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.     

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.     

An epidemiogenetic study of typical retinitis pigmentosa in Japan--a preliminary report of nationwide, multicenter study]

We performed a nationwide, multicenter study of typical retinitis pigmentosa with reference to the inheritance patterns of the disease. A total of 253 probands were registered during two months of 1989, and an analysis of the parental consanguinity of 182 probands with the method of inbreeding coefficient enabled us to estimate the relative prevalence of genetic types; autosomal recessive trait: 47.6%; autosomal dominant trait: 17.3%; sporadic cases: 34.6%. A comparison of the results with previous studies has indicated a decrease in the prevalence of the autosomal recessive trait and an increase in the sporadic cases, as would be expected from the decrease in consanguineous marriages and offsprings in the past few decades in Japan. X-linked retinitis pigmentosa was rarely identified, but precise evaluation of its frequency needs further investigation.     

Genetic features of retinitis pigmentosa in Turkey

Sixty-two cases with retinitis pigmentosa from 42 index families were investigated to reveal the genetic features of the disease in Turkey. There were 42 propositi of whom 5 had a systemic syndrome associated with retinitis pigmentosa. Of the remaining 37 cases the condition was autosomal recessive in 21 (56.8%), sporadic in 12 (32.4%), autosomal dominant in 3 (8.1%) and X-linked recessive in one (2.7%). Sporadic cases may be more frequent as many hereditary cases are not brought to medical attention in rural families. Male preponderance among sporadic cases may indicate that there may be more X-linked cases. Nine out of 21 cases initially classified as sporadic displayed parental consanguinity and they were included as having autosomal recessive trait. Large families with autosomal recessive inheritance may prove valuable in linkage analysis and in defining future gene abnormalities.     

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 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.     

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.     

Correlation between Goldmann perimetry and maximal electroretinogram response in retinitis pigmentosa

To evaluate the relationship between Goldmann perimetry and maximal electroretinographic responses in patients with retinitis pigmentosa, analyses were performed on 220 affected subjects and separately on two subgroups with autosomal dominant (n = 35) and autosomal recessive (n = 29) inheritance. Electroretinograms were recorded averaging 100 iterations elicited with a 20-lux/s, 0.5-Hz white flash ganzfeld stimulation. The peripheral isopters of the visual fields were delimited with I4e, IIIe and V4e targets, measured on conventional perimetry charts with a light pen and expressed in square centimeters. Unlike most previously published reports, this investigation showed a definite correlation (p = 0.0001) between maximal electroretinographic response amplitude and visual field areas. This correlation was more evident for I4e and IIIe isopters (r = 0.89 and 0.87, respectively) than for V4e isopter (r = 0.69). This phenomenon appears to be related to distortion occurring on standard isometric charts and to spatial summation effects in the peripheral field. Such correlations held for both the autosomal dominant and autosomal recessive subgroups. It appears that, if enough accuracy is provided, maximal electroretinographic responses and Goldmann visual fields are both good measures of the remaining functioning retina in nonsyndromic retinitis pigmentosa, irrespective of inheritance models and dystrophic patterns.Abbreviations ADRP autosomal dominant retinitis pigmentosa - ARRP autosomal recessive retinitis pigmentosa - RP retinitis pigmentosa - VF visual field     

Preserved para-arteriole retinal pigment epithelium (PPRPE) in retinitis pigmentosa.

Five patients with retinitis pigmentosa (RP) with probable autosomal recessive inheritance have been identified in whom there is relative preservation of retinal pigment epithelium adjacent to and under retinal arterioles despite a panretinal degenerative process. All the patients were hypermetropic, though patients with RP tend to be myopic. This implies that there is a factor associated with retinal arterioles which locally retards the RP process in these patients. It may be appropriate to look for the PPRPE pattern in hypermetropic RP patients.     

Mutation of human retinal fascin gene (FSCN2) causes autosomal dominant retinitis pigmentosa

PURPOSE: To characterize the clinical features of 14 Japanese patients with autosomal dominant retinitis pigmentosa (ADRP) who were found to have a mutation in the FSCN2 gene. METHODS: Mutation screening by single-strand conformation polymorphism (SSCP) was performed in 120 unrelated patients with ADRP, 200 unrelated patients with autosomal recessive retinitis pigmentosa (ARRP), and 100 patients with simplex RP (SRP). The DNA fragment that showed abnormal mobility on SSCP was sequenced. The clinical features of these patients were determined by visual acuity, slit lamp biomicroscopy, electroretinography, fluorescein angiography, and kinetic visual field testing. RESULTS: A novel 208delG mutation in the FSCN2 gene was identified in 14 patients from four unrelated families with ADRP. The ophthalmic findings were typical of RP. CONCLUSIONS: The findings show that a 208delG mutation in the FSCN2 gene produces ADRP. This mutation was found in 3.3% of the patients with ADRP in Japan, which suggests that it may be relatively common in Japanese patients with ADRP.     

Peripheral absolute threshold spectral sensitivity in retinitis pigmentosa.

Dark-adapted spectral sensitivities were measured in the peripheral retinas of 38 patients diagnosed as having typical retinitis pigmentosa (RP) and in 3 normal volunteers. The patients included those having autosomal dominant and autosomal recessive inheritance patterns. Results were analysed by comparisons with the CIE standard scotopic spectral visibility function and with Judd's modification of the photopic spectral visibility function, with consideration of contributions from changes in spectral transmission of preretinal media. The data show 3 general patterns. One group of patients had absolute threshold spectral sensitivities that were fit by Judd's photopic visibility curve. Absolute threshold spectral sensitivities for a second group of patients were fit by a normal scotopic spectral visibility curve. The third group of patients had absolute threshold spectral sensitivities that were fit by a combination of scotopic and photopic spectral visibility curves. The autosomal dominant and autosomal recessive modes of inheritance were represented in each group of patients. These data indicate that RP patients have normal rod and/or cone spectral sensitivities, and support the subclassification of patients described previously by Massof and Finkelstein.     

On the heredity of retinitis pigmentosa.

The aims of this study are: (1) to determine the frequencies of the various genetic forms of retinitis pigmentosa; and (2) to perform segregation analysis on autosomal dominant, autosomal recessive, and X-linked families. The families studied consisted of 2 series of patients at Moorfields Eye Hospital: (1) 426 families seen in the Genetic Clinic; and (2) 289 families seen in the Electrodiagnostic Department. Comparison between the 2 series identified biases of ascertainment, and it was estimated that the combined series included 53% of simplex cases and a minimum of 15% of X-linked families. Segregation analysis of the Genetic Clinic series showed good agreement with expectation in autosomal dominant and X-linked families, but indicated that no more than 70% of all simplex cases were autosomal recessive. The rest of the simplex cases were mildly affected and may represent fresh autosomal dominant mutations, autosomal dominant transmission with reduced penetrance, the heterozygous state of X-linked disease in some of the females, and phenocopies.     

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.     

Autosomal recessive retinitis pigmentosa is associated with mutations in RP1 in three consanguineous Pakistani families

PURPOSE: To localize and identify the gene and mutations causing autosomal recessive retinitis pigmentosa in three consanguineous Pakistani families. METHODS: Blood samples were collected and DNA was extracted. A genome-wide scan was performed by using 382 polymorphic microsatellite markers on genomic DNA from affected and unaffected family members, and lod scores were calculated. RESULTS: A genome-wide scan of 25 families gave an hlod = 4.53 with D8S260. Retinitis pigmentosa in all three families mapped to a 14.21-cM (21.19-Mb) region on chromosome 8 at q11, flanked by D8S532 and D8S260. This region harbors RP1, which is known to cause autosomal dominant retinitis pigmentosa. Sequencing of the coding exons of RP1 showed mutations in all three families: two single-base deletions, c.4703delA and c.5400delA, resulting in a frame shift, and a 4-bp insertion, c.1606insTGAA, all causing premature termination of the protein. All affected individuals in these families are homozygous for the mutations. Parents and siblings heterozygous for the mutant allele did not show any signs or symptoms of RP. CONCLUSIONS: These results provide strong evidence that mutations in RP1 can result in recessive as well as dominant retinitis pigmentosa. The findings suggest that truncation of RP1 before the BIF motif or within the terminal portion results in a simple loss of RP1 function, producing a recessive inheritance pattern. In contrast, disruption of RP1 within or immediately after the BIF domain may result in a protein with a deleterious effect and hence a dominant inheritance pattern.     

视网膜色素变性的实验研究进展

视网膜色素变性是一种遗传性眼病,遗传方式包括常染色体显性遗传、常染色体隐性遗传及性连锁隐性遗传等,目前已知的突变位点超过3 000个,造成本病临床治疗困难。眼科学者致力于探索视网膜色素变性的治疗方式,进行了大量实验研究,主要有药物治疗、细胞移植、基因治疗等治疗方式。药物治疗包括中药、抗氧化剂、抗凋亡剂、神经营养因子等,与其它治疗方式相比,无侵入性,且方便价廉,但其作用机制尚需更深入的研究。细胞移植被认为是治疗视网膜色素变性的有效方法,但有可能引起视网膜前膜及黄斑皱褶。基因治疗虽然存在一定的局限性,但随着基因编辑技术和新型基因递送载体的发展,未来会成为视网膜色素变性最有希望的治疗方式之一。本文对近年来视网膜色素变性的实验研究进行了综述与展望。     

CRB1 mutations may result in retinitis pigmentosa without para-arteriolar RPE preservation

Purpose: To report a new phenotype in retinitis pigmenotosa (RP) patients with CRB1 mutations at the RP12 locus. Patients: Thirty-seven patients from two Pakistani families with severe retinitis pigmentosa. Methods: Samples were screened with single-strand conformation polymorphism analysis followed by DNA sequencing of the coding sequence of the CRB1 gene. Results: Two novel CRB1 mutations were discovered. No patients had evidence of preservation of the para-arteriolar retinal pigment epithelium (PPRPE) that has been previously reported in all cases of RP associated with CRB1 mutations. Conclusions: Patients with severe autosomal recessive (or simplex) RP who lack the finding of PPRPE should not be excluded from molecular analysis of CRB1 purely because they lack the clinical feature of PPRPE. This report illustrates that RP at the RP12 locus is not clinically uniform. The absence of PPRPE cannot be used to exclude CRB1 as a potential molecular explanation for RP.     

常染色体隐性遗传视网膜色素变性的相关基因研究进展

视网膜色素变性(rentinitis pigmentosa，RP)是一种发病机制尚未完全明确的遗传性致盲性视网膜疾病，特征性表现为夜盲、进行性视野缩窄和视力下降，眼底可见骨细胞样色素沉着、视网膜血管变细和视盘蜡黄三联症。RP具有较大的遗传异质性和临床异质性，其中常染色体隐性遗传视网膜色素变性(autosomal recessive RP，ARRP)占RP的5%～20%，目前已定位43个致病基因，克隆了其中40个，并且不断有新的相关致病基因被报道。本文就近3a发现与ARRP相关的AGBL5、ARHGEF18、HGSNAT和ZNF408四个基因研究进展作一综述。     

视网膜色素变性1基因在常染色体显性遗传视网膜色素变性家系中的突变分析

目的:研究常染色体显性遗传视网膜色素变性(autosomal dominant retinitis pigmentosa,ADRP)家系中视网膜色素变性1(retinitis pigmentosa-1,RP1)基因的突变特征及其在RP发病机制中的作用。方法:运用聚合酶链反应和直接测序方法,对6个ADRP家系的47例成员和50例对照者进行了RP1基因全编码区和邻近剪切位点的内含子区域序列突变的筛选与检测。运用单因素分析、多因素Logistic回归分析研究RP1基因点突变在RP发病中的作用。结果:ADRP家系成员和对照组RP1基因第4外显子上检测出2个变异位点。在1691和1725密码子存在杂合的两种类型的密码子(S1691P,Ser-Pro,TCT→CCT;Q1725Q,Gln-Gln,CAA→CAG)。ADRP家系成员中Ser-1691-Pro及Gln-1725-Gln位点突变率显著高于正常对照组(χ2=11.202,P<0.05)。结论:RP1基因Ser-1691-Pro及Gln-1725-Gln位点多态性可增高RP的危险性,具有潜在的致病性,考虑为ADRP家系的易感基因。     

Prevalence of retinitis pigmentosa in Maine

Between 1976 and 1980, medical and social service sources were used to ascertain cases of retinitis pigmentosa in Maine (1980 population, I, 124,660). As of July 1, 1980, 241 clinically prevalent cases of retinitis pigmentosa were ascertained. Extensive pedigrees were collected for 185 of the subjects and medical records were obtained. One hundred fourteen cases were further evaluated by clinical examination including electroretinography. Adjusting for incorrect diagnosis (eight of 114, 7%) and underascertainment (23 of 185, 12.5%), we estimated that prevalence of retinitis pigmentosa in Maine is 236 cases, 21 per 100,000 population or 1:4,756. Excluding Usher and Bardet-Biedl syndromes, the prevalence is 1:5,193. Estimated birth incidence of persons who will become affected with non-syndrome retinitis pigmentosa is 1:3,544. Incidence of newly diagnosed cases per year is about six per 1,000,000 population. Among kindreds, 16 of 85 (19%) were autosomal dominant, 55 of 85 (65%) autosomal recessive or isolated cases, seven of 85 (8%) X-linked recessive, and seven of 85 (8%) not classified by mode of transmission.