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.     

Prevalence of tapeto-retinal dystrophies among Danish children

Age specific prevalence rates are presented based on 110 cases of pigmentary retinopathy (RP) recorded in the Danish child population of a little over one million individuals on January 1, 1988.A steady and steep rise in age specific prevalences of notified RP throughout infancy and childhood was found. The material consisted in 52 non-systemic and 58 systemic cases. 35 of the systemic cases could be nosologically identified, leaving 23 cases unidentified with respect to known diseases or syndromes.Among the genetic types autosomal recessive inheritance was the most common with 60 cases (55%). Parental consanguinity was less frequent than hitherto reported. On the other hand undetected carrier state for X-linked tapeto-retinal dystrophy played a more significant role than expected. A clear excess of males among the simplex cases indicated that some X-linked cases may still be unrecognized.A significant proportion of non-systemic, early infantile RP with an autosomal recessive or simplex mode of inheritance are clinically and electrophysiologically characterised as cone-rod dystrophies.     

Current mutation discovery approaches in Retinitis Pigmentosa

With a worldwide prevalence of about 1 in 3500–5000 individuals, Retinitis Pigmentosa (RP) is the most common form of hereditary retinal degeneration. It is an extremely heterogeneous group of genetically determined retinal diseases leading to progressive loss of vision due to impairment of rod and cone photoreceptors. RP can be inherited as an autosomal-recessive, autosomal-dominant, or X-linked trait. Non-Mendelian inheritance patterns such as digenic, maternal (mitochondrial) or compound heterozygosity have also been reported. To date, more than 65 genes have been implicated in syndromic and non-syndromic forms of RP, which account for only about 60% of all RP cases. Due to this high heterogeneity and diversity of inheritance patterns, the molecular diagnosis of syndromic and non-syndromic RP is very challenging, and the heritability of 40% of total RP cases worldwide remains unknown. However new sequencing methodologies, boosted by the human genome project, have contributed to exponential plummeting in sequencing costs, thereby making it feasible to include molecular testing for RP patients in routine clinical practice within the coming years. Here, we summarize the most widely used state-of-the-art technologies currently applied for the molecular diagnosis of RP, and address their strengths and weaknesses for the molecular diagnosis of such a complex genetic disease.     

A population-based epidemiological and genetic study of X-linked retinitis pigmentosa

PURPOSE: To perform a nation-wide elucidation of the prevalence and the mutation spectrum in X-linked retinitis pigmentosa (XLRP), and to make genotype-phenotype comparisons. METHODS: The study comprised 96 affected males and 149 female carriers from 42 families representing all identified XLRP individuals in the Danish population (5.4 million inhabitants). RPGR and RP2 were screened for mutations in 34 families, the medical files of the patients were scrutinized, and phenotype data were extracted. RESULTS: The prevalence of affected males was estimated to be 1:26,200 and 1:18,000 of female carriers. A rough estimate, however, indicates that the real prevalence of affected males was approximately 1:15,000. The cumulated life risk of development of XLRP in carriers was strongly age dependent and included one third of the carriers older than 60 years. Molecular analysis of RP2 and RPGR uncovered 28 different mutations in 33 of 34 index cases analyzed. Twelve patients carried a mutation in RP2, 12 in exons 1 to 14, and 9 in open reading frame (ORF) 15 of RPGR. Males with RP2 mutations tended to have higher degrees of myopia, lower visual acuities, and more preserved visual fields than did males with RPGR mutations at the same age. No significant differences in phenotype were found in age of onset and type of mutation in either RP2 or RPGR. CONCLUSIONS: A very high mutation detection rate in familial cases makes genetic testing a valuable clinical tool for genetic counseling and prenatal testing. The proportion of RP2-mediated XLRP in the Danish population is higher and the proportion of RPGR-ORF15 is lower than reported in other studies. Thus, strategies for diagnostic procedures should take into account the population-specific mutation spectrum.     

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.     

The empirical risk of retinitis pigmentosa in Japan]

The empirical risk of hereditary retinitis pigmentosa (RP), was studied based on a survey of the data from 378 families with RP who were seen in Juntendo University hospital from 1980 to 1988. If the cases have had affected sibling, the empirical risk is 19% for the other siblings, and 29% if they have parental consanguinity. Moreover the risk for male siblings is about 1.7 times higher than for female siblings. The prevalence in the general population of carriers with autosomal recessive hereditary RP was calculated to be about 0.8 to 1.7 in 100 persons. If a hereditary RP case marries a normal and unrelated partner, the risk is 0.4-0.9% for their child. If a case has many affected relatives (parents, grandparents, uncles or aunt etc), the risk is 24% for a son, and 30% for a daughter. Some normal persons among autosomal dominant families with incomplete penetrance are suspected to be carriers. The rate of penetration of the autosomal dominant gene was estimated to be 0.54. Therefore, the risk is 8.6% for the children of such persons. If the carriers are among X-linked families, the risk is 36% for their son. The risk is 1% or more for children of sporadic cases.     

