindred 6 cases of retinitis pigmentosa belonging to 4 sibships. Noteworthy was the extremely benign character and slow progression of this form of retinitis pigmentosa. As a matter of fact, these patients had no notable visual defects, apart from pronounced night-blindness. Ophthalmoscopic findings were those of atypical retinitis pigmentosa.
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Fig. 4. Retini.tis pigmentosa and spino-cerebellar ataxia (PIERRE MARIE'S type) in the same family.
In 1962 we were able to confirm the benign and very slow progressive character of this form of retinitis pigmentosa in most of the original cases of HANr~ARr. Furthermore, we were able to expand HANHART'S pedigree by adding three new families with four affected cases (Fig. 5). The new cases of retinitis pigrnentosa added to the pedigree turned out, however, to be typical and progressive with reduction of visual acuity to perception of light (cases Su, Hans, 1920, XII-22; Ell, Edwin, 1898, XII-1 and Heinrich, 1901, XII-3). It is possible that the aggravated manifestation of the new cases is due to the exogenous source of one of the two alleles. Most of the families belonging to the Wartau isolate could be traced back to the J. neurol. Sci. (1965) 2:183--196
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190
E. A M M A N N , D. K L E I N , A. F R A N C E S C H E T T I
same ancestor living in the 17th century. Furthermore one of these families wit h retinitis pigmentosa (XII-31) is related to a sibship with three cases of BARDET-B1EDt. syndrome (XH-33, 34 and 35). This argues in favour of a certain relationship between the two entities.
ASSOCIATED AFFECTIONS
Deaf-mutism Deaf-mutism appears to be the most important affection associated with retinitis pigmentosa. A m o n g the 118 living individuals of our total material (dominant, recessive, etc.), 16 (i.e., 13.3%) have associated congenital deafness. This is in agreement with the findings in the literature (10.4% according to BELL 1922). In taking in consideration only typical recessive cases of retinitis pigmentosa, the following types of association were met with, each of which is illustrated by one example.
(1) Retinitis pigmentosa combined with deaf-mutism in two brothers (VI-5, 6), offspring of consanguineous parents (family Wy, Fig. 6). (2) Simple retinitis piguaentosa in the mother (IX-12) and retinitis pigmentosa complicated by deaf-mutism in two children (X-7, 8) (family H~i-Lii, Fig. 1).
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IU
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I []
IV
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Fig. 6. Pedigree showing retinitis pigulentosa combined with deaf-mutism.
(3) Simple retinitis pigmentosa (IV-3) and retinitis pigmentosa combined with dcaf-muti~m (VI-3) in two branches of one family (family Hu-Bo, Fig, 7). (4) Alternation of simple retinitis pigmcaRosa (IX-11) and recessive deaf-mutism (X-10, 13; VIH-2, 3, 4) in different sibships and S~nerations of the same family (family Fa-13~, Fig. 8). The last-named pedigree comes from the famous isolate Ayent (Canton Valais), a villag~ with 2400 inhabitants, where HANHARTin 1955 found 70 living deaf-mutes (42 males and 28 females) o r 2 . 9 ~ o (see HANHART1962). Most of the families have been examined otolngically by S~CS]~TnN (1954).
J. neurol. Sci. (1965) 2:183-196
PIGMENTARYDEGENERATIONOF RETINAAND ALLIEDDISORDERS IN SWITZERLAND
191
These examples support the assumption that retinitis pigmentosa and congenital deafness are due to the same autosomal recessive gene with variable expressivity. Our findings are therefore in agreement with the conclusions of LINDENOV (1945) and HALLGREN (1959).
0 II [ ] = Male
i
i
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Fig. 7. Retinitis pigmentosa sine pigmento combined with deaf-mutism, and typical retinitis pigmentosa without deafness, in the same family.
Mental abnormalities and heredo-ataxia
Other affections described in the literature as associated with retinitis pigmentosa, are mental abnormalities and heredo-ataxia (BELL 1922; HALLGREN 1959). Our pedigrees indeed show a certain tendency for the retinitis pigmentosa-families to develop neurological and psychical disorders (see Figs. 9 and 10; see also Figs. 1, 4, 6, 7, 8 and 11), but they do not yet permit us to estimate the frequency of these associations. Bardet-Biedl syndrome
A particular association is the BARDET-BIEDL syndrome. So far, we have encountered 8 cases belonging to 5 families. Two of these families are of special interest. (1) The family Sch-Je - - originally published by JEr~qe (1953) and completed by us (see Fig. 9 of AMMANNet aL 1961) - - shows an alternation of the BARDET-BIEoLsyndrome with a FR6HUCH type of adiposo-genital dystrophy in another branch. (2) The family Ad, published by WILL1(1931) shows an alternation of the BARDET-BmOLsyndrome (XII-33, 34, 35) with simple retinitis pigmentosa in 7 branches from the Wartau isolate (see Fig. 5). Leber's congenital tapeto--retinal amaurosis We were able to establish a genealogical connection between a family affected J. neurol. Sci. (1965) 2:183-196
192
F. A M M A N N
D . K L E I N , A. F R A N C E S C H E T T I
with LEBER'S type of congenital tapeto-retinal degeneration published in 1957 by J/SHR (VI-3, 4, 7, 9), and a family showing 3 cases of typical retinitis pigmentosa (V-3, 5, 7; Fig. 11). The patients belonging to these two sibships were cousins of 3rd to 4th degree. This suggests a certain relationship between LEBER'Scongenital tapetoretinal amaurosis and typical juvenile retinitis pigmentosa. In this connection, we
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Fig. 8. Retinitis pigmentosa in an isolate with deaf-tourism (Ayent, Canton Valais).
would like to mention that the cases published by JOHR (VI-3, 4, 7, 9) were initially considered as examples of congenital optic atrophy, and that it was only owing to electro-retinography that the correct diagnosis could be established (see JtiHR 1957). J. neurol. Sci.
(1965) 2:183-196
PIGMENTARY DEGENERATION OF RETINA A N D ALLIED IN DISORDERS SWITZERLAND
193
i H
I
I
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= Died in infancy II = Consanguineous marriage
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Fig. 9. Retinitis pigmentosa combined with mental disorder.
0 8 1
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Fig. 10. Retinitis pigmentosa in association with mental disorder. J. neurol. Sci. (1965) 2:183-196
194
F. AMMANN, D. KLEIN, A. FRANCESCHETTI
Re,
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I F~ebl. act. Ophta1,1,559~69;
1957,Karger, B$ e
Fig. 11. Typical retinitis pigmentosa and congenital tapeto-retinal amaurosis (Leber) occurring in the same family.
CONCLUSION
In conclusion, we would like to stress the importance of the investigation of isolates (see KLErNANDAMMA~rN1964). A high concentration of heredo-degenerative affections such as retinitis pigmentosa, FRmm'.EICn'Sataxia and deaf-mutism, in these isolates, are fated to be lost for investigations because of the improvement of means of communication. At the present time, these isolates still constitute suitable subjects for a clinical and genetic study of abiotrophies. In fact, such investigations are of particular value, because they afford information as to modes of irtheritance, clinical variability, evolution and associations of heredo--degenerative affections, and thus afford a more adequate classification of abiotrophic diseases. SUMMARY
The authors describe the results of a genetic and epidemiological investigation of pigmentary degeneration of the retina and allied diseases (Bardet-Biedl syndrome, congenital tapeto-retinal amaurosis of Leber, retinitis punctata albeseens, fundus albipunctatus cum hemeralopia, etc.) in Switzerland. About 90% of all cases of pigmentary degeneration of the retina are transmitted by the recessive mode, and 9% by the dominant mode of inheritance. One family alone presents a recessive sex-linked transmission of retinitis pigmentosa. In this family, the female heterozygotes show the typical tapetal reflex as described by FALLS AND COIII~RMAN in 1948. The frequency of pigmentary degeneration of the retina in Switzerland can be estimated at 1 : 7000, the gene frequency at 1 : 84, and the frequency of heterozygotes at 1 : 42. About 10% of all cases are offspring of marriages between first cousins. J. neurol. Sci. (1965) 2:183-196
PIGMENTARY DEGENERATIONOF RETINA AND ALLIED DISORDERS IN SWITZERLAND
195
There are some isolates in Switzerland with a high incidence of retinitis pigmentosa. O n e isolate, in particular, i n the C a n t o n of Valais, allowed us to d e m o n s t r a t e a p h e n o t y p i c a l a l t e r n a t i o n between different types of p i g m e n t a r y degeneration within several branches of a large family originating from a c o m m o n ancestor. A m o n g the hereditary affections associated with t a p e t o - r e t i n a l degenerations, congenital deafness is the most frequent (being associated with retinitis pigmentosa in 13 ~o). The Bardet-Biedl s y n d r o m e was observed in 4 patients out of a p o p u l a t i o n of 700,000 i n h a b i t a n t s (1 : 175,000). Finally, the a u t h o r s stress the i m p o r t a n c e of a n investigation of isolates, since they permit a more satisfactory classification of abiotrophic diseases.
ACKNOWLEDGEMENTS This study was supported by grants of the F o n d s N a t i o n a l Suisse de la Recherche Scientifique (No. 2729) a n d of the Public Health Service, Bethesda, Md. (grant NB 04590-01).
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J. neurol. Sci. (1965) 2:183-196