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.     

Anterior chamber depth and primary angle-closure glaucoma. II. A genetic study.

The genetics of primary angle-closure glaucome (a.c.g.) was studied: a) through the prevalence in sibs and children of a.c.g. probands, and b) through the family distribution of the closely correlated axial anterior chamber depth (ACD). The material emerged from an epidemiologic study in Greeland Eskimos. a) Compared with the general population, the observed prevalence of a.c.g. was increased in sibs of a.c.g. probands and the estimated, future prevalence was found to be the same in sibs and children. Age influence prevented a proper Mendelian analysis, but no simple monogenic inheritance seems probable. b) The biometric study showed a relatively shallow chamber in sibs, children, nephews, nieces and grandchildren of a.c.g. probands. Regression analyses revealed a corresponding pattern, also in control families of probands with shallow chambers and in general population families. A heritability of 70% was found, indicating that about two thirds of the age and sex independent variation in ACD seems to be genetic.     

Sutural cataract,retinitis pigmentosa,microcephaly and psychomotor retardation a new autosomal recessive disorder?

We report four children (three sibs and one sporadic case) with congenital sutural cataract (opacity of the sutures of the crystalline lens), retinitis pigmentosa (leading to diminished visual acuity), microcephaly, and moderate to severe psychomotor retardation.

The three sibs (two F and one M) were born to healthy, consanguineous Moroccan parents; the sporadic case is an 11-year-old Dutch girl who presented at the age of nine months with a small head circumference (third percentile) and sutural cataract. Psychomotor development was retarded in all cases, retinitis pigmentosa became evident during middle or late childhood.

Congenital cataract has been described in association with a large number of various congenital abnormalities, such as renal, nervous system, skeletal, dermal and ocular (including retinal) defects.

A computer-assisted literature search has not revealed similar cases to those presented here. The cases described here appear to have a previously undescribed combination of ophthalmological and cerebral abnormalities.

The inheritance of the condition appears to be autosomal recessive as a brother and two sisters (offspring of normal consanguineous parents) are affected. The differential diagnosis is discussed.     

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.     

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.     

Oculometric characteristics of extreme hypermetropia in two faroese families.

PURPOSE: To describe and analyze the oculometric features of small eyes with high hypermetropia in two Faroese families, with emphasis on refractive components. METHODS: Members of the two families (N=40; age, 1 to 77 years), including 15 cases of extreme hypermetropia (+7.5 to +19.25 D), had an ophthalmic evaluation including refractometry, keratometry, and axial ocular measurements using A-scan ultrasound. Eye-wall thickness was assessed using B-scan. Nonparametric statistics were used, mainly the Mann-Whitney U test. RESULTS: In the two families, there were six and nine probands, respectively, with hypermetropia more than +7 D and short eyes as defined by axial eye lengths <21 mm. The median corrected visual acuity was 0.4 (range, 0.2 to 0.9). Gross fundus abnormalities were not observed. All 15 had a short posterior segment with a thick eye wall and a relatively thick lens. Furthermore, steep and rather small corneas were present. In one of the families, 70% of the affected had a corneal curvature radius of < or =7.0 mm. Five probands from family 2 were labeled as possibly affected because of hypermetropia and borderline axial length findings (21 to 22 mm). The remaining 20 subjects had visual acuity and oculometric findings within physiologic limits. CONCLUSIONS: The axial measurement features in our series of highly hypermetropic eyes mainly presented as an extension downward from the hypermetropic bottom line of the normal distribution. The axial shortness of the eyes was primarily the result of a short posterior eye segment ("posterior microphthalmos"). A steep cornea was a feature in most small eyes in our series, particularly in one family branch.     

The familial contribution to non-syndromic ocular coloboma in south India

AIMS: To identify the proportion of familial cases of isolated ocular colobomatous malformations in a case series from south India. METHODS: Children with ocular coloboma without systemic features were recruited from multiple sources in Andhra Pradesh, India. Their families were traced, pedigrees drawn, and family members examined. RESULTS: 56 probands, 25 females (44.6%) and 31 males (57.4%) with a colobomatous malformation were identified. In 12 cases (21.4%) another family member was affected. The risk to siblings was 3.8%. The parents were consanguineous in 25 cases (44.6%). CONCLUSIONS: 21.4% of cases of isolated ocular coloboma in this highly consanguineous population of south India were familial, with both autosomal dominant and autosomal recessive mechanisms likely in different families.     