A survey of hereditary aspects of pigmentary retinal dystrophies

A study of 707 cases of retinitis pigmentosa and choroideraemia presenting over 12 years were classified according to their modes of inheritance--439 autosomal recessive (62%), 193 autosomal dominant (27%), 75 X-linked (10.7%). The patients with autosomal recessive transmission included 58 Usher syndrome, 12 Laurence-Moon-Bardet-Biedl syndrome and 33 Leber's congenital amaurosis. Another 37 had an early onset with macular degeneration and 31 were of late onset with pericentral dystrophy. Forty two were offspring of consanguineous parents. Of 193 individuals (78 families) with autosomal dominant inheritance, 20% had night blindness from early childhood. With X-linked transmission, 33 males and 31 female carriers comprised the retinitis pigmentosa group and eight males and three carrier females, choroideraemia. Almost all this X-linked group were of British ancestry. Of patients originating from the Mediterranean area, 94% had autosomal recessive disease.     

Multicenter genetic study of retinitis pigmentosa in Japan: I. Genetic heterogeneity in typical retinitis pigmentosa

A nationwide, multicenter study of typical retinitis pigmentosa (RP) was carried out in collaboration with 18 hospitals throughout Japan to obtain current information for genetic counseling. We analyzed the genetic heterogeneity of RP based on the parental consanguinity of 434 probands registered during a 6-month period in 1990. A gradual decline in the frequency of consanguineous marriage was recognized among the normal parents of RP patients. The relative frequencies of inheritance patterns were estimated as: autosomal recessive, 25.2%; autosomal dominant, 16.9%; X-linked, 1.6%; and simplex, 56.3%. A comparison of these results with previous reports in Japan revealed a decline in the relative frequency of autosomal recessive cases and an increase in simplex cases. This suggests a decrease in the incidence of autosomal recessive retinitis pigmentosa in Japan, as well as the necessity for exhaustive investigations aimed at identifying inheritance patterns for RP patients seeking genetic counseling.     

The Wisconsin Epidemiologic Study of Diabetic Retinopathy. VI. Retinal photocoagulation

The prevalence of focal and panretinal photocoagulation and its relationship to demographic and other characteristics were examined in a population-based study in southern Wisconsin. For participants whose age at diagnosis was less than 30 years and who were taking insulin (996 persons) the prevalence rate of panretinal photocoagulation (13.9%) was higher than that of focal photocoagulation (3.6%). For those whose age at diagnosis was 30 years or older (1370 persons), the prevalence rate for panretinal photocoagulation (3.6%) was slightly higher than that of focal photocoagulation (3.0%). Seventy-two percent of eyes of younger onset and 45% of eyes of older onset persons that had received panretinal photocoagulation treatment were found to have incomplete regression of retinal new vessels, and in approximately half of these eyes severe proliferative retinopathy (Diabetic Retinopathy Study High Risk Characteristics [DRS-HRC]) was present. Among eyes with DRS-HRC, 55% were found to be untreated.     

Multicenter genetic study of retinitis pigmentosa in Japan: II. Prevalence of autosomal recessive retinitis pigmentosa

Retinitis pigmentosa (RP) is a group of genetically heterogeneous diseases with autosomal recessive (AR), autosomal dominant, and X-linked modes of inheritance. Autosomal recessive retinitis pigmentosa (ARRP) is the most common form in Japan. A genetic analysis was done to determine the prevalence of ARRP indirectly, to provide an estimation of changing trends in the overall prevalence of RP. Data on the frequency of consanguinity and marriage year of normal parents of 59 ARRP patients were obtained from a nationwide multicenter survey of typical retinitis pigmentosa conducted in 1990. The gene frequency of ARRP was 0.01145 (Dahlberg's formula). In 1990, the number of young symptomatic ARRP patients decreased, while the number of patients aged 40 years and older increased. The total number of symptomatic ARRP patients in 1990 was nearly 21% higher than in 1970. Despite a dramatic decline in consanguinity in recent decades in Japan, the number of ARRP patients has increased. This increase is attributed to greater longevity and overall population growth. Our results suggest that the total number of RP patients has not decreased, and may even have increased.     

