The epidemiology of retinitis pigmentosa in Denmark


Marianne Haim, Johanne Korchsvej 56, DK-4700 Nastved, Denmark

The dissertation is based on the following publications:

  • 1Haim M, Holm N V & Rosenberg T (1992a): A population survey of retinitis pigmentosa and allied disorders in Denmark. Completeness of registration and quality of data. Acta Ophthalmol (Copenh) 70: 165–177.
  • 2Haim M, Holm N V & Rosenberg T (1992b): Prevalence of retinitis pigmentosa and allied disorders in Denmark I. Main results. Acta Ophthalmol (Copenh) 70: 178–186.
  • 3Haim M (1992a): Prevalence of retinitis pigmentosa and allied disorders in Denmark II. Systemic involvement and age at onset. Acta Ophthalmol (Copenh) 70: 417–426.
  • 4Haim M (1992b): Prevalence of retinitis pigmentosa and allied disorders in Denmark III. Hereditary pattern. Acta Ophthalmol (Copenh) 70: 615–624.
  • 5Haim M & Rosenberg T (1993): Retinitis pigmentosa and allied disorders in Denmark IV. Ophthalmic features in systemic and non-systemic cases. Acta Ophthalmol (Copenh) 71: 597–605.
  • 6Haim M (1993): Retinitis pigmentosa. Problems associated with genetic classification. Clin Genet 44: 62–70.
  • 7Haim M, Grundmann K, Gal A & Rosenberg T (1996): Novel rhodopsin mutation (M216R) in a Danish Family with autosomal dominant retinitis pigmentosa. Ophthalmic Genet 17: 193–197.

The calculations which underlie the fiugures and tables in the basis papers and in the thesis are unified in the addenda, which are available from the author in printocypy or electronically.


Retinitis pigmentosa (RP) was first described and named by Donders in 1857 (Donders 1857). This diagnosis now includes a heterogeneous group of inherited retinal diseases, the precise number of which vary according to the inclusion criteria defined by different investigators (Heckenlively 1982).

RP is considered to be one of the most frequent causes of blindness during working life in the industrialized countries. It is caused by a multiplicity of genetic defects leading to a slowly progressing retinal dystrophy primarily affecting photoreceptors and pigment epithelial cells.

Night blindness, progressive visual field defects and serious glare in daylight conditions are common symptoms, together with decreased visual acuity. Ophthalmoscopic abnormalities such as retinal pigment deposits, attenuation of retinal arterioles, pigment epithelial atrophy and a pale optic nerve head are common signs, together with an early affection of the dark adapted electroretinogram.

The present project was promoted by my former Chief, Thomas Rosenberg, MD, the late Professor Mogens Hauge and by The Danish Association of the Blind. Encouragement was also gained in the course of almost 3 years of working among partially sighted and blind persons. During this time, I became aware of their interest in research of relevance to either themselves or future generations.

The project included the establishment of a National Danish RP-Register. The registered data provided the basis for the epidemiological calculations. Furthermore, some of the problems and experiences revealed by the study were the subject of further investigation. The long-term purpose of the Danish RP-Register was to establish a database for future research, thereby facilitating therapeutic and preventive measures. During the study, several interesting questions arose; regrettably, many of these problems had to be left for future investigations. Nevertheless, since the main study was performed, several topics have been further elaborated in the present text.

Purpose and design

The purpose of this project was to give a complete description of the epidemiology of RP in Denmark. This would be necessary in the study of the molecular aetiology of various types of RP, it would allow comparison with the epidemiology of RP in other countries and could be used as an index in surveillance of hereditary disorders in Denmark. Treatment of RP is central to experimental studies in many laboratories and if or when it becomes clinically available, a survey of patients and families who qualify for the treatment will be essential. Meanwhile, a complete outline of individuals and families with RP in Denmark would improve genetic counselling and explanation of the prognosis in different families.

Unfortunately, a register of Danish RP patients was not available; hence, a complete retrospective inventory of all cases in Denmark was necessary to fulfil the aim. The study thus comprised criteria for registration, a multisource registration of all known cases from 1850 to 1988, and a calculation of the death rate from 1988 to 1997. The epidemiology of RP in general could then be studied.

RP is heterogenous both phenotypically and aetiologically. The second part of the study is a description of the epidemiology of the modes of inheritance of RP and of clinical disorders and syndromes with RP. For this purpose a classification and a flowchart of signs was constructed to improve the taxonomy of the disorders with RP.

Previous Danish RP-literature

Danish epidemiology

The first known epidemiological RP-studies in Denmark were performed by Hansen (1918, 1938) who scrutinized the protocols from some of the large Danish eye clinics of that time. He registered 400 cases and analysed them according to heredity. Epidemiological RP-research concerning children has been resumed in the last two decades and was based on the Register for the Visually Impaired Children (Rosenberg 1987, 1989) and later by the Nordsyn study group (Hansen et al. 1992).

Nosological papers

Systemic RP (diseases in alphabetical order):

Ehlers & Hansen (1981) presented a case with A-beta-lipoproteinemia.

Autosomal dominant microcephaly with lacunar retinal hypopigmentation was described by Warburg & Heuer (1983). Rosenberg et al. (1986, 1987) published two families with syndromic choroideremia in X-chromosomal deletions. A report on Cohen syndrome was published by Warburg et al. (1990). Hobolt & Pedersen (1978) published a family with six cases of mild Hunter disease. A patient with the Hurler/Scheie phenotype was described by Warburg et al. (1978) and followed by a study by Jensen et al. (1980) on two children from a consanguineous marriage presenting with Hurler/Scheie disease. Lawrence-Moon–Bardet–Biedl Syndrome was presented in a review by Warburg (1972a). Brandt et al. (1989) published a case of infantile Refsum disease. Spielmeyer–Vogt–Batten disease was reviewed in Danish by Warburg (1972b) and in English in 1983. Usher syndrome was studied by Lindenov (1945) and by Kjerrumgaard (1948). Christensen et al. described sarcosinemia in a subject with Usher syndrome in 1989 (Christensen et al. 1989). Rosenberg attended a genetic study on Usher syndrome type I (Janecke et al. 1999).

Nonsystemic RP

Westerlund described Choroideremia and its inheritance in 1956 (Westerlund 1956) and Øther investigated choroideremia and the Xg blood group in 1968 (Øther 1968). Genetic mapping of choroideremia was done by Rosenberg & Schwartz (1987) and by Rosenberg et al. (1986, 1987). Rosenberg & Schwartz participated in identification of mutations in choroideremia patients in 1993 (Schwartz et al. 1993) and in 1994 (Bokhoven et al. 1994).

Warburg et al. (1991) dealt with deletion mapping of a retinal cone-rod dystrophy.

In 1957, Ohrt described a patient with gyrate atrophy of choroid and retina (Ohrt 1957). No hyperornithinemia was found. Bargum (1986) discussed the differential diagnoses of ‘normoornithinemic gyrate atrophy’.

Fluorophotometric studies of the blood–retinal barrier permeability in retinitis pigmentosa and in the carrier state were performed by Larsen et al. (1986, 1998) and by Krogsaa et al. (1986).

Warburg & Simonsen (1968) examined a large X-linked family. Two families with X-linked RP (including the above mentioned) were studied by Friedrich et al. (1985, 1992, 1993), including linkage studies. Further linkage studies in these families were published by Friedrich et al. (1987). Inactivation of the X-chromosome in retinitis pigmentosa was covered by Warburg in 1971. Among others, Rosenberg and coworkers studied the X-linked RP-families: both RP2 and RP3 genes were found (Roepman et al. 1996a,b). They also cooperated with Schwahn (Schwahn et al. 1998; Rosenberg et al. 1999).

Finally, Fledelius & Simonsen (1970) and later Henning et al. (1981) discussed sectoral RP.

Recent publications based on the Danish RP-register

As expected, the establishment of the RP register (Haim et al. 1992a) has been essential in later studies of mutations and prevalence of RP. A study on hearing impairment in RP-patients (Parving et al. 1995) showed that 20–50-year-old individuals affected by retinitis pigmentosa had a significantly elevated risk of intrinsic hearing impairment compared with the normal population. The differentiation of Danish patients with Usher syndrome in types I, II and III has been the subject in a study by Rosenberg et al. in 1997. Furthermore, a syndrome with retinitis pigmentosa, progressive hearing impairment, vestibular dysfunction, and congenital cataract was published by Rosenberg & Parving (1996). A novel RP-locus (RP18) was found by linkage analysis in family no. 1 (paper 7; Haim et al. 1996) and described by Xu et al. (1996).

Earlier international epidemiological studies

Several authors have studied nonpopulation based groups of RP patients with the purpose of genetic classification (Jay 1972; Bird 1975; Boughman 1978; Fishman 1978; Berson 1981; Moore 1992).

Epidemiological surveys from geographically well-defined populations have been reported from different parts of the world. Amman et al. (1965) reported the genetic delineations of 93 families (101 patients) from different parts of Switzerland a prevalence rate of 1:7000. Unfortunately, the authors did not define their inclusion criteria. All families already published from the country were included and families registered at the Genetic Clinic in Geneva were probably also included. The registration of the families started in 1959, but the number of persons examined is not known. The first epidemiological (Population based) investigation intending to include all cases from a geographically demarcated area was made by Bunker et al. in 1984 in the State of Maine, USA. The state comprised 1 124 660 inhabitants in 1980. The cases were ascertained through multiple sources within the health system. Patients were visited in their homes for evaluation of the genetic pattern and medical records were consulted to ensure the diagnosis. If the diagnosis was not found to be convincing, the patients were invited for further examination. This program was more intensive than the present, because the number of patients included was 226 and only prevalent cases were registered. A prevalence rate of 1:4756 was found.

Bundey & Crews (1984a) presented a population study on RP from the City of Birmingham, England. Multiple sources were used. Due to the lack of an outpatient diagnostic index, appointment books were consulted. Some 252 patients were identified as prevalent in Birmingham, 30 June 1978; 227 were seen at home or at the eye clinic. Medical files were used to supplement the clinical investigations. The prevalence rate found was 1:4869.

Grøndahl (1986) performed an analysis of 89 RP-probands from four Norwegian counties. All available sources were used and all patients and 407 first relatives were examined thoroughly by the author. Hearing evaluation was also included. In contrast to the present study this work was very intensive, covering only a small population of 800 000 inhabitants. His RP prevalence rate was therefore 1:8247.

One year later Hu (1987) performed an RP-population study in China and found a 1:3784 prevalence rate. In this 10-year study, probands were found by ophthalmic workers and by a survey of hospital files. The probands were ascertained from a district in Shanghai counting 24 100 inhabitants. The author examined 151 probands and 58 secondary cases. Age at onset and refractive state were studied besides the genetic pattern (Table 1).

Table 1.  RP prevalence
Amman et al.19651:7000
Bunker et al. 19841:4756
Bundey & Crews19841:4869

A multicentre 2-month study in Japan was carried out in 1989, initially in 13 hospitals (Hayakawa et al. 1993) and followed up later (Hayakawa et al. 1997) in a total of 18 hospitals. They encountered a total of 253 patients with typical retinitis pigmentosa. The study was nation-wide and estimated to cover the Japanese population. There was, unfortunately, no figure included for the total population in Japan that year, but the 253 cases were probably a small portion of all RP-cases in that country. Inclusion criteria were not presented except for typical, nonsystemic disease. The papers were primarily concerned with genetic types and the influence of consanguineous marriages on the prevalence of the autosomal recessive type of RP.

In Valencia, Spain, Najera et al. (1995) investigated 145 typical RP-cases from 132 families with respect to genetic classification. The persons were retrieved from the local RP association created in 1986. The population in the community comprised 3 875 234 individuals. A large number of autosomal recessive cases (31.8%) were found, while the X-linked cases (1.5%) were rare.

From the previous epidemiological studies an RP prevalence rate of 1:4000–8000 inhabitants could be estimated. The epidemiological picture of RP with respect to systemic involvement, clinical spectrum and inheritance does, however, vary considerably.

Statistical methods

In the published papers as well as in the present dissertation, the odds-ratio is used as a means of the ratio between two prevalence rates. This can also be designated as prevalence ratio. This ratio was used to compare standardized prevalence rates, thereby compensating for different age distributions among different study populations.

Moving average was used to smooth out the differences in prevalence to eliminate random fluctuations (Kemp & Nielsen 1967) according to the expression: ‘prev’ b = (a + b + c) × 100 000/(A − a) + (B − b) + (C − c). A, B and C were numbers of live born individuals in three successive cohorts. a, b and c were the number of registered RP-affected individuals in these cohorts. The sum of the registered cases in the same three cohorts (a + b + c) was used to calculate a “prevalence” for cohort number two (‘prev’ b). The calculation then moved one cohort and repeated the procedure until all new “prevalence” values were found.

The age specific prevalence values were evaluated with a test for trend, meaning a dose–response relationship using a Chi-square-test as described by Schlesselman (1982). With one degree of freedom, χ2 = [T1 − (n1T27N)]2/V.

The calculations of completeness of selected groups of patients in the Danish RP-register used the method of Bishop et al. 1975) which is based on the assumption that the more patients registered from multiple independent sources, the higher the completeness. (Formulas: Estimate = ^N = [X(+a) × X(+b)]/X(a,b) = number of persons with RP neither registered in source a nor in source b

X(+a) = number of persons registered in source a and not in source b. X(+b) = number of persons registered in source b and not in source a. X(a,b) = number of persons registered in both sources a and b.

Completeness = [X(a − total) + X(b − total)  −  X(a,b)]  ×  
100%/X(a  −  total)  +  X(b  −  total)  −  X(a,b)  +  ^N

X(a − total) = total number of persons registered in source a. X(b − total) = total number of persons registered in source b (see calculations in addendum 1).

To secure the classification reliability kappa-statistics were used (Fleiss 1973, pp. 140–147, 175) (see calculations in addendum 6).

The χ2 test was used to compare refractive errors in the Leber groups.

Ninety-nine per cent confidence limits were employed (Lentner 1982) comparing the sex-rate in the simplex group of nonsystemic RP-cases with typical RP. The same method was employed when the number of males and females were compared for the age-at-onset groups other than 6–<18 years (see addendum 6).

The Danish RP-register (Haim et al. 1992a)

The Danish RP-register was established in the period from 1986 to 1989, and ready for study with a cut-off date of 1 January 1990. The material was intended to include all RP-cases in Denmark diagnosed in the 139-year period from 1850 until 1989. The inclusion criteria is in Table 2. The paper (Haim et al. 1992a) includes a detailed description of the following topics: 1. RP-criteria, 2. Data verification, 3. Completeness of the register, and 4. Quality of the material. The main result of the study was determining an overall expression for the frequency of retinitis pigmentosa in the Danish population over the whole study period of 140 years. During this period, the population had grown from 1 414 648 inhabitants in 1850 to 5 129 778 in 1990. It is assumed that the gene pool of the population was unchanged. Immigration was estimated to be too small to significantly influence the result. The incidence rate therefore was assumed constant for the period in question. Premature death was limited to 16% (see page 9 of this thesis) of the material. The rate of reproduction was not calculated in this material. It is assumed that RP does not alter the rate of reproduction compared to the general population. Decreased reproduction was only suspected in small groups of seriously systemically affected persons. Accordingly, the Hardy–Weinberg equilibrium was assumed to be fulfilled. This was considered to legitimate the use of the proportion: cumulated incidence rate = cumulated number of affected persons/number of live-born individuals in the birth year cohorts studied (Kleinbaum et al. 1982, pp. 103–104).

Table 2.  Inclusion criteria for the Danish RP-register
Inclusion criteria for the Danish RP-register:
Persons who are
 1. Fulfilling the diagnostic criteria*
 2. Identifiable through civil registers
 3. Born before 1 January 1988
 4. Living in Denmark after 1850 and before 1990
*Diagnostic criteria: (described in more detail in Haim et al. 1992a)
 a. Night blindness
 b. Ophthalmoscopic abnormalities of the retina
 c. Electroretinographic changes
 d. Abnormalities of the visual field
Cases were classified as possible, probable or certain according to the presence of specified diagnostic criteria
  At least
a or ba+d ora+b or
 b+d ora+c or
 cb+c or

Data sources and data verification

The use of all available geographically well distributed sources secured the inclusion of patients from all cities, towns, and rural areas, and all social classes were represented. The exhaustive criteria (Table 2) for inclusion (and exclusion) of probands and secondary cases make up a ‘standardization’ effort and implicate a precise delimitation of the material. The criteria used were common clinical and civil parameters, which guarantee that the material is generally applicable, and comparably independent of differences in the clinical conception of RP contingent on the use of identical criteria.

The great majority fulfilled most inclusion criteria and subsequently was described as ‘certain’. This was true for 77% of nonsystemic probands and for 74% of the systemic probands. In most cases the temporal sequence of the symptoms used for RP-definition and classification was also ‘typical’, with night blindness as the initial symptom followed by visual field defects and by decreasing visual acuity (60% of nonsystemic RP-cases prevalent at 1 January 1988) (Table 3).

Table 3.  Probands and secondary cases registered according to the presence of a nonsystemic or systemic disease
 ProbandsSecondary casesTotal
Nonsystemic RP608472941093
Systemic RP30124046551
Unknown if systemic71776335246

ERG, when present, was a valuable inclusion criterion. Of the prevalent cases, 734 (56%) had their diagnosis verified by ERG.

About 100 cases diagnosed as RP in the original files did not fulfil the diagnostic criteria and were therefore excluded.

Three persons with unilateral RP were excluded. Patients with a verified inflammatory disease mimicking RP (e.g. bird-shot retinopathy, diffuse chorioretinitis, and congenital syphilis) were also excluded. Finally, seven cases with cicatricial changes after retinopathy of prematurity fulfilling the inclusion criteria were excluded.

Data quality

Any registration method suffers from inherent shortcomings. The present data collection included a direct collaboration with the RP patient organization. Members are kept up to date by periodicals and by attending meetings. Patients were informed about the project and encouraged to answer a questionnaire when visiting practising ophthalmologists and eye departments. All practising ophthalmologists and eye departments in Denmark were notified at the beginning of the project.

The efficiency of a retrospective registration of disease within a certain geographical area depends on the existence, the quality, and the accessibility of relevant data in already existing registers, provided the necessary legislative rules are followed. Registration from primary sources depends on cooperation from patients, medical personnel, and institutions.

Consecutive cases seen in an ophthalmological department may under certain limitations be considered representative of the RP-prevalence in an area (Amman et al. 1965) or of the relative genetic frequencies (Fishman 1978; Jay 1982; Dickinson & Mulhall 1989). Bias of ascertainment in such materials depends on referring methods, tradition, and severity of symptoms, as well as accessibility and financial considerations. A population survey encouraging patients to answer a questionnaire may cover an even larger part of the RP-population through self-registration depending on patient information and possible personal benefits from registration (Boughman 1978). Hu (1982) performed a very thorough registration by ophthalmoscopic screening of a large population.

The registration method which was applied in the present work (Haim et al. 1992a) benefited from the Danish health care system, which is free of charge for the patient and equally accessible for all inhabitants, and thus reduces the barriers of accessibility and income. The patient accept of registration remains an even more important factor. The strict Danish laws concerning registration, Personal Registration Act, no. 239 (1968) and recommendations (Betænkning no. 784, 1976) from the Committee for Integration of Electronic Data Processing in Civil Registration offer a high degree of protection against misuse of the registered data. In consequence, there was a positive attitude towards the establishment of the RP-register.

Data completeness

Eight sources were employed: 1. The National Eye Clinic for The Visually Impaired and the National Institute for the Blind and Partially Sighted; 2. Hospital departments; 3. Ophthalmologists with private practice; 4. Other physicians; 5. Other institutions; 6. The National Diagnostic Index for In-patients; 7. The Danish Association of the Blind; 8. Family members. The sources 1, 2, 3, 6, 7 and 8 were the most relevant for this study.

Estimates of the completeness of registration were carried out by comparing the sources in pairs using Bishop's formula (see page 7 of this thesis and addendum 1). The method of Bishop was found suitable for estimation of completeness, well knowing that the sources were not completely independent (Haim et al. 1992a).

Regarding persons born before 1911, 1,2,7 and 8 were the sources that registered patients in the first half of this century. The combination of source 7 and source 8 reveals 16.6% completeness while the other combinations suggest 35.8%, 42.1%, 38.4%, 42.3% and 51.7%. The last figure was based on source 1 and 2. These differences indicate that the sources were not totally independent. Overall, the completeness was estimated to 40%, the relevance of the different sources taken into consideration (Haim et al. 1992a).

Regarding persons born 1911–80 the relevant sources were 1, 2, 3, 6, 7 and 8, while 4 and 5 contributed with only very few cases. Based on the relative contribution, source 1, which was the largest, was compared with three other sources: 6, 7 and 8 being the most independent. Regarding source 6, ‘the National Diagnostic index for in-patients’, patients who died before 1977 were not included. Of the 1003 cases registered through source 1, 174 had died before 1977. Excluding these 174 patients, the completeness calculated from source 1 and 6 was 68%.

Source 7 only comprised persons with a visual acuity of 0.1 or less or a visual field of 10 degrees or less. About half of the 1003 persons registered by source 1 probably had a better visual acuity. If they were excluded, the combination of sources 1 and 7 resulted in a completeness of 48%. The calculation is seen to be rather insensitive to such differences in the sources, but small increases appear.

An overall estimate of the completeness of registration of the 1911–80 birth cohort was 80%. This estimate was motivated by the high weighting of the combination of source 1 and source 8, because they were the most independent and none of these sources was limited with regard to visual acuity. Both sources covered the whole period in question. The considerations above concerning sources 6 and 7 also tend towards a higher completeness than a simple average of the chosen calculations.

It is obvious that the inclusion of additional sources tended to increase completeness. A simultaneous evaluation of all eight sources therefore would also increase registration completeness.

Sources 2 and 3 represented 19 hospital departments and 59 ophthalmologists in private practice. Some patients were registered from more than one of these. This fact also tended to increase the general completeness.

The subgroups: males, females, systemic cases, nonsystemic cases, cases with known inheritance, simplex cases, typical cases, atypical cases, Usher syndrome and mentally retarded persons were estimated according to Bishop (addendum 6). The results were nonsignificant, indicating that these subgroups were too small for this calculation.

To sum up, a completeness of about 40% was estimated for the persons with RP born before 1911 and about 80% for the cohorts born 1911–80, while the youngest patients were registered by the National Registry for Visually Impaired Children and therefore estimated to be included with a completeness of 90%.

Cumulated incidence rate

With the purpose of describing a lifelong risk of developing RP, I estimated the proportion ‘cumulated incidence rate’ defined as the number of new cases diagnosed in a period per number of unaffected persons at the beginning of the period (Kleinbaum et al. 1982). The period starts at the beginning of life for each birth cohort, and ends late in life.

The method presupposes that the study population is the same during the observation period. This is not true because of deaths and movements to and from the country. On the other hand, in a stable population as in Denmark this will only induce a small error because of the large size of the population compared to the number of RP-patients. Another possible source of error would be premature death of some RP-patients. The great majority, 84%, however, have a normal life span (see below). In the beginning of the study period the infant mortality rate was a reduction factor. The oldest figures from the Danish vital statistics on this subject are from 1901 where the postnatal death rate was 1711 per 10 000 live-born children with married parents and 2566 per 10 000 live-born children with unmarried parents. Ten years later, in 1911, these figures were 916 and 1834 per 10 000, increasing the number of surviving individuals with chronic disease-genes such as RP-genes, and thereby the risk of having RP. As the completeness in this period is estimated to be as low as 40%, this error is estimated to be small. Later the post natal death rate was even lower and was supposed not to influence the cumulated incidence of RP.

When corrected for completeness the curve in Fig. 1 reveals estimated risks of approximately 40–45 males/100 000 live-born and 35–40 females/100 000 live-born (Haim et al. 1992a).

Figure 1.

Estimated number of RP patients per 100 000 live-born in Denmark divided in birth cohorts and corrected according to completeness. The upper parts of the columns therefore include the number of patients per 100 000 live-born calculated to have escaped registration.

A more precise measurement for the risk would be obtainable if either age at RP-debut or RP-diagnosis was compared with the life length for the persons with RP. Unfortunately, the most common initial symptom of RP, night blindness, has an insidious onset and may be unperceived for many years; the patients may become cognisant of this disability by chance. As an example, many Danish RP-patients reported that their night blindness started during the blackout in the years of World War II. The time of diagnosis was equally uncertain because most files did not include this information.

Death rate

The prevalent RP-cases per 1 January 1988 were analysed with regard to the deaths occurring in the period from 1 January 1988 to 18 September 1997. A number of 213 died in this period. These cases were analysed according to complexity showing a death rate equal to the rest of the Danish population in the groups: Nonsystemic RP, Usher syndrome, and unknown if systemic disease (95% confidence intervals). They included 84% of the deceased. The residual groups (Bardet–Biedl syndrome, Spielmeyer–Vogt disease, other defined syndromes, and unknown syndromes or associations) had a higher death rate due to their systemic disease (Haim 1992a).

By re-analysing the figures, it appeared that seven of the 1301 patients included as prevalent at 1 January 1988 in fact had left the country before this date and they were all still living. One of them had Bardet–Biedl syndrome and one had Usher syndrome. One was unknown regarding systemic disease and four were nonsystemic cases. The published results are not significantly influenced by this re-analysis (calculations in addendum 6).

To obtain an estimate of the incidence of RP, the annual numbers of newly registered patients during the period 1990–97 were studied.

Only persons being alive at 1 January 1990 were included in the incidence calculations. Even persons that obviously had been affected for years were included, taking into account the possible delay from debut of the first RP-symptom to diagnosis, and the time span from diagnosis to registration. ‘Recent RP’ was defined as an RP-case with a debut of the first RP-symptom within the last three years prior to registration. An average incidence for the years 1990–97 was 0.79 persons per 100 000 population per year. The size of the total population was used as a figure for the population at risk due to the rareness of the disease (Table 4).

Table 4.  Persons registered in the Danish RP-register since 1 January 1990
 PersonsPersons with
recent RP-debut
% recent
at 1 Jan
per 100 000
  • ‘Mean figures’ for 1990–97.

  • *

    of registration.

199035165465 135 4090.68
199149255515 146 4690.95
199230203675 162 1260.58
199325151605 180 6140.48
199455343625 196 642 1.06
199543341795 215 7180.82
199643270635 251 0270.82
199748412855 275 121 0.93
Total3282122066(5 195 3910.79)

An average of 41 persons were registered per year: 21 males and 20 females. It is surprising that males and females were almost equally represented in contrast to the rest of the material (Males/females: 1990: 20/15. 1991: 29/20. 1992: 14/16. 1993: 10/15. 1994: 25/30. 1995: 21/22. 1996: 22/21. 1997: 29/19). If only patients with ‘recent’ RP-debut were included a male/female ratio of 131/111 (54%/46%) was found, corresponding to the findings in the rest of the material.

To sum up the cumulated incidence of RP was 40–45 males and 35–40 females per 100 000 live-born individuals and the incidence was 0.79 persons per 100 000 population.

Classification reliability

The nosological classification of the material was, with two inevitable exceptions (Usher syndrome was defined with noncongenital RP, and choroideremia as an X-linked trait), based on mutually independent criteria. This principle has been adopted to establish a database in which it is always possible to cross-reference between two characteristics, thus avoiding arguing in a circle. The classification has been evaluated by an intra- and inter-observer test. Randomly selected cases were reclassified by the author (A1 and A2) and by the second observer (B) Fig. 2. Kappa-statistics are applied, finding a highly significant agreement concerning all tests: P < 0.0001 (see addendum 6 for calculations) (Fleiss 1973).

Figure 2.

Intra- and inter-observer variation. Evaluation of the classification validity concerning diagnostic reliability, age at onset, complexity, mode of heredity, nosological groups and electroretinographic groups. A1 is the original classification by the first observer. A2 is the classification by re-inspection by the first observer (intra-observer trial). B is the classification by the second observer (inter-observer trial). Unchanged parameters are shown in the dark diagonal and deviations in the white fields. The columns in the bottom right indicate the unspecified group of classification (except for diagnostic validity). The grey squares indicates the classical Mendelian modes of inheritance.

Prevalence calculations

World Standardized Prevalence Rates

The purpose of this part of the study was to obtain reliable population based prevalence figures on a national scale.

The prevalence calculations were based on the assumption of a stable population and on the data defined in paper 1 (Haim et al. 1992a). The World Standardized Prevalence Rates (WSPR) based on the WHO standard populations (IARC 1987) was for the first time introduced in RP-research. WSPR enabled the material to be compared with future studies, independent of the age pattern of the populations in question. The use of this method is based on rather stable specific prevalence rates within the age groups. The increase of female cases in the 1960s may induce an error, estimated to be small in comparison with the advantage of the method.

WSPR was found to be 25.3/100 000 for males and 19.3/100 000 for females. The overall WSPR of RP was 22.4/100 000 population.

Age specific prevalence rates

Based on Figs 3 and 4 the age specific prevalence rates were found to be 35–40 male cases per 100 000 population and 25–30 female cases per 100 000 (Haim et al. 1992b). To evaluate whether the fluctuations shown in Fig. 3 were random or represented a tendency, the figures for annual fluctuation were recalculated by a moving 3-cohort average technique (Kemp & Nielsen 1967) (Figs 5 and 6; values in addendum 6). After averaging, there was still a maximum prevalence of 35–40 males per 100 000, but reaching the maximum level at 50 years of age instead of 35–40 years.

Figure 3.

Age specific prevalence rates: number of RP patients in Denmark at 1 January 1998 per 100 000 inhabitants of the same age and sex.

Figure 4.

Corrected age specific prevalence rates: number of RP patients in Denmark at 1 January 1988 per 100 000 inhabitants of the same age and sex. Figures are corrected according to the completeness of the material.

Figure 5.

RP prevalence: males (crude values and 3-cohort moving average).

Figure 6.

RP prevalence: females (crude values and 3-cohort moving average).

The female prevalence levelled out at age 45 years with 25–30 cases per 100 000 population. This level remained stable until 55 years of age when a new increase in prevalence appeared from 55 to 74 years. The maximum was 38 females/100 000 population (Figs 3 and 4).

Calculations on nonsystemic RP alone did not change the picture (Fig. 3 in Haim et al. 1992b, and Figs 7 and 8 in this paper). The trend is highly significant (P = 0.64) for both males and females, confirming the increase in prevalence with increasing age until the curves cross each other at the age of 60. The values with the moving average technique are shown as a curve to give a better visual expression, well knowing that the figures were not illustrating a course.

Figure 7.

Nonsystemic RP prevalence: males (crude values and 3-cohort moving average).

Figure 8.

Nonsystemic RP prevalence: females (crude values and 3-cohort moving average).

The excess of affected women aged 55–74 years of age prompted a recapitulation of their files. Three-quarters of these women had a late debut of RP (>30 years of age). The hypothesis was made that the phenomenon is due to a later manifestation of X-linked RP in heterozygous women (see paper 2 and paper 3; Haim et al. 1992a,b). It was documented that one-quarter were actually carriers of X-linked RP. The study revealed that 50% were sporadic cases (simplex cases, see paper 3; Haim 1992a) with a debut later than 30 years of age. Moving average technique was applied to this group too, showing that these females had a statistically significant excess of cases from 60 to 74 years of age (see pages 16–17 of this thesis). This result might suggest that the simplex group includes a number of women who are carriers of X-linked RP.

Systemic involvement in retinitis pigmentosa


The presence or absence of systemic manifestations represents a taxonomic master key within the field of tapetoretinal dystrophies. The molecular background for this is that some RP-genes are expressed in the retina exclusively while other RP-genes are expressed ubiquitously or in other organs in embryological or postnatal life. A multitude of signs of different types makes up a heterogeneous collection of congenital anomalies, metabolic defects, cognitive and perceptual impairment, as well as other organ specific dysfunctions. Approximately 140 nosological entities are known that include RP as a manifestation. Some of these disorders have been known for more than a hundred years, e.g. Laurence–Moon syndrome (1866). A number of new disorders were delineated in the first half of this century, e.g. Usher disease (1914), Bardet–Biedl syndrome (1920, 1922) and Refsum disease (1949). The list of new diseases extended rapidly in the second half of the century, e.g. Kearn–Sayre syndrome (1958), Zellweger syndrome (Bowen et al. 1964), Cohen syndrome (1973) and CDG syndrome (1980). The development of new methods within molecular biology, histobiochemistry, pathology, and cytogenetics was instrumental for the identification and characterization of new diseases associated with RP. The growing insight in the pathophysiology of these disorders has led to new classifications according to the subcellular localization of the disturbance, e.g. lysosymal, membrane-bound mitochondrial or peroxisomal disorders. Recently, molecular genetics have expanded our insight in the aetiology of many types of syndromic RP. On the other hand, the recognition of a noticeable genetic heterogeneity in what was believed to be homogenous disorders, and genetic homogeneity among what was believed to be separate diseases, has disturbed our handed down clinical taxonomy (Warburg 1998).

Clinical heterogeneity of Danish RP patients

Tables 5 and 6 shows the total RP-population prevalent at 1 January 1988. Twenty-eight per cent had systemic involvement and were therefore classified as having systemic RP. According to the protocol of the RP register, systemic RP was subdivided into six parts, the three of which constituted the relatively frequent clinical entities of Usher disease, Bardet–Biedl syndrome, and Spielmeyer–Vogt (Battens) disease. The corresponding prevalence rates of these disorders have to my knowledge not been elucidated in the same population prior to this investigation. With a few exceptions, RP syndromes are extremely rare in the Danish population, which was the reason why they were lumped under the heading, other defined syndromes. The subgroup, unknown syndromes or associations, includes identified syndromes, unidentified syndromes, and random associations. This distinction was made necessary because many cases were diagnostically obscure despite meticulous evaluation. Finally, the subgroup, unknown if representing a syndrome or not, was made up of cases with inconclusive information on possible systemic involvement.

Table 5.  Prevalent RP patients (probands and secondary cases) at 1 January 1988, divided into age groups and groups of complexity
Systemic (syndromes and diseases)Unknown if
Other defined
0–4270 284311005313
5–9287 2281723127133
10–14343 77126324210249
15–19369 348431086215387
20–24421 64359910225289
25–29378 7504610112110888
30–34373 119581410036293
35–39378 02873167021310121
40–44416 7359512402119133
45–49315 99661173016593
50–54272 51060124024688
55–59255 36061113003886
60–64255 48066111007691
65–69242 61360122002884
70–74203 6184870003866
75–79166 9782960001642
80+177 7923240000945
Total5 129 254837157691519108961301
Table 6.  Sex distribution and prevalence rates in nonsystemic and in different types of systemic RP (complexity groups)
 No. of patientsOdds
Prevalence rates
FemaleMaleTotal (%)Per
100 000
Corrected for completeness*World
  • *

    An overall completeness of 80% is used.

Nonsystemic RP3724651.3837 (64)16.320.413.8
Usher disease66911.4157 (12)
Bardet–Biedl syndrome26431.769 (5)
Spielmeyr–Vogt disease781.215 (1)
Other defined syndromes9101.119 (1)
Unknown syndromes or
49591.2108 (8)2.12.6 
Unknown, if syndrome57390.796 (7)1.92.3 
Total5867151.31301 (98)25.431.7 

The principal division of the material into systemic and nonsystemic RP offered no problems in the majority of cases. The largest group, nonsystemic RP, was simply applied in the absence of information on systemic findings. This may have introduced a certain degree of under-registration of systemic RP due to the ignorance of milder systemic signs such as milder dysmorphologies, borderline hearing impairment, or slight mental retardation. Also, some disorders with a late manifestation of generalized symptoms may incorrectly be classified as nonsystemic.

Certain population groups in need of special care and services from the society, do have a recognized overrepresentation of RP. This is an especially pronounced tendency in individuals with either mental deficiencies or hearing impairments. The material represents a unique basis for further analysis of these groups.

Mental retardation

To preserve a collegiate mutual agreement concerning these patients, details have not been published until now.

