Prevalence of retinitis pigmentosa and allied disorders in Denmark. I Main results.

In a nation-wide study we utilized all available sources to characterize the prevalence rates of retinitis pigmentosa. 1301 persons, 715 males and 586 females, were identified, with a diagnosis of retinitis pigmentosa or some other tapetoretinal dystrophy, and living in Denmark per January 1, 1988. The corresponding completeness corrected prevalence rate of retinitis pigmentosa was 1:3026. All cases were classified as 'certain', 'probable', or 'possible'. The age specific prevalence rates increased until 40-50 years, reaching a level of 35-40 male cases per 100,000 and 25-30 female cases per 100,000. Age specific prevalence rates were standardized to the WHO World Standard Population and compared to rates reported from Britain and The United States. World standardized prevalence rate for males was 25.29 per 100,000 and for females 19.31 per 100,000. The preponderance of males was highly statistically significant, (P less than 0.01).     

Prevalence of retinitis pigmentosa and allied disorders in Denmark. III. Hereditary pattern.

A national epidemiological study revealed 1301 prevalent cases of retinitis pigmentosa (RP) in the Danish population on January 1, 1988. The corresponding number of 974 families were analyzed with respect to Mendelian inheritance groups. Thirty families, comprising 6.9% of the prevalent RP-cases, were categorized with an autosomal dominant inheritance pattern. In 187 families, 22.6% of RP-cases, autosomal recessive heredity was encountered. X-linked heredity was found in 45 families, 10.8% of the RP-cases. Simplex RP-cases comprised 562 persons (43.2% of RP-cases). About a fourth of the non-systemic X-linked cases were females. Half of these had an age at onset after 30 years, but a third had their first RP-symptoms before age 18 years. A representative fraction of parents to non-systemic autosomal dominant, autosomal recessive, X-linked, and simplex cases were evaluated concerning their age at the time they had their first affected child. Mothers of the male simplex cases were of statistically significant higher age than mothers of the other inheritance groups. This may imply a high rate of new mutations among simplex cases, especially on the X-chromosome.     

Prevalence of retinitis pigmentosa and allied disorders in Denmark. II. Systemic involvement and age at onset.

A population survey of retinitis pigmentosa and allied disorders in the Danish population disclosed 1301 cases prevalent in Denmark per January 1, 1988. Crude prevalence rates and World Standardized prevalences of systemic and non-systemic RP are presented. Sixty-four per cent of all RP-cases were non-systemic. A preponderance of males was encountered in both systemic and non-systemic RP. Usher disease was diagnosed in 12%, Bardet-Biedl syndrome constituted 5%, and the frequency of Spielmeyer-Vogt disease was 1% of all prevalent RP-cases. Other defined syndromes occurred in 1% of the cases. The Danish figures with respect to Usher disease are compared with standardized prevalence rates from Sweden and Finland. Nineteen per cent of patients affected by non-systemic RP had an onset later than 30 years of age. In patients affected by systemic RP the eye disease tended to an earlier debut with only a few per cent beginning after the age of 30 years.     

Epidemiology of retinitis pigmentosa in Denmark

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.     

Bilateral symmetry of vision disorders in typical retinitis pigmentosa.

Bilateral symmetry of disorders of vision is examined in 60 typical patients with retinitis pigmentosa. We observed a very high degree of interocular congruence in the patterns of both kinetic visual field defects and threshold profiles and in abnormalities of foveal colour discrimination and visual acuity. Abnormalities of foveal colour vision are highly correlated with the extent of visual field loss.     

A genetic analysis of retinitis pigmentosa.

Genetic analysis of 457 patients with retinitis pigmentosa (RP) included categorisation of families by recognised mendelian pattern of inheritance and formal segregation analysis of all informative sibships. Of the 368 probands a surprisingly high 18% (68) had significant congenital loss of hearing and were diagnosed as having Usher syndrome. The RP probands were categorised as: 21.7% autosomal dominant, 9.0% X-linked, 16.0% autosomal recessive, 3.3% genetic type uncertain, and 50.0% simplex. Segregation analysis reflected this high proportion of simplex cases, accounting for reduced penetrance in dominant families; only 20% remain classified as sporadic (possibly nongenetic). In the matings between normal persons estimates of the segregation ratio also indicate lower values than expected. Unlike in RP sibship, segregation in the Usher syndrome is consistent with the hypothesis of recessive inheritance. Therefore RP with significant hearing loss segregates as expected, while even if a proband is classified as a dominant or recessive the recurrence risk for the RP phenotype may be below mendelian expectation.     

Photoaversion in retinitis pigmentosa.

Photoaversion, or light-induced interference with visual comfort and performance, has been a recognised but poorly documented symptom in retinitis pigmentosa (RP). We found that a majority of our RP patients complained of photoaversion even in the absence of significant cataract. RP patients had reduced contrast sensitivity relative to normal people, but the decrement in their visual performance as a result of glare or photostress was only slight. RP patients had raised short-term adaptation and increment threshold levels, but their rate of short-term or photopic adaptation was normal. Photoaversion in RP may result because a small interference with contrast sensitivity or adaptation can place patients in a range of functional disability, or it may derive from a combination of minor aberrations.     

Plasma vitamin A and beta-carotene in retinitis pigmentosa.

Plasma levels of vitamin A and beta-carotene were measured by spectrophotometry in 39 patients with genetically determined retinitis pigmentosa, No difference was found between the levels in these patients and the levels in a control group.     

Asymmetric retinitis pigmentosa, luetic retinopathy and the question of unilateral retinitis pigmentosa.

A seropositive patient with the fundus appearance of monocular luetic retinopathy is presented. Electrophysiologically, this patient shows a late-onset form of progressive tapetoretinal degeneration (retinitis pigmentosa) presenting in an extremely asymmetric manner. The differential diagnosis of luetic and other inflammatory retinopathies vs. tapetoretinal degenerations is briefly discussed. Features distinguishing unilateral retinitis pigmentosa from bilateral tapetoretinal degenerations are reviewed, and the existence of unilateral retinitis pigmentosa as a genetic entity is questioned. Prolongation of ERG- a- and b-wave implicit times is characteristic of the tapetoretinal degenerations, and normal implicit times in the fellow eye are suggested as an additional criterion for the diagnosis of unilateral retinitis pigmentosa.     

Motion thresholds in retinitis pigmentosa.

Minimum displacement thresholds, or dmin, were measured in 29 subjects with retinitis pigmentosa (RP) and 10 subjects with normal vision. The results showed that RP can affect an observer's ability to judge the correct direction of motion in a random-dot pattern. The majority of RP subjects had elevated dmin. They required a larger displacement to perceive the correct direction of motion. Only 5 of the 29 RP subjects had thresholds within two standard deviations of the mean of the normal-observer distribution. Moreover, three RP subjects were unable to detect the correct direction of motion regardless of the displacement magnitude, and four RP subjects consistently reported motion in the opposite direction at small displacements. The results cannot be explained by abnormal temporal processing or a reduction in the effective luminance. There was a statistically significant correlation (r = 0.72, P less than 0.001) between log threshold and log MAR, consistent with the hypothesis that a reduction in the spatial density of the photoreceptors contributes to the motion-threshold elevation. Motion thresholds also were measured in subjects with normal vision under conditions of simulated "photoreceptor" dropout. The results showed that a random elimination of information from over 25% of the image positions significantly elevates motion thresholds. These results also support the spatial-density reduction hypothesis.     

Immune complexes in retinitis pigmentosa.

In a group of 46 patients with retinitis pigmentosa (RP) we studied the presence of circulating immune complexes (CIC) and the alterations in the complement system. Our results showed the presence of CIC in 43.5% of the patients studied, reduced levels of the complement components C3 and C4 (p less than 0.001), and of the haemolytic activity CH50 (p less than 0.001) when compared with a control group consisting of a 100 healthy subjects. We found a statistically significant correlation between the values of C3 and CIC (p less than 0.01), C4 and CIC (p less than 0.01), and between CH50 and CIC (p less than 0.001). These findings indicate that the CIC may play a role in the pathogenesis of primary retinitis pigmentosa.     

Contrast sensitivity in retinitis pigmentosa.

Arden gratings were used to measure contrast sensitivity in 40 patients with retinitis pigmentosa whose Snellen visual acuity was 6/12 or better. When compared with a group of 30 normal subjects the patients with retinitis pigmentosa had substantially decreased contrast sensitivity, especially at high frequencies. The Arden grating test appeared to be a sensitive test of abnormal central visual function in patients with retinitis pigmentosa.     

HLA typing in retinitis pigmentosa.

HLA serological typing was performed on 173 patients with retinitis pigmentosa (RP) of all hereditary types. No significant difference was found in the frequency of any HLA (A, B, C) antigen, when comparing autosomal dominant and recessive RP patients with a control population.     

A clinical, psychophysical, and electroretinographic survey of patients with autosomal dominant retinitis pigmentosa.

We have surveyed 104 patients (44 families) with autosomal dominant retinitis pigmentosa. The range of the survey includes clinical history, ocular examination, documentation of genetic history, Goldmann kinetic perimetry with IV/4 and I/4 white targets, two-colour static perimetry, and scotopic and photopic electroretinography. Comparison of interfamilial and intrafamilial patterns in the static perimetry data strongly suggests there may be at least two genetic subgroups within the disease characterised by the pattern of loss of rod function: in subgroup D (13 patients, 4 families) this is diffuse and severe, while in subgroup R (28 patients, 13 families) it is regional. In both D and R loss of cone function is regional, and in R it coincides with loss of rod function. In D patients the rod electroretinogram is absent; in all but two R cases it is present and usually substantial. All D patients were aware of night blindness before the age of 10, but most R patients not until after the age of 20. Many of the patients could not be classified because their disease was so advanced. The effect of disease duration on visual acuity and visual field area is described for all patients.     

Amino acids in retinitis pigmentosa.

A survey of fasting whole blood amino acids in 65 patients with various subtypes of retinitis pigmentosa performed. Eight X-linked recessive patients showed decreased taurine and aspartate. Nineteen autosomal recessive patients, and to lesser extent 10 autosomal dominant patients, showed reduced levels of whole blood threonine and histidine. Branched-chain amino acids and arginine were present in increased amounts in 2 patients with Laurence-Moon-Bardet-Biedl syndrome. These findings in LMBB patients are probably related in part to their obesity and emphasise that appropriate controls are required, and other factors (including age) known to affect amino acid levels must be accounted for. The biochemical implications of our findings are not yet apparent.     

Copper metabolism in retinitis pigmentosa.

Clinically and electrophysiologically confirmed cases of primary retinitis pigmentosa have been investigated regarding their copper metabolic state. It is observed that these patients show a normal or near normal serum copper concentration, very low plasma caeruloplasmin concentration, and a very high copper urinary excretion. A similarity between this condition and hepatolenticular degeneration is drawn and it is suggested that retinitis pigmentosa may also be a condition caused by an inborn error of copper metabolism.