Prevalence of posterior subcapsular lens opacities in patients with retinitis pigmentosa.

We clinically evaluated 338 patients with various genetic types of retinitis pigmentosa (RP) for the presence of posterior subscapsular (PSC) lens opacities. Of these, 180 (53%) had PSC lens changes or were bilaterally aphakic. Patients with X-linked recessive RP showed a greater prevalence and patients with autosomal dominant RP a lesser prevalence of PSC lens changes compared with autosomal recessive or isolated cases.     

Prevalence of primary angle-closure disease in retinitis pigmentosa

Purpose:To determine the prevalence of primary angle-closure disease (PACD) in patients with retinitis pigmentosa (RP).Methods: This was a retrospective review of the electronic medical records of all RP patients over the age of 10 years attending the Genetics Eye Clinic of a tertiary-care hospital during a 7-year period. Information regarding age, gender, vision, refraction, lens, intraocular pressure (IOP), type of RP, and inheritance pattern using pedigree charts for all patients were obtained. Patients with a shallow anterior chamber, high IOP, or glaucomatous optic discs were referred to the glaucoma department where they underwent additional IOP measurements, a gonioscopy, and disc evaluation by a glaucoma specialist. The prevalence of PACD was determined.Results: A total of 618 RP patients were examined during the study period, of which 95.1% had typical RP. The prevalence of primary angle-closure suspects was 2.9%, primary angle closure was 0.65%, and primary angle-closure glaucoma (PACG) was 2.27%. In contrast, the prevalence of primary open-angle glaucoma was 1.29%. The prevalence of PACG in those older than 40 years was 3.8% (95% confidence interval: 1.6–6.0).Conclusion: The prevalence of PACG in RP patients over 40 years was higher than that found in the general population of a similar age (3.8% vs. 0.8%). In our cohort of RP patients, 5.9% had PACD. Hence, gonioscopy is warranted in all RP patients to identify this condition and treat it appropriately.     

Novel deletion of the RPGR gene in a Chinese family with X-linked retinitis pigmentosa

Purpose: To characterize a Chinese family with inherited retinitis pigmentosa (RP). Methods: Linkage studies and haplotype analysis were used for gene mapping, and single-strand conformation polymorphism (SSCP) analysis and direct DNA sequence analysis were used for identifying the responsible mutation. Results: Pedigree analysis suggests that RP in the Chinese family RP002 is inherited either as an autosomal recessive trait or as an X-linked trait. Linkage analysis of RP002 excluded all known autosomal recessive RP loci. Further analysis with 17 polymorphic markers covering the entire X chromosome localized the RP gene in RP002 between markers GATA175D03 and GATA144D04 on Xp11.4, a region where the RP3 gene ( RPGR ) is found. Mutation analysis of the RPGR gene in RP002 revealed a novel 28-bp deletion in exon 7. This deletion resulted in an in-frame stop codon that eliminates the C-terminal two-thirds of the RPGR protein. The 28-bp deletion co-segregated with the disease in the family and was not present in 100 normal Chinese individuals. Female carriers of the deletion were affected with myopia and had ERG abnormalities and mild constriction of visual field. Conclusions: A novel 28-bp deletion in the RPGR gene identified in an X-linked Chinese RP family causes severe RP in male patients as well as myopia and ERG abnormalities in female carriers. The deletion represents the largest microdeletion identified in RPGR to date, and expands the spectrum of RPGR mutations causing XLRP.     

Cone and rod ERG phototransduction parameters in retinitis pigmentosa

PURPOSE: To analyze cone and rod phototransduction parameters from ERG a-waves in patients with RP and to determine the relationships among these parameters, age, and mode of inheritance. METHODS: Sets of four white flashes (3.2-4.4 log scotopic troland [scot td-s]) were presented in the dark. The same stimuli were later presented against a rod-saturating background and the generated cone a-waves were subtracted from the dark-adapted responses to produce rod-only a-waves. The rod-only and cone a-waves were fit with computational models. RESULTS: Of 418 consecutive patients with retinitis pigmentosa (RP), cone a-waves were quantifiable in 136 (33%), whereas rod a-waves were quantifiable in 125 (30%). Cone R(max) (maximum response) and cone S (sensitivity) parameters were significantly below normal in all RP subgroups. Cone R(max) was lower in XlRP than in other forms of inheritance (P < 0.05). Cone S was abnormal in 77.9% of all patients with RP and in 96.8% of those with XlRP. More than 95% of the rod R(max) values were abnormal, whereas rod S was abnormal in 61.6% of these patients. CONCLUSIONS: The efficiency of cone phototransduction appears to be affected in all forms of RP, even in some patients in whom the sensitivity of rod phototransduction is normal. In this cross-sectional sample, there was no evidence that transduction efficiency decreased with increasing age of the patient. The X-linked mode of inheritance is associated with greater abnormalities in cone and rod photoreceptor function at a younger age compared with the other modes of inheritance.     