The prevalence study (Haim et al. 1992b) included 144 (11% of all RP-cases) mentally retarded individuals. Children below the age of 18 years accounted for 37/144 (26%). The Bardet–Biedl syndrome accounted for 57 persons. Seven mentally retarded RP-patients were ascertained with other known syndromes (Ayazi syndrome (2 patients), Cohen syndrome (1 patient), Usher syndrome type I with ataxia (1 patient), del X (q13q21.3) with cleft palate and agenesis of corpus callosum (1 patient), Cockayne syndrome (1 patient), and Refsum syndrome (1 patient). Eventually, 80 patients were classified within the group of unknown syndromes or associations because of their mental handicap.

Features found in association with mental retardation and RP are listed in Table 7.

Table 7.  Symptoms found in association with mental retardation and RP, listed according to prevalence in Denmark at 1 January 1988
Symptom/featureNumber% of the 144 cases
Congenital hearing1510
Cerebral palsy75
Acquired hearing54
Cleft palate32
Diabetes mellitus32
Congenital myxoedema21.4
Malformations of hands21.4
Malformations of larynx21.4
Each of the following features was found in one case only:
Haemolytic anaemiaAnal atresia 
Congenital megacolonHepatic cirrhosis 
Kyphosis ScheuermannSkeletal malformations 
Feet malformationsGenital malformations 
Nail malformationsSkin malformations 
Teeth malformationMyotonic dystrophy 
OxycephalyPubertas praecox 
Pyloric stenosis

The mentally retarded persons with RP comprised 107 adults and 37 children. Children were defined as persons aged 0 to <18 years in agreement with the National Registry for the Visually Impaired Children. Mentally retarded persons comprise 1–2% of the Danish population (Dupont 1975), but 144/1301 = 11% of the RP-population, indicating a much larger prevalence of RP among the mentally retarded. The RP-prevalence study (Haim et al. 1992b) included 148 children, among which 37/148 (25%) were mentally retarded. These figures are in accordance with the estimates by Warburg (1994), Grimsmo (1990) and Hansen et al. (1992). The mentally retarded individuals are probably still underdiagnosed, as with the CDG syndrome (Andreasson et al. 1992). Difficulties with visual orientation, especially in the dark, and intolerance to bright light should therefore lead to ophthalmological examinations with special reference to some type of RP, and ERG should be measured on liberal criteria.

Conclusion: The prevalence of RP among the mentally retarded persons is much higher, especially among the children, than expected from the prevalence of mental retardation in the population (1–2%).

Hearing impairment

Information on congenital hearing impairment was present in 157/1301 RP cases prevalent at 1 January 1988 (12%). These cases were classified with the Usher group. RP-patients with acquired hearing loss were included in the nonsystemic group. In the present study (Haim 1992a) 3.1 Usher cases/100 000 (all ages) were found. Usher-2 and Usher-3 cases are probably included in the nonsystemic cases. A later prevalence study among the 20–49-year-old individuals based on the RP-register and complemented with an audiological investigation confirmed this assumption (Rosenberg et al. 1997). A prevalence of 1.5/100 000 Usher type I was found. Type II had a prevalence of 2.2/100 000, while type III included 0.1/100 000. The recent study (Rosenberg et al. 1997) revealed that 21% of the Usher cases were misclassified as nonsystemic RP-cases in the primary study, using only retrospective ophthalmological informations. An even higher prevalence (6.2/100 000) among persons aged over 15 years, based on both ophthalmological and audiological sources was found in the Birmingham study of Usher syndrome (Hope et al. 1997). Probably, the Usher diagnosis is prone to be missed both in primary ophthalmological and audiological care units. An audiological examination should be included in the assessment of every RP case and the examination of patients with neuronal hearing impairment should include an ophthalmological examination as well.

Bardet–Biedl syndrome

Sixty-nine individuals with the Bardet–Biedl syndrome were found among the 1301 prevalent RP-cases per 1.1. 1988, representing 5% of the prevalent RP-cases. The age profiles were different in nonsystemic RP and in the Bardet–Biedl syndrome (Haim 1992a) (Fig. 9). Assuming stable populations this indicated both an earlier debut of the ocular disease and a premature death. The premature death in Bardet–Biedl syndrome has been confirmed by Riise (1996).

Figure 9.

The age distribution among persons with Bardet–Biedl syndrome compared with the age distribution among nonsystemic RP patients. Different scales for the crude prevalence are used according to the number of persons in the two patient groups.

A reassessment of the files of the 69 prevalent cases of Bardet–Biedl syndrome showed that 57 (83%) had mental retardation, often to a mild degree. Some of these patients had IQ-scores below normal and/or received special educational support. Some were working in sheltered workshops. Other patients (12 cases, 17%) had normal IQ-scores and/or had been able to complete a normal school education without extra help and/or were employed in a normal job.

Common symptoms were polydactyly (74%) and obesity (86%). Renal disease was noted in 13 files (19%), and one (1.4%) had diabetes mellitus.

Compared with the findings of Riise (1997), the large number of cases with polydactyly (80%) and obesity (88%) were concurrent. Riise found mental retardation in 8–20%, but remarked that 7 out of 9 patients exhibited normal social accomplishments in adult life even though they had had a low intelligence score while in school!

Unidentified syndromes

The files of the 108 cases with ‘unknown syndromes or associations’ were recently revisited to see if new diagnoses were established. Eighty of these cases had mental retardation. Out of these, 12 specific diagnoses were established (some with random association with RP), after the closing date for the prevalence study:

  • • Usher II disease with mental retardation of unknown cause (2);

  • • CDG syndrome(Carbohydrate deficient glycoprotein syndrome) (1);

  • • Bardet–Biedl syndrome (3);

  • • cystathionase deficiency (1);

  • • Trisomia 9 and myotonic dystrophy (1);

  • • Down syndrome and RP (2);

  • • mentally retarded individual being a member of a known X-linked RP-family (1);

  • • Dandy–Walker syndrome (1).

Patients without mental retardation were included in the group because of one of the following disorders: skeletal malformations, polydactyly, cleft palate, myotonic dystrophy, cerebral paresis, muscular dystrophy, epilepsy, progressive encephalopathy (other than Batten disease/Spielmeyer–Vogt disease), cerebellar ataxia, congenital heart disease, congenital liver disease, chronic nephritis, the combination of obesity and thyroid insufficiency, dwarfism, or pulmonary stenosis.

Incomplete assessment

The group called ‘unknown if syndrome or not’ contained cases with a minimum of or no supplementary information other than RP-symptoms. This group differed from the nonsystemic RP-group regarding sex ratio, underscoring the importance of keeping these cases apart from the calculations. On the other hand, a large proportion of nonsystemic RP was supposed to be included in this group.

Age at onset

The age at onset has been used as a prognostic parameter (Krill 1972). The purpose of studying the age at onset in RP was to assess if age and prognosis were associated, being able to answer clinical questions as: When should a child of an affected RP-patient be examined? When should deaf children be screened for RP? When is the Bardet–Biedl patient expected to have visual problems? At what age is an unaffected RP-family member no longer in the risk group?

The age at onset of RP-symptoms is a subjective parameter, which for many patients is difficult to recall, especially when asked later in life. The patient's answer concerning age at onset is also dependent on the manner in which the question is formulated. Symptoms of night blindness and visual field defects appear insidiously and progress slowly. The use of an exact age of debut in this study therefore was estimated to give misleading information. Patients most often become aware of visual discomfort in association with some specific event. As an example, many persons suffering from night blindness reported that the first symptoms occurred during the blackout in World War II. Males often became aware of the symptom in connection with military service. The most frequent problem concerning age at onset was the statement of ‘always’ being night blind. In this study, the statement ‘always’ night blind in the absence of nystagmus led to the categorization of ‘3 months to <3 years’. Nevertheless, during the project detailed interviews with some of the patients on later occasions have disclosed that an age at onset between 6 and <18 years may be a more realistic ‘translation’ of ‘always’. Consequently, age at onset for the different entities was a rough estimate.

Males and females

Figure 10 presents the age of debut for males and females separately (Haim 1992a). The relative frequency of age at onset between 6 and 18 years was significantly higher for males (37% of male cases with known age at onset) than for females (28%). In other age intervals no significant differences were found.

Figure 10.

Distribution of age at onset in the whole material of RP patients (N = 1301). Note the unequal length of the age intervals chosen.

RP is generally considered a disease with debut in children and young adults. The present study confirmed this view, especially with regard to systemic RP-groups. Nevertheless, in the nonsystemic RP-cases age at onset was often recorded at an older age. Figure 11 illustrates this observation. Nineteen per cent of all nonsystemic RP-cases had an RP-debut after the age of 30 years.

Figure 11.

Distribution of age at onset within the age groups: nonsystemic cases, Usher disease, Bardet–Biedl syndrome and Spielmeyer–Vogt disease. Cases with unknown age at onset were excluded from this figure.

Late-onset RP

Separate calculations were made to analyse the data of patients with late onset RP. Excluding all RP-patients younger than 40 years, the number of patients with a debut >30 years of age was counted for each birth year cohort. The total background population in each cohort was stated in Table 8 and the calculations are in addendum 6.

Table 8.  Prevalent RP-patients (probands and secondary cases) at 1 January 1988, divided into age groups of complexity
Systemic (syndromes and diseases)Unknown if
Other defined
0–4270 284311005313
5–9287 2291723127133
10–14343 77126324210249
15–19368 348431086215387
20–24421 64359910225289
25–29378 7504610112110888
30–34373 119581410036293
35–39378 02873167021310121
40–44416 7359512402119133
45–49315 99661173016593
50–54272 51060124024688
55–59255 36061113003886
60–64255 48066111007691
65–69242 61360122002884
70–74203 618487003866 
75–79166 9782960001642
80+177 7923240000945
Total5 129 254837157691519108961301

The prevalence of nonsystemic RP with debut later than 30 years of age was, like in the whole group of nonsystemic RP-cases, highest among 60–74 year-olds. With moving average technique, increasing values appeared until 65 years of age (Tables 9–11). By calculating the same values for males and females separately, it is seen that the maximum prevalence for both males and females appeared in the cohort 65–69 years of age. For males, the values were slowly increasing until a level of 8.4 per 100 000 male population, while a steep increase from 6.8 to 9.5 was found among women from the 60–64 cohort to the 65–69 cohort.

Table 9.  Nonsystemic RP in the group of patients older than 40 years of age
at risk
PrevalenceNo. in 3
5-year groups
at risk
per 100 000
at risk
  1. The observed cases with age at onset >30 years were calculated with moving average technique. The population in each cohort was stated in Table 1 in paper 3 (Haim 1992a).

40–4415416 735416 7203.6   
45–4918315 996315 7025.7491 005 1994.9
50–5416272 510272 4965.944843 8255.2
55–5910255 360255 3503.953783 3016.8
60–6427255 480255 45310.653753 3967.0
65–6916242 613242 5976.663701 6499.0
70–7420203 618203 5989.841613 1666.7
75–795166 978166 9733.033548 3546.0
80+8177 792177 7864.5   
Table 10.  Nonsystemic RP in the group of male patients older than 40 years of age
at risk
PrevalenceNo. in 3
5-year groups
at risk
per 100 000
at risk
  1. The observed cases with age at onset >30 years were calculated with moving average technique. The population in each cohort was stated in Table 1 in paper 2 (Haim et al. 1992b).

40–449213 044213 0354.2   
45–4911160 079160 0686.928508 6025.5
50–548135 507135 4995.926420 3316.2
55–597124 771124 7645.626382 0296.8
60–6411121 777121 7669.026358 6297.2
65–698112 107112 0997.127323 1158.4
70–74889 25889 2509.017268 7026.3
75–79167 35467 3531.515215 4367.0
80+658 83958 83310.2   
Table 11.  Non-systemic RP in the group of female patients older than 40 years of age
at risk
PrevalenceNo. in 3
5-year groups
at risk
per 100 000
at risk
  1. The observed cases with age at onset >30 years were calculated with moving average technique. The population in each cohort was stated in Table 2 in paper 2 (Haim et al. 1992b).

40–446203 691203 6852.9   
45–497155 917155 9104.521496 5904.2
50–548137 003136 9955.818423 4914.3
55–593130 589130 5862.327401 2686.7
60–6416133 703133 68712.027394 7716.8
65–698130 506130 4986.136378 5339.5
70–7412114 360114 34810.524344 4667.0
75–79499 62499 6204.018332 9195.4
80+2118 953118 9511.7   

These results may be due to late onset of RP for affected X-linked carriers or they may reveal an even later onset than the 40–50 years of age proposed earlier, perhaps up to 65 years for nonsystemic RP. The results agree with the above proposed assumption that concerning the nonsystemic RP, age at onset may be as late as 65 years of age for noncarriers as well as for carriers.

Leber's congenital amaurosis

This entity was not separately described in the papers, but was included in the group of congenital RP. In Haim et al. (1992b) Leber's congenital amaurosis was defined as congenital RP with nystagmus, well knowing that some individuals might have Leber's congenital amaurosis without nystagmus. Two siblings were encountered in which one child had congenital nystagmus and the other had not. Their tapetoretinal dystrophies were otherwise similar.

All the files of patients registered in the RP register on 21 February 1997, with an age at onset 0 to <3 months were scrutinized. Among 158 registered cases the 132 fulfilled the diagnosis of Leber's congenital amaurosis according to the following inclusion criteria:

  • 1a history of blindness or severely impaired vision from birth;
  • 2congenital nystagmus;
  • 3severely reduced or abolished ERG (>50% b-wave amplitude reduction);
  • 4ophthalmoscopic evidence of attenuated vessels and/or pigmentary retinopathy without signs of any other retinopathy.

Criterion (1) was compulsory together with either (3) or (2 + 4). If ERG amplitude reduction was 50% or less, no diagnosis of Leber's congenital amaurosis was made.

Among the 132 persons with Leber's congenital amaurosis, the 88 were ‘nonsystemic’. A further six cases had ‘known syndromes’ (see below), 32 had ‘unknown syndromes or associations’, and six cases were allocated to the ‘unknown group’.

In many cases, especially when visual acuity was very low, no information on the refractive error was available. Hypermetropia was seen in almost 70% of the nonsystemic cases with known refractive state. Often, large values up to +10D were measured, while high myopia was only present in 7% (Table 12).

Table 12.  Leber's congenital amaurosis: 132 patients registered in the Danish RP-register 21.2. 1997.
With known
  1. Unknown syndromes = unknown syndromes or associations.

  2. Parentheses in column 6 refer to ≥+3 in one eye only. The other parentheses contain figures for cases unknown in relation to the subject. *% means percentage of cases with known refraction.

88 nonsystemic cases4956616942(1)694769(2)7876(3)861719
6 known syndromes350467125250610023300
32 unknown syndromes18562372104352226(2)8122(1)6900
6 unknown if systemic1171171100005(1)834(2)6700

Nystagmus was present in 79% of the 132 cases. Nystagmus was most frequent in nonsystemic RP (86%) and was less frequent in systemic cases (63%). Among the known syndromes only 2(33%) had nystagmus (Table 12).

The most striking finding was that all patients with keratoconus (17) belonged to the nonsystemic group.

Mental retardation was found in 21 patients with Leber's congenital amaurosis: 16 males and 5 females. These included six subjects with the following syndromes: Warburg syndrome (1), Senior–Löken syndrome (2), and microcephaly with choroidal lacunar atrophy (1) (Warburg & Heuer 1983), CDG syndrome (1) and trisomy 9(1). In the group of ‘unknown syndromes or associations’ other symptoms in addition to mental retardation were epilepsy, microcephaly, hearing impairment, and congenital malformations of different types, cerebral palsy, and encephalopathy. Hypermetropia ≥+3D was present in 39% and myopia ≤−3D in 33% of the 18 mentally retarded individuals with known refraction. Large refractive errors were found in this group, and the frequency of high myopia was not significantly (Poisson with confidence limits 99%) different from the frequency of high hypermetropia.


The reason for not finding keratoconus in the mentally retarded patients with Leber's congenital amaurosis could be a short life, which of course would reduce the risk of having keratoconus. On the other hand, the ages of the mentally retarded persons either at death (8 persons) or at 21 February 1997 were 2–48 years. Most cases had reached adulthood and could have had keratoconus for a length of time.

The differences in refraction and in frequency of nystagmus and keratoconus indicate that Leber's congenital amaurosis in nonsystemic RP-patients and Leber's congenital amaurosis as a part of a syndrome represent distinct entities, clinically as well as genetically.

Some authors exclude syndromes from the group of Leber's congenital amaurosis (Lambert et al. 1989); the differences found above support such distinction. Having this in mind, the results of Lambert et al. agree well with the present finding of 76% hypermetropes ≥+3D and 2% myopes ≤−3D, 11% with keratoglobus/keratoconus and 13% with mental retardation.

DeLaey (1991) included syndromes such as Senior–Löken syndrome, Saldino–Mainzer syndrome, and Joubert syndrome. The same author refers to Foxman et al. (1985) and to Wagner et al. (1985); who both found hypermetropia more common among nonsystemic cases of Leber's congenital amaurosis than among systemic cases.

The absence of corneal affection in mentally retarded individuals with RP has to my knowledge not been reported previously.

Recently, the identification of genes involved in Leber's congenital amaurosis and early infantile RP suggests further heterogeneity among nonsystemic cases. Genes known to cause Leber's congenital amaurosis: RETGC1 (Perrault et al. 1996, 1999), RPE65 (Gu et al. 1997; Marlhens et al. 1997; Morimura et al. 1998), and CRX (Freund et al. 1998; Sohocki et al. 1998; Swaroop et al. 1999) can be associated with either early onset severe retinal dystrophy or with RP that begins later in life, even in late adult life. The genes TULP1 (Lewis et al. 1999), GCAP3 (Rozet et al. 1999), and AIPL1 (Sohocki et al. 2000) are only found in association with classical Lebers amaurosis.

Clinical features

Pertinent clinical delineation and descriptive classifications are important preconditions for the comparison of clinically selected materials. Regarding RP the ophthalmological picture in retrospect has remained the most used criterion for clinical classification supplemented by the symptomatology, the extraocular signs, and the mode of transmission. Based on the two first of the above-mentioned criteria, the author divided the material into five categories: Typical RP, atypical RP, vitreoretinal RP, chorioretinal dystrophies and unclassified RP-group.

Electroretinographic evaluation of the clinical type was a priori considered valuable. However, the present material was not suitable for this purpose due to the retrospective design of the study and the many contributing sources.

One or more ERG recordings were present in only 739 of the 1890 registered cases. Among the prevalent cases, only 657 (50%) were examined with ERG, out of which the 491 were extinct. The ERG recordings present in the files were recorded over a long period and reflected the current recording equipment available at the time (see addendum 6 for additional ERG-figures). Only 13% of those evaluated had residual potentials. Among these, only a part was suitable for allocating the cases into subgroups according to the inter and intraobserver test described by Haim et al. (1992a).

Clinical classification

A clinical and ophthalmoscopic description was presented for the above mentioned 5 categories (Haim & Rosenberg 1993) and examples of fundus appearances are presented in Fig. 12. Haim and Rosenberg showed that the proportion typical/atypical RP was high in nonsystemic cases and in the group of Usher syndrome (Table 13). In Bardet–Biedl syndrome, Spielmeyer–Vogt/Battens disease and other syndromes the proportion was 0.5 or less. Most atypical cases were autosomal recessively inherited.

Figure 12.

Fundus pictures illustrating examples of ‘typing’ with respect to retinal morphology. RPE: retinal pigment epithelium. a: Typical RP. note the waxy pallor of the optic disc, narrow arterioles and ‘bonespicule’ pigmentations arranged in an arcuate pattern in the equatorial region. b: Atypical RP. Atypical pigmentary pattern. Other characteristics as in typical RP. The patient had X-linked RP of early onset. c: Atypical RP. Atypical pigmentary pattern, including a diffuse irregular atrophy of RPE and relative sparing of the retinal arterioles in a case of Leber's congenital amaurosis. d: Atypical RP. ‘Inverse type’. Note the central affection of RPE, narrowing of arterioles, optic disc pallor and the absence of spicule pigmentations in a case of Bardet–Biedl syndrome. e: Chorioretinal dystrophy. Early stage of an autosomal dominant type of a ‘Stargardt like’ central RPE-atrophy which later progresses into a diffuse RPE-chorio-capillary atrophy. f: Chorioretinal dystrophy. Late stage of a ‘Stargardt like’ central affection with peripheral involvement. Note the relatively well preserved retinal arterioles, coarse and irregular hyperpigmentations and the polygonal reticular pattern of RPE atrophy in the midperiphery. g: Chorioretinal dystrophy. Choroideremia. Intermediate stage. h: Chorioretinal dystrophy. Chroideremia. Late stage with extreme atrophy of RPE and choroidal vessels. Retinal arterioles are still visible.

Table 13.  Appearance of the different ophthalmic types among the groups of systemic and nonsystemic RP
  1. 1 (column headings), Classification with respect to ophthalmic patients; 2 (column 1 entries), classification with respect to the presence of extraocular manifestations.

Usher disease13714015157
Bardet–Biedl syndrome165200169
Spielmeyr–Vogt didease01500015
Other defined syndrome51003119
Unknown syndrome or
Nonsystemic RP50624575029837
Unknown if syndrome289135596

The nonsystemic prevalent cases were distributed according to heredity and clinical type as presented in Table 14.

Table 14.  The distribution of ‘typical’ and ‘atypical’ RP among 808 cases in 837 nonsystemic RP-cases prevalent at 1 January 1988 divided into hereditary groups
 Typical course
and ophthalmoscopy
Atypical course
and ophthalmoscopy
  • Cases of unknown heredity, any group (35), choroideremia (17) and unclassified cases were excluded. Cases with other clinical classifications (86) were included in N-total.

  • Choroideremia included 12% of all X-linked cases.

  • *

    This group was included in the group above it, so these figures were not added to the total amount.

Autosomal dominant856013971
Autosomal recessive53833961156
X-linked, males and females,
except for choroideremia
X-linked males, except for
Total 490 234762

Since the ratio typical/atypical was different in nonsystemic RP and in syndromes (except Usher syndrome) evaluation of the genetic types in the group ‘unknown syndromes or associations’ might indicate whether this group was composed of real syndromes or of random associations of nonsystemic RP and other diseases.

Among persons with ‘unknown syndromes or associations’ no autosomal dominant group was present. In the other genetic groups the distributions among typical and atypical phenotype are shown in Table 15.

Table 15.  The distribution among ‘typical’ and ‘atypical’ RP among 95 classified cases in 108 RP–cases ‘unknown syndromes and associations’ prevalent at 1 January 1988
 Typical course
and ophthalmoscopy
Atypical course
and ophthalmoscopy
  1. Cases with unknown heredity (15) were excluded. No cases with autosomal dominant heredity appeared. Cases with clinical pictures other than typical and atypical were included in N-total.

Autosomal recessive621038616
Total 34 468

Discussion and conclusions: The ratio typical/atypical RP was equally high for autosomal dominant and X-linked RP when choroideremia was excluded, while the autosomal recessive group had a larger proportion of atypical RP. The ratio for the simplex group points to the possibility of this group as a mixture of the other genetic groups.

The great majority of typical cases among multiplex families agrees well with the assumption that the multiplex group almost exclusively was composed of families with either autosomal dominant or X-linked inherited RP. On the other hand, the ratio typical/atypical RP was smaller among the multiplex families than among the families belonging to the autosomal dominant and X-linked inheritance groups. This probably indicates that some cases with autosomal recessive inherited RP, and maybe other modes of inheritance (digenic, mitochondrial) were included in the multiplex group.

If the group of ‘unknown syndromes and associations’ represented merely random associations of nonsystemic RP and some systemic disease, the ratio typical/atypical RP should be as high as found in Table 14 (490/234 = 2.1). The ratio found for this group was 0.7 (Table 15). The ratio for the nonsystemic simplex cases was 56%/38%. For the simplex cases belonging to the group of ‘unknown syndromes and associations’ it was 27%/70%, suggesting that the last group contains a majority of real syndromes.

Typical and atypical cases of RP may occur in the same family, and the symptomatology, including the type and extent of visual impairment, is often the same in typical and atypical RP. It may be argued that atypical RP, e.g. chorioretinal dystrophies (including choroideremia) does not belong to the RP group. Nevertheless, diagnostic procedures and symptoms are equivalent. It therefore was considered appropriate to include all clinical forms in the study. This delineation, of course, increased the proportion of atypical RP in this study.

Genetic classification

Prevalence rates of RP are approximately equal in different parts of the world. The international variations in frequency of simplex RP-cases, where no additional cases occur in the family, are also minimal. The figures, however, vary considerably concerning autosomal dominant, autosomal recessive and X-linked RP (Haim 1992b) (Table 16). In the near future, molecular genetics may help us to understand the reason for this. Until then, the classic Mendelian genetic rules provide not only the best means of classifying RP-families according to mode of inheritance, but also some of the foundation for future progress in molecular genetics itself.

Table 16.  Genetic percentages of RP published previously
Genetic categoryAD (%)AR (%)X-linked
Country of
  • *

    Dickinson's original percentages included unaffected female carriers, which were excluded from this table for comparison. Her autosomal recessive fraction also included the simplex cases, but could be separated in this table for comparison.

  • **

    AR + multiplex in Jay's definition may be considered equivalent to AR in the other materials and comprises 11.5%.

 Fishman (1978)261916381USA
 Amman et al. (1965)9901Switzerland
 Dickinson & Mulhall (1989)*2925640Australia
 Pearlman & Saxton (1979)
 (% of eyes)
 Fishman (1978)19198522USA
 Jay (1982)20.6**1552.9**Great Britain
 Sommer & Gizycki (1983)8.383.45.92.4Germany
 Hu (1987)

The material was classified according to the following hereditary groups; autosomal dominant, autosomal recessive, X-linked, simplex, multiplex, and unknown cases. The criteria for classification, and their advantages and shortcomings in clinical practice, are discussed below. Family relations were documented by family history. Patients examined at The National Eye Clinic for the Visually Impaired have been interviewed extensively about family relations and other possibly RP-affected relatives. In families with multiple affected persons extensive genealogical investigations have been performed since 1988.

Patient difficulty in remembering family relations may result in errors, making the genetic classification less reliable. It is also a well-known genealogical problem that some fathers are not the biological fathers. Concerning the large number of siblings in families from the last century and the beginning of the present century, the stated mother of the youngest siblings may in reality be the oldest sister taking care of the youngest siblings.

Genetic classification was based on family relations only, disregarding other parameters such as clinical type and age at onset, for evaluation in each group (Tables 17 and 18).

Table 17.  Genetic frequencies calculated from the Danish Retinitis Pigmentosa Register: all cases prevalent at 1 January 1988, with corresponding families
Hereditary groupsPatientsMales
Crude prevalenceNo.%No.%
Autosomal dominant1.75/100 000906.94941303.1
Autosomal recessive5.73/100 00029422.615513918719.2
X-linked2.75/100 00014110.810338454.6
Simplex10.96/100 00056243.231424856257.7
Multiplex2.61/100 00013410.34886707.2
Unclassified1.56/100 000806.14634808.2
Total25.36/100 000130199.9715586974100.00
Table 18.  Genetic frequencies calculated from the Danish Retinitis Pigmentosa Register: nonsystemic cases prevalent at 1 January 1988, with corresponding families
Hereditary groupsCrude
no. (%)
RP (%)
no. (%)
RP (%)
  • *

    Prevalence rate per 100 000.

  • †WSPR, World Standard Prevalence Rate.

Autosomal dominant1.361.2170 (8.4)10.9353528 (4.4)6.0
Autosomal recessive3.062.58159 (19.0)16.47881113 (17.9)17.2
X-linked2.342.14120 (14.3)17.0893139 (6.2)6.3
Simplex7.005.92359 (42.9)38.9204155359 (56.7)53.8
Multiplex1.831.5394 (11.2)13.6365859 (9.3)12.3
Unclassified0.680.4535 (4.2)3.2231235 (5.5)4.4
Total16.27 837 (100.0)100.0465372633 (100.0)100.0

The author's genetic definitions (Haim 1993) were:

  • 1Autosomal dominant (AD) heredity
  • Cases belonging to families in which the following events occur at least once:

    • 11 father-to-son transmission of the trait, not explained by consanguinity;
    • 12 at least one transmission from an affected person, through an unaffected male, affecting a third person in lineal descent, not explained by consanguinity;
    • 13 affected half-siblings of an unaffected father and his two unrelated and unaffected partners, who have no family history of RP.
  • 2Autosomal recessive (AR) heredity
    • 21 Cases belonging to families with only one affected sibship and at least two affected (full) siblings. (half-brothers and half-sisters: see autosomal dominant (AD 1.3) and X-linked (XL3.2) heredity); or
    • 22 cases belonging to families where all affected children have consanguineous parents, even if isolated cases; and
    • 23 no typical carrier fundus among mothers, daughters or sisters of the affected persons; and
    • 24 choroideremia excluded.
  • 3X-linked (Xl) heredity
  • Cases belonging to families with: no father-to-son transmission, and no transmission through unaffected males, and at least one of the following events:

    • 31 at least two affected generations in lineal descent, and at least one affected son of an unaffected female;
    • 32 affected half-brothers of an unaffected mother and her two unaffected partners, who are not predisposed to RP;
    • 33 typical carrier fundus in mother, daughter or sister;
    • 34 a diagnosis of choroideremia.
  • 4Simplex
  • Isolated cases

    • 41 without information of parental consanguinity; and
    • 42 without carrier signs in mother, daughter or sister; and
    • 43 choroideremia excluded.
  • 5Multiplex
  • Cases belonging to families with at least two affected family members, not fulfilling the criteria for other groups.

    • 6Unknown cases
  • With no information about family members.

  • One generation may include more than one sibship as, for example, cousins.

Mitochondrial inheritance was theoretically possible (transmission through women only) in 5 families classified as X-linked and in 22 multiplex families. The families were no.27, 31, 33, 34, 36 and no.47, 48, 49, 50, 51, 52, 54, 55, 56, 57, 62, 65, 67, 68, 72, 77, 78, 79, 81, 82, 85, 90 (Fig. 13). Nevertheless, 12 of the ‘possibly mitochondrial’ families referred to in Haim (1992b) later on appeared to have transmission through a male. Mitochondrial heredity is known in Kearn-Sayre disease and Holt et al. (1990) described mitochondrial heredity in a disease with RP, developmental delay, dementia, seizures and ataxia. Mitochondrial heredity was not included in the classification table, and it still represents a merely hypothetical possibility. Therefore, until nonsystemic mitochondrial RP should be identified the genetic classification table above remains unchanged.

Figure 13.

Figure 13.

Pedigrees presenting the autosomal dominant. X-linked and multiplex families, including at least one member affected by nonsystemic typical RP. Generations of unaffected offspring of unaffected persons were excluded from the pedigrees. Secondary cases were termed affected if they were night blind, but unaffected if they were only known to be blind or partially sighted. Female carriers were only marked if they had typical fundus abnormalities, thus discernible from autosomal dominant RP with decreased expression.

Figure 13.

Figure 13.

Pedigrees presenting the autosomal dominant. X-linked and multiplex families, including at least one member affected by nonsystemic typical RP. Generations of unaffected offspring of unaffected persons were excluded from the pedigrees. Secondary cases were termed affected if they were night blind, but unaffected if they were only known to be blind or partially sighted. Female carriers were only marked if they had typical fundus abnormalities, thus discernible from autosomal dominant RP with decreased expression.

Parental age: a statistically significant preponderance of males was found in the simplex group of nonsystemic RP. This points to the possibility of a proportion of X-linked cases in this group. These cases either represent families with unaffected carrier females through generations or families with sparse information of affected members. Another possibility could be new mutations. Older parents are thought to have a higher risk of giving birth to children with a new mutation. It therefore was considered relevant to investigate the age of the parents at the time of birth of the affected children compared with the age of parents to other nonsystemic RP-cases. Probably, an optimal comparison should include a control population of mothers and fathers having given birth to the same number of children with the same interval as in the family in question. Such a population would, however, be difficult to construct without bias and the construction would be very time consuming. A comparison with the parent's age in other genetic groups was therefore attempted. To avoid the systemic error contingent on the fact that parents were older when they had child number two than when they had number one, the ages were registered when they had the first affected child (Table 19). The risk of having an affected child is not the same for parents of children with different hereditary modes, so the results of parental age were, after renewed discussion, left out of the comparisons. No figures then point directly to the existence of new X-linked mutations in the simplex group. Looking at the individuals in the simplex group who had typical RP, a statistically significant excess of males was found, P < 0.01. The same was true for the subgroup with age at onset 6 to <18 years, P < 0.01. These results, however, indirectly point to the existence of X-linked cases in the simplex group.

Table 19.  Parental age in nonsystemic RP
No.Ave. ageMedian ageNo.Ave. ageMedian age
  1. The patients were the eldest affected in the sibship. Both parents were included independently of whether or not they were known to carry the gene.

Autosomal dominant males131123.7221327.824
Autosomal dominant females111025.925.51124.528
Autosomal recessive males262526.2262228.028
Autosomal recessive females393626.1253929.830
X-linked males616124.5244529.327
X-linked females232026.424.51729.126
Simplex males373728.2283731.130
Simplex females454528.0294530.630
Total255245  229  

A classification experiment

The main problems associated with genetic classification of retinitis pigmentosa may be presented as follows:

The present material was reclassified (Haim 1993) according to definitions given by five research groups: Bunker et al. (1984), Bundey & Crews (1984b); Jay (1982), Fishman (1978), and Heckenlively (1988). These definitions have all been used in population studies, including the same diagnostic group of RP-patients as presented in this experiment. The genetic definitions of the five groups are presented in addendum 6, pp. 90–91.

All the above mentioned five research groups classified as strictly as possible according to the Mendelian rules. The obvious difficulties in determining the hereditary group of retinitis pigmentosa (varying expressivity and cases of nonpenetrance in the autosomal dominant form and affected carriers of the X-linked group) gave rise to different additional defining.

Bunker et al. (1984), Fishman (1978) and Heckenlively (1988) demanded three consecutively affected generations to define autosomal dominant RP. Bunker et al. (1984) and Fishman (1978) included an additional possible autosomal dominant group with only two generations. These two groups were not separated in their results. Jay (1982) and Bundey & Crews (1984b) only demanded two consecutive affected generations in their definition of autosomal dominant RP. In addition, Bunker et al. (1984), Fishman (1978), Heckenlively (1988), and Jay (1982) demanded that males and females should be equally affected.

Concerning autosomal recessive inheritance the classification of Fishman (1978) and Bundey & Crews (1984b) agreed well with mine. Jay (1982) and Bunker et al. (1984) isolated male sibships from the autosomal recessive inheritance group because of the possibility of X-linked inheritance in these cases. Heckenlively (1988) described autosomal recessive cases as ‘sparsely scattered in a pedigree, however, when clustering of the affected appeared, it was in sibships’. Bunker and Heckenlively did not accept isolated cases with consanguineous parents as autosomal recessive cases. Multiplex inheritance was not mentioned by Bundey and Crews or Fishman who simply called the group unclassified or undetermined. The simplex group of Bunker et al. (1984) was also undetermined. These undetermined cases may be so because they belong to more than one group. According to my definitions, the multiplex cases are characterized by not belonging to any of the other groups. To define a family as multiplex, Heckenlively (1988) and Jay (1978) demanded that two or more in a sibship be affected. The results of the reclassification are shown in Fig. 14, and the frequencies of genetic types in Table 20.

Figure 14.

‘Movements’ of the families in the present study according to different genetic classifications. Bunker et al. (Bunker et al. 1984), Bundey & Crews (Bundey & Crews 1984b), Heckenlively (Heckenlively 1988), Fishman (Fishman 1978), Jay (Jay 1982) and Haim (present study). Modes of inheritance: AD, autosomal dominant; Xl, X-linked; AR, autosomal recessive; Mp, multiplex; Sp, simplex; ?, not classifiable according to the definition. Unchanged mode of inheritance is shown in the dark diagonals and the deviations in the white fields.

Table 20.  The effect of different genetic classifications on distribution of families and prevalent cases in the present study expressed as percentages
Bunker et al.
Bundey & Crews
Jay (1982)Heckenlively (1988)Fishman (1978)
  1. The 16 cases without family information were excluded. *9/350 families unclassifiable according to the genetic definitions of Jay were excluded from this calculation. †18/551 cases unclassifiable according to the genetic definitions of Jay were excluded from this calculation.

Prevalent cases

The above mentioned differences illustrate well some of the discrepancies found in the literature and the outcome of the classification experiment.

The reason for reconsidering the definition of X-linked and autosomal heredity in the present study, was my experience with the large X-linked families recorded at The National Eye Clinic for the Blind and Visually Impaired. Increasing numbers of X-linked families appeared when families primarily classified as autosomal dominant became larger. Yet, they still fulfilled the existing definitions of autosomal dominant inheritance. (The same tendency is seen in the UK, probably because of the large RP-register in London (Jay 1978).) Recently, mutation analysis of the RP3-gene and RP2-gene was performed in the following X-linked families: no. 25 (Roepman et al. 1996b, family 2555), no. 28 (Friedrich et al. 1992), no. 30 (Warburg & Simonsen 1968; Warburg 1971; Friedrich et al. 1985), no. 38 (Roepman et al. 1996b, family 2603), no. 44 (Roepman et al. 1996b, family 2550), and no. 42 (Roepman et al. 1996a, family 2557) confirming the X-linked inheritance in these families. Family 28 and 30 both have 3 consecutive generations of affected members (Fig. 13). The male/female ratios were 6/5 in family 28 and 14/5 in family 30. Had only the right branch of family 30 been known, autosomal dominant inheritance would be convincing, following the definitions of the five research groups. In other words, these definitions favour the autosomal dominant inheritance pattern, so that a pedigree will be classified as autosomal dominant until a more convincing X-linked pedigree appears. My definition has overcome this dilemma by adding the following criteria to the X-linked definition: at least one affected son of an unaffected female and at least two affected generations in linear descent (but not necessarily consecutive). This means, however, that the X-linked inheritance pattern may be favoured at the expense of the autosomal dominant in some cases. This might be the reason for at least some of the excess of Danish X-linked RP-cases compared to the number reported from other countries. For the above mentioned reasons, I suppose that I have come closer to the true balance between the two groups of Mendelian heredity. On the other hand, certainty of X-linked inheritance in suspected families will only present when molecular genetics can be employed in every family.

Hence there is need for reconsidering the common criteria regarding genetic classification, in order to create an exclusive and exhaustive definition fulfilling the demand of one, and only one group for each family or patient.

Finally, an additional motive for the presented definition was to avoid the use of clinical parameters, as discussed below.

The reclassification of the 350 pedigrees mentioned above (Fig. 14) revealed a considerable discrepancy among authors. As expected, a large part of the cases classified as autosomal dominant by the five research groups were altered by my classification. Some 16–19% became X-linked and about 50% were changed to multiplex. Among Fishman 1978) autosomal dominant cases, however, none were reclassified as X-linked but 2/3 became multiplex. These results reflect the tendency, stated previously, to increase the portion of X-linked cases at the expense of the autosomal dominant. Thus results mirror the uncertainty concerning classification when referring to autosomal dominant and X-linked families, which have similar pedigree patterns. Fishman 1978) definition demanded that no unaffected person must transmit the trait in autosomal dominant RP. Therefore, no person in this group could be reclassified as X-linked in my classification, demanding at least one unaffected mother with an affected son. Heckenlively (1988) mentioned among his distinguishing characteristics of autosomal dominant RP that ‘unaffected persons do not transmit the trait to their children’. This is not in his primary definition and it is followed by a discussion of expressivity and penetrance.

Persons classified as X-linked by the five research groups were for the most part also accepted by my classification.

Concerning autosomal recessive cases, the differences between the definitions reflected that Bunker et al. (1984) and Jay (1982) classified male sibships without affected family members in the multiplex group, and Heckenlively (1988) categorized all sibships without affected family relations as multiplex.

All authors classified the 197 simplex cases/families in a similar manner. Heckenlively and Bunker et al. added the isolated cases with parental consanguinity to this group.

Genetic heterogeneity of RP

The genetic classification, based on the categorization of the family, is at this time the most important subclassification of retinitis pigmentosa. It is the most exact, because different hereditary modes separate otherwise similar phenotypes. Unfortunately, it is not exact enough to fulfil the basic demand of having one, and only one classification group for each RP-case or RP-family. This is because of the irregular hereditary patterns in which RP presents in many families, and because of the small number of affected members known in each family.

Background and considerations leading to a new approach to genetic classification of RP

Definitions for the genetic classification were not mentioned in the original protocol for the Danish RP-register. The author consequently made a genetic RP-classification constructed according to a study of the literature and according to clinical experience, posing the following questions: How are the hereditary modes in RP defined? How are RP-families allocated to a hereditary group? What is the coherence between definition and practice?

The frequency of skipped generations in autosomal dominant inherited RP and of affected X-linked carriers is unknown. The presence of nonpenetrance in autosomal dominant RP and of affected females in X-linked RP is intermingled due to the existence of large groups of families in which more than one mode of inheritance is possible.

The question concerning autosomal versus X-linked inheritance is often answered by adding clinical signs, such as the typical golden reflex of carriers, to the criteria. Carriers of X-linked RP, on the other hand, sometimes have signs similar to these found in persons with autosomal dominant inherited RP with variable expressivity. The usual guidelines (McKusick 1988) for Mendelian genetic classification are therefore not exhaustive in the case of RP, and consequently additional clinical characteristics, such as degree of affection, age at onset, or sex ratio among affected individuals have been added.

Fishman (1978), Jay (1982), Bunker et al. (1984), and Heckenlively (1988) demanded ‘males and females equally affected’ before categorizing them as having autosomal dominant RP. These authors indirectly use the fact that affected female carriers of the X-linked mode of heredity exist.

Irrespective of the occurrence of reduced expressivity and nonpenetrance in autosomal dominant RP-families, most definitions are based on two or three direct transmissions. This demands that the frequencies of affected X-linked carriers and of unaffected carriers of autosomal dominant RP are low. On the other hand, the difference between Jay (1982) finding 90.6% penetrance in ADRP, and Boughman & Fishman (1983) estimating 62% penetrance in their ADRP-material may be explained by either a significant fraction of affected female carriers of X-linked RP or, alternatively, a significant number of unaffected individuals carrying a gene for autosomal dominant RP.

When looking at the variation in genetic frequencies among different authors and at the large group of RP-patients without other known cases in the family, reduced expressivity of autosomal dominant RP or small sibships may be partly responsible.

Flowchart of classification of inheritance in RP (Fig. 15)

Figure 15.

A. Choroideremia and typical carrier signs. Before utilizing the genetic classification diagram, those families in which the RP is diagnosed as choroideremia should be excluded. These families are X-linked by definition. So are those families in which an affected individual has at least a mother, sister, daughter or another relative in the female line with typical carrier fundus abnormalities. Occurrence of father-to-son transmission or transmission through an unaffected male should promote a second examination with respect to diagnosis and genealogy. B. Consanguinity. In families including at least one affected person with consanguineous parents, the genetic classification should probably rely on that part of the family without consanguinity. If all affected persons have consanguineous parents, they are assessed as having an autosomal recessive inherited RP. Concerning half-siblings, when these are the only persons affected, consanguinity between the common parent and one of the partners should be ignored and regarded as being unimportant. If the two partners are related, the family should be classified as autosomal recessive, as if there were only one partner. C. Half-siblings as the only persons in the family known to be affected (no consanguinity). Half-siblings, with the same unaffected father and mothers both unaffected are assumed to have autosomal dominant RP, with evidence of transmission through an unaffected male. Half-siblings, with the same unaffected mother and fathers both unaffected, are assumed to be X-linked when at least one of the siblings is an affected son, and multiplex when all siblings are females. D. Presence of at least one affected person whose parents are both affected or both have RP in their family (no consanguinity). The pedigree is first evaluated excluding the mother, then re-evaluated excluding the father. If both these procedures give the same mode of heredity, then this heredity represents the result. If the procedures give different modes of inheritance, the result is multiplex. If the families of both the father and the mother are large, the families may be classified separately excluding the common family members from the assessment. When the families have RP with different modes of inheritance, these common members are categorized as multiplex.

As a consequence of the foregoing discussion, the new approach to genetic classification of RP-families should take into account the possibility of affected X-linked carriers and of unaffected persons transmitting the ADRP. Otherwise, one would be unable to determine the frequency of those cases.

By means of drawing a pedigree, an attempt was made to avoid using any clinical signs as classification parameters, because the database itself should be able to deduce clinical characteristics. However, a few exceptions were inevitable. A typical carrier fundus (Falls & Cotterman 1948; Francois 1962; Berendschot et al. 1996) was accepted as a criterion for X-linked inheritance, and a diagnosis of choroideremia (Haim & Rosenberg 1993) was taken as evidence for X-linked inheritance. The diagnosis of choroideremia was often confirmed after the demonstration of carrier signs in the mother, sister or daughter of the patient. After the conclusion of this study, mutation analysis confirmed the genetic classification in the majority of the investigated families (Schwartz et al. 1993; Bokhoven et al. 1994). In a few systemic cases, deletions of the X-chromosome confirmed the genetic classification based on clinical signs (Rosenberg et al. 1986).

Due to the varying expressivity, the reduced penetrance in autosomal dominant families and the small number of affected family members available for probability calculation, clinical parameters such as ‘males and females equally affected’, should not be used to categorize single families.

Minor symptoms and objective signs, different from the typical golden central reflex found in female carriers of unquestionable X-linked families (Fishman et al. 1986), cannot always be separated from abnormalities in females with autosomal dominant inherited RP with reduced expressivity. I therefore find this parameter of limited value in genetic classification. Persons with such minor signs and symptoms not fulfilling the diagnostic criteria were consequently marked as unaffected in the pedigree.

The genetic classification was constructed to be exclusive and exhaustive, offering one, and only one group for each family. In order to obtain unambiguity the logical determinants ‘and’ and ‘or’ were used. ‘And’ was used when both conditions should be fulfilled and ‘or’ was used when at least one of the conditions should be true for this RP-family. The priority of the parameters was also taken into account. The classification, according to tradition, was presented by defining each mode of heredity. However, a more logical way would be a key in accordance with the clinical practice in which an RP-pedigree with a given pattern of occurrence is allocated to a certain group of inheritance. A diagram illustrating this situation has been constructed (Fig. 15). With this diagram, the clinician is guided by means of binary questions to one, and only one group of inheritance characterizing the family in question. The diagram was primarily constructed to take into account every usual and unusual pedigree pattern. A large diagram resulted, requiring that a variety of questions should be answered for each family. To simplify, the diagram was reduced so that it is only necessary to refer to four different items in the text (A, B, C, and D) when special patterns occur. The diagram is thus easy to run through for the majority of pedigrees. Since the diagram is constructed with binary questions, it is prepared for an electronic data processing program.

Autosomal dominant RP

Male-to-male pseudodominant inheritance presents, when a male affected by autosomal recessive RP has an affected son with a female heterozygote with a mutation in the same gene giving rise to homozygosity or compound heterozygosity for the condition. The possibility of male-to-male pseudodominant inheritance is estimated to be so small in a country with little consanguinity that a father-to-son transmission is used as a criterion for autosomal dominant heredity. This assumption was regarded justified for use in a population study. Other combinations of pseudodominant inheritance (mother-to-son, mother-to-daughter and father-to-daughter transmission) would lead to the multiplex inheritance group with the present classification, leaving all possibilities open.

The criterion ‘an unaffected male transmitting the trait’ is used to indicate an autosomal dominant mode of inheritance. This is based on the assumption that any male carrying an RP-gene on his X-chromosome would manifest the disease before the possible affection of his daughter. To my knowledge, the opposite has not been seen in any X-linked family, but theoretically this assumption might be wrong.

X-linked RP

The criterion for X-linked inherited RP, i.e. ‘At least one affected son of an unaffected mother’, is open to discussion, while two or more affected sons of unaffected mothers could possibly have been used instead. The mother in question should of course be a member of the RP-family and not merely the wife of a family member. The ratio between this occurrence and direct female-male transmission within a family might be used as an additional criterion. The value of such a ratio would be arbitrarily determined, because the frequency of affected X-linked carriers and of skipped generations in ADRP is unknown.

The use of the suggestions above would all tend to increase the number of multiplex cases.

The possibility of mitochondrial heredity (Holt et al. 1990) must be held in mind. Families only transmitting the trait through females, may present this hereditary mode and at the same time fulfil the present criteria for X-linked Mendelian inheritance.

When regarding the large group of multiplex families, a discussion about the possibilities of allocating families from the multiplex group to one of the Mendelian hereditary groups is of current interest.

  • 1The ratio between affected and unaffected females with affected sons tends towards an autosomal dominant (AD) mode of inheritance when it increases and towards an X-linked mode of inheritance when it decreases.
  • 2A large ratio of affected females/unaffected females in the family also increases the possibility of AD inheritance.
  • 3When most affected females belong to the younger generations, an autosomal dominant inherited RP is possibly present, whereas a larger proportion of older affected females increases the probability of an X-linked inheritance.
  • 4A preponderance of affected females points towards an autosomal dominant inheritance, while X-linked RP is an increased possibility with a preponderance of males.

The ratios 1–4 indicate that the possibility of allocating the multiplex group to the primary hereditary modes does exist. However, no exact coefficient can be calculated separating AD and X-linked families as long as the frequencies of skipped generations in the various types of ADRP and of affected female carriers with various X-linked RP mutations remain unknown.

Dominant X-linked inheritance has been proposed earlier (Duke-Elder & Dobree 1967), but has since been rejected with the argument that the abnormalities seen in female carriers are unlike each other and appear sporadically (Goodman et al. 1965). These findings were explained by skewed X-chromosome inactivation (Lyon 1961). Subsequent molecular genetic studies (Friedrich et al. 1993) have supported this notion.

Two genetic loci (Ott et al. 1990) for RP have been demonstrated in a multicentre project including 62 families with X-linked RP. These families were selected according to a definition of X-linked recessive inheritance. In 1996 two independent groups cloned one of the two RP-genes on the X-chromosome (RP3) (Meindl et al. 1996; Roepman et al. 1996). The positional cloning of the RP2-gene was performed in 1998 by Schwahn et al. (Schwahn et al. 1998). Zito et al. (1999) identified 5 mutations in the RP3-locus. A possibility of an X-linked dominant mode of inheritance, as described for hypophosphatemia rickets (Gelehrter & Collins 1990), still exists. In this case, they may be found among the multiplex cases. Theoretically, females should be affected twice as often as males in dominant X-linked inheritance, but this fact depends on full penetrance and is invalid for use in small families. One result of the present study, namely, that all families with more than four generations could be classified according to the classical Mendelian inheritance groups, also speaks against a possibility of an X-linked dominant mode of inheritance of RP.

Autosomal recessive RP

Skipped generations in ADRP and unaffected female carriers in the X-linked mode of inheritance point towards the possibility that cases categorized as autosomal recessive or simplex cases may belong to X-linked or autosomal dominant families.

When males only, and only in a single generation, are affected, an X-linked mode of inheritance may be suspected. In this situation, mild affection of sisters, mothers or daughters, not fulfilling the diagnostic criteria and not having typical carrier fundi, are valuable in genetic classification and point towards an X-linked heredity. Mild RP-signs in male relatives in lineal descent suggest an autosomal dominant mode of inheritance, independent of the sex of the affected siblings.

When half-siblings are both affected, the common parent is suspected of transmitting the trait. When the common parent is the father, an autosomal dominant mode of inheritance is probably present. A common mother to at least one affected son, according to my definition, is categorized as X-linked, but autosomal dominant inheritance remains a possibility. In both examples, an autosomal recessive mode of inheritance may represent another possibility.

Parental consanguinity increases the possibility of autosomal recessive inheritance, but should of course be considered together with other information in the pedigree.

One report of digenic retinitis pigmentosa has been published (Kajiwara et al. 1994). The families described were formerly classified as autosomal dominant with reduced penetrance. They were shown to be double heterozygotic. These findings indicate that the allelic and nonallelic heterogeneity known to be a feature of monogenic RP is complicated further by interactions between unlinked mutations.

Digenic aetiology, if present with some abundance, may be one of the first steps in resolving some of the remaining problems associated with genetic classification of RP.

Precision of classification

The analysis above includes many possible family constellations and combinations. The equilibrium or balance between the inheritance groups depends on the importance of each available criterion, estimated by the investigator.

Another factor that should be made clear is the purpose of the classification. If the purpose is to identify families with one mode of inheritance for molecular genetic research, the criteria should be very strict, limiting the possibility of errors to a minimum. Similarly, genetic counselling demands strict criteria. Such a method leaves a large fraction of cases with unknown heredity and is therefore unsuitable for the characterization of the hereditary pattern in a population. Fishman (1978) reported 60% with known inheritance, and in the present study 40% of the patients were characterized by having a known Mendelian mode of inheritance. The more strict the criteria, the smaller portion of subjects classified in the known Mendelian groups. For each purpose, it must be decided how large a fraction of ‘unknown cases’ would be acceptable. A certain degree of uncertainty depending on the purpose therefore should be accepted.

Using different genetic definitions for similar purposes, however, may give a picture of a worldwide heterogeneity of RP erroneously increased by the methods employed.


The present investigation was based on the extensive collection of a large material including all types of retinitis pigmentosa from a well-defined geographic area. One of the results was the establishment of a national research database. The separate registration of different parameters independent of each other was intended to create a possibility for future studies. The number of included patients (1890) and included data gives a good overview of the Danish RP-population. On the other hand, the retrospective design, the large period of time, and different sources reduced the scientific value of the register. The main purpose of this project was to provide epidemiological data from a large study population. A national prevalence of 1:3026 corrected for completeness was found at 1 January 1988. The specific prevalence rates were 25–30 females per 100 000 female population and 35–40 males per 100 000 male population. World Standard Prevalence rates were for the first time applied for an ophthalmological study and compared with the recalculated figures from other investigations. No significant differences were found among different populations in the world. Patients (including 541 probands) with systemic manifestations were registered as a part of the RP-population. In the Danish RP-population 12% had Usher syndrome, 5% had Bardet–Biedl syndrome and 1% suffered from Spielmeyer–Vogt disease. In the present survey further details concerning 144 mentally retarded persons with RP and the subgroup with Leber's congenital amaurosis are added. The age at onset of the different RP-groups revealed a late onset for many nonsystemic RP-patients and earlier debut for the systemic cases. Patients were grouped according to ophthalmoscopic morphology and clinical course, showing a significant number of atypical RP, mainly confined to the systemic RP-group. In retrospect, the ERG was not suitable for subclassification of RP in this material because only about 50% were examined and most of them had extinguished curves. The genetic analysis suggested a possibility of a fraction of X-linked heredity in the simplex group. The large pedigree material gave an excellent opportunity for discussion of genetic categorization and prompted the launch of a new genetic classification key ready for data processing. Further research in this field is suggested to elucidate the implication of ‘skipped generations’.

This might possibly either shed light on a treatment modality for or a prevention of RP, answering the question: What factors protect these family members from presenting RP-symptoms?


A nation-wide registration of Danish cases of retinitis pigmentosa (RP) provided 1890 persons diagnosed during the period 1850–1989. Prevalent at 1 January 1988 were 1301 persons (1:3943) comprising a multitude of different RP-types. Age specific prevalence rates demonstrated increasing rates of RP during the first four decades of life and a rather stable prevalence over the next 20–30 years. Corrected for incompleteness, a late decrease was found, reflecting an incomplete ascertainment of the oldest patients. A moving average method indicated an even later steady state value for the age-specific prevalence.

The Danish prevalence figures were standardized according to the WHO World Standardized Prevalence Rates and compared with large studies from the USA and UK. No statistically significant difference was found.

Usher syndrome was present in 12% of all RP-cases and Bardet–Biedl syndrome comprised 5%. Mental retardation was found in 144 cases (11%), mostly characterized by atypical RP.

Nineteen per cent of patients affected by nonsystemic RP had an onset later than 30 years of age, whereas only a few per cent of persons with systemic RP had an RP onset after age 30 years.

The Mendelian inheritance type of all cases was evaluated according to an unambiguous genetic classification, finding a larger amount of X-linked RP compared with other studies. Among nonsystemic RP-cases, 14.3% were found to be inherited as an X-linked trait whereas only 8.4% were autosomal dominantly inherited. The largest fraction was, as in previous materials, the simplex group (isolated cases) comprising 42.9% of the nonsystemic RP patients.

Some factors influencing the results are discussed, with special emphasis on the problems associated with precise definitions of the Mendelian inheritance groups. A diagram according to the author's definition was constructed as a guideline ready for clinical application.

Summary in Danish

Retinitis pigmentosa (RP) er betegnelsen for en gruppe alvorlige øjensygdomme, som rammer nethindens sanseceller. Disse sygdomme er arvelige og begynder oftest i barnealderen og de unge år. I mange tilfælde medfører RP blindhed i løbet af en kortere eller længere årrække.

RP har været kendt siden 1850-erne og i nærværende arbejde er alle tilfælde i de forløbne 140 år søgt tilvejebragt ved gennemgang af alle tilgængelige kilder.

Forfatteren har opbygget et dansk retinitis pigmentosa register, som kan anvendes til vejledning af de enkelte patienter og deres familier og ikke mindst til forsat udforskning af sygdommen, som endnu ikke kan helbredes.

Beregninger af registrets komplethed viser, at det er lykkedes at opspore c.40% af de ældste tilfælde (1850–1910) og c.80% af de der er født fra 1911–80. Af de yngste årgange skønnes 90% registreret.

I Danmark er hyppigheden af RP c.1 for hver 3026 indbyggere. Mænd rammes oftere end kvinder. Den overvejende del af tilfældene (64%) er uden anden sygdom. Blandt de, der tillige har andre handicaps, er gruppen med medfødt hørenedsættelse (Usher syndrom) den største(12%).

RP debuterer ofte tidligere hos mennesker med andre handicaps (systemiske RP-tilfælde), end hos personer, der udelukkende har øjensygdom (nonsystemiske RP-tilfælde). Symptomerne og nethindens udseende varierer betydeligt i begge grupper.

En væsentlig del af arbejdet beskæftiger sig med klassificering efter arvegang af personer og familier med forekomst af nonsystemisk RP. Verden over angives forskellige hyppigheder af de samme arvegange.

Forfatteren har analyseret dette i forhold til de anvendte genetiske klassifikationsmetoder. I analysen indgår bl.a. en reklassifikation af 350 danske RP-familier efter fem forskellige tidligere beskrevne genetiske definitioner. De forskellige metoder viser sig at have væsentlig indflydelse på den fundne hyppighed af de forskellige arvegange.

Forfatteren har, til hjælp for fremtidig bestemmelse af arvegangen, udarbejdet en skematisk nøgle, som tager udgangspunkt i fordelingen af RP-tilfældene i familien og ikke, som vanlig, i beskrivelsen af den enkelte arvegang. Konstruktionen er binær med mulighed for edb-anvendelse.


I am indebted to Thomas Rosenberg, MD, for his never-ending support, constructive criticism and inspiring discussions. I am also indebted to Niels V. Holm, MD, PhD, for the epidemiological supervision of the project. I thank Mette Warburg, Dr. med., for her critical and constructive scientific advice. Mrs Anne Munk is to be thanked for excellent secretarial help and valuable discussions, which especially concerned the ethical aspects of the project. I thank Mr Michael Davidsen who offered statistical advice. Mr Erik Kann is to be acknowledged for the genealogical and civil registry work and Mr Steen Lærke for expertise in electronic data processing. Knud Juel from the Danish Institute for Clinical Epidemiology (DIKE) is acknowledged for his analysis of the rate of mortality in the material. The staff of The National Eye Clinic for the Visually Impaired is to be thanked for their willingness to accommodate the extra load of the project. I am grateful to the many ophthalmologists that provided me with their patient data and to the heads and staffs of the eye departments from all parts of the country. The co-operation and interest from the patient group has been a source of constant encouragement during the study period.

Generous economic support is gratefully acknowledged from:

  • • The Danish Association of the Blind;

  • • The Danish Eye Research Foundation (Øjenfonden);

  • • Fabrikant Einar Willumsens Mindelegat;

  • • Dagmar Marshall's Fond;

  • • C.C. Klestrups and hustru Henriette Klestrups Mindelegat;

  • • Maleren Hjalmar Westerdahls forskningslegat;

  • • Victor Larsens Mindelegat and;

  • • Glaucomfondet from the former department of Ophthalmology, Hvidovre Hospital.