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.     

Familial occurrence of pseudoexfoliation in Canada.

BACKGROUND: Genetic factors may play an important role in pseudoexfoliation syndrome. We describe the familial occurrence of pseudoexfoliation in Canadian families. METHODS: Probands with pseudoexfoliation were referred to a tertiary care glaucoma service in Ottawa because of a family history of pseudoexfoliation or glaucoma, or both. Probands and family members who agreed to participate underwent a systematic interview and eye examination. The pseudoexfoliation status was classified as affected, suspect or unknown based on preestablished criteria for the diagnosis of pseudoexfoliation and glaucoma. RESULTS: Thirty-four members of 10 families were assessed (18 affected, 2 suspect and 14 status unknown). Six families had two or more generations with pseudoexfoliation, and four families had one generation affected. There was a predominance of females among the affected subjects (17:1), and transmission in all cases appeared to be maternal. Eight of the families were of Irish/Scottish ancestry. Nine (50%) of the affected subjects had cardiovascular disease. Affected subjects tended to be older than suspects and those whose status was unknown (mean age 77, 67 and 55 years respectively). Seven subjects were affected unilaterally and 11 bilaterally. Affected subjects had moderate angle pigmentation in both eyes (mean +2.7, where 0 = no pigment and +4 = dense homogeneous pigment). The mean intraocular pressure in both eyes was higher for the affected subjects (23.1 [standard deviation (SD) 8.6] mm Hg) than for the suspects (16.8 [SD 6.1] mm Hg) and those of unknown status (16.8 [SD 2.9] mm Hg). An enlarged cup:disc ratio was seen in the affected subjects (mean 0.62). Eleven (61%) of the affected subjects had open angles on gonioscopy, and five had occludable angles and required peripheral iridectomy. Ten (56%) of the affected subjects were classified as having glaucoma, and 14 (78%) had evidence of cataract formation in at least one eye. INTERPRETATION: Pseudoexfoliation appears to be transmitted matrilineally, which raises the possibility of mitochondrial inheritance, X-linked inheritance or autosomal inheritance with genomic imprinting. A larger study of families with pseudoexfoliation is necessary to clarify the mode of transmission and to identify the gene(s) involved in the etiology of this disorder.     

High myopia with cone dysfunction

All 3 children, 2 boys and 1 girl (the probands), in a family had high myopia and subnormal visual acuities. The boys had high myopia in both eyes, the girl had high myopia in 1 eye and low myopia in the other eye. Both of the boys had a protanomalous colour vision defect. The colour vision testing of the high myopic eye of the girl was not successful, the other eye had normal colour vision. In the electroretinogram examination, both cone and rod responses were decreased in 2 of the children. In the family study, results of an eye examination of 30 relatives were available. No other cases of high myopia or subnormal visual acuities were found. The father of the children, 1 of the paternal relatives, and 5 of the maternal relatives had low myopia. One maternal male cousin of the probands had a protanomalous colour vision defect. In the genealogical study, no relationship was found between the families of the father and the mother of the probands going back to the fifth generation. The heredity of this disorder is difficult to define. It could be autosomal dominant or recessive if the myopia only are taken into consideration. If the high myopias and cone dysfunction are considered to be parts of the same syndrome, the heredity could be x-chromosomal recessive or autosomal recessive.     