视网膜色素变性发病机制及治疗进展

视网膜色素变性（retintis pigmentosa,RP）是指以进行性感光细胞及色素上皮功能丧失为共同表现的遗传性、退行性的疾病,RP是主要的致盲性眼病。其遗传方式包括X连锁遗传、常染色体隐性或者显性遗传,也有散发。临床表现为典型的三联征:骨细胞样色素沉着、视网膜血管缩窄和视盘蜡样苍白。RP具有高度的基因异质性(多个突变位点引起同一疾病）及表型异质性。本文对RP的发病机制和治疗方法进行简要综述。     

Molecular genetic basis of primary inherited optic neuropathies

AIM: To review the molecular genetic basis of primary inherited optic neuropathies. METHODS: Medline and Embase search. RESULTS: Inherited optic neuropathies are a genetically diverse group of disorders that present with reduced visual acuity and the clinical appearance of optic atrophy. The inherited optic neuropathies may be sporadic or familial, in which case the mode of inheritance may be Mendelian (autosomal dominant, autosomal recessive, X-linked recessive) or non-Mendelian (mitochondrial). Two genes for dominantly inherited optic atrophy have been mapped (OPA1 and OPA4), of which the gene has been identified in one (OPA1). A gene for recessive optic atrophy (OPA3) has also been identified. X-linked optic atrophy (OPA2) has been mapped but to date no gene has been identified. Mutations in mitochondrial DNA have been identified in Leber's hereditary optic neuropathy. CONCLUSIONS: Mutations in genes from both the nuclear and mitochondrial genomes appear to be responsible. Mitochondrial dysfunction, in the broadest sense, is emerging as central to the pathogenesis of this group of conditions.     

The prevalence and causes of bilateral and unilateral blindness in an elderly urban Danish population. The Copenhagen City Eye Study

PURPOSE: To study the prevalence and causes of bilateral and unilateral blindness in an elderly urban Danish population. METHODS: Data originated from a Danish epidemiologic cross-sectional random sample population eye survey conducted during the years 1986-1988. The population consisted of 1,000 inhabitants aged 60 to 80 years in Copenhagen. The participants underwent an extensive ophthalmologic examination. A participation rate of 96.9% was achieved. Any blindness was defined as best-corrected visual acuity (VA) worse than 0.05 (the WHO criteria) and VA of 0.1 or worse (the National criteria (NC) of blindness). RESULTS: The prevalence rates of bilateral and unilateral blindness were, respectively, 0.53% and 3.38% according to WHO, but 1.06% and 4.44% using NC. Bilateral blindness rose significantly with age (p=0.02). According to NC, age-related macular degeneration (AMD) was the leading cause of bilateral blindness, accounting for 60% of all blind persons. Glaucoma, myopic macular degeneration, cataract and retinitis pigmentosa were jointly the second most common cause, each accounting for 10% of all bilaterally blind persons. Diabetic retinopathy was not a cause of bilateral blindness. Amblyopia was the most frequent, AMD the second most frequent, and diabetic retinopathy was among the third most common cause of unilateral blindness accounting for, respectively, 28.60%, 16.66% and 9.52% of all unilateral blindness. CONCLUSIONS: Blindness was associated with increasing age. A calculation indicates that among Danes aged 60 to 80 years 7,736 are bilaterally blind and 35,503 suffer from unilateral blindness. This study highlights AMD as the most important cause.     

用科学的态度正确认识视网膜色素变性

视网膜色素变性(RP)是最常见的遗传性致盲眼底病,具有高散发性和高临床异质性.除了常见的遗传类型外,还具有双基因遗传,线粒体遗传,不完全显性遗传等新遗传方式.RP的表型复杂,Peripherin/RDS、RHO、RP2和RP3等RP基因出现了基因型和表型不一致现象,中心性、单发性、无色素性和缓慢型视网膜变性等少见RP具有复杂的临床表型.视网膜移植术、视网膜植入术、药物及神经营养因子治疗和基因治疗等治疗体系已经建立.但是,一些眼科医师对于RP治疗的新进展和新知识了解不多,因此积极地更新知识,以科学的态度正确地认识RP非常必要.(中华眼科杂志,2009,45:193-195)