Oculodentodigital dysplasia: study of ophthalmological and clinical manifestations in three boys with probably autosomal recessive inheritance

Oculodentodigital dysplasia (ODDD) is a rare inherited disorder affecting the development of the face, eyes, teeth, and limbs. The majority of cases of ODDD are inherited as an autosomal dominant condition. There are few reports of probable autosomal recessive transmission. Affected patients exhibit a distinctive physiognomy with a narrow nose, hypoplastic alae nasi, and anteverted nostrils, bilateral microphthalmos, and microcornea. Sometimes iris anomalies and secondary glaucoma are present. There are malformations of the distal extremities such as syndactyly. In addition, there are defects in the dental enamel with hypoplasia and yellow discoloration of the teeth. Less common features include hypotrichosis, intracranial calcifications, and conductive deafness secondary to recurrent otitis media. We describe three brothers with ODDD. Their parents are first cousins and present no features of ODDD. These data are in favor of autosomal recessive inheritance and suggest genetic heterogeneity for this entity.     

Oculodentodigital dysplasia: study of ophthalmological and clinical manifestations in three boys with probably autosomal recessive inheritance

Oculodentodigital dysplasia (ODDD) is a rare inherited disorder affecting the development of the face, eyes, teeth, and limbs. The majority of cases of ODDD are inherited as an autosomal dominant condition. There are few reports of probable autosomal recessive transmission. Affected patients exhibit a distinctive physiognomy with a narrow nose, hypoplastic alae nasi, and anteverted nostrils, bilateral microphthalmos, and microcornea. Sometimes iris anomalies and secondary glaucoma are present. There are malformations of the distal extremities such as syndactyly. In addition, there are defects in the dental enamel with hypoplasia and yellow discoloration of the teeth. Less common features include hypotrichosis, intracranial calcifications, and conductive deafness secondary to recurrent otitis media. We describe three brothers with ODDD. Their parents are first cousins and present no features of ODDD. These data are in favor of autosomal recessive inheritance and suggest genetic heterogeneity for this entity.     

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.     

Unilateral Isolated Microphthalmia Inherited as an Autosomal Recessive Trait

Purpose: To report a family with unilateral isolated microphthalmia showing an autosomal recessive pattern of inheritance. Case report: We report a family in which three out of four children, one male and monozygotic female twins, were born with unilateral isolated microphthalmia to healthy consanguineous parents. One twin additionally had a horseshoe kidney. Rare cases of familial isolated microphthalmia/anophthalmia have been previously described. This is the first report of a family with autosomal recessive isolated microphthalmia occurring unilaterally in all affected individuals. It remains unknown how this inherited genetic disease results in unilateral manifestation. Conclusion: Mirror imaging of this condition in the monozygotic twins may help elucidate the underlying mechanism. The constellation of features in this family may contribute to solve remaining questions of research into symmetry and asymmetry.     

Mutations in the peripherin/RDS gene are an important cause of multifocal pattern dystrophy simulating STGD1/fundus flavimaculatus

AIM: To describe the phenotype and to analyse the peripherin/RDS gene in 10 unrelated families with multifocal pattern dystrophy simulating Stargardt disease (STGD1). METHODS: The probands of 10 families and 20 affected family members underwent an ophthalmic examination including dilated fundus examination, fundus autofluorescence imaging and optical coherence tomography (OCT). In all probands and in selected family members, fluorescein angiography, electrophysiological testing and visual field analysis were performed. Blood samples were obtained from affected and unaffected family members for analysis of the peripherin/RDS gene. RESULTS: All 10 probands carried mutations in the peripherin/RDS gene. Nine different mutations were identified, including six mutations that were not described previously. All probands showed a pattern dystrophy with yellow-white flecks in the posterior pole that strongly resembled the flecks seen in STGD1, on ophthalmoscopy as well as on autofluorescence and OCT. Clinical findings in the family members carrying the same mutation as the proband were highly variable, ranging from no visible abnormalities to retinitis pigmentosa. CONCLUSIONS: Mutations in the peripherin/RDS gene are the major cause of multifocal pattern dystrophy simulating STGD1/fundus flavimaculatus. This autosomal dominant disorder should be distinguished from autosomal recessive STGD1, in view of the different inheritance pattern and the overall better visual prognosis.     

Homozygous and heterozygous retinal phenotypes in families harbouring IMPG2 mutations

Introduction: Biallelic mutations in interphotoreceptor matrix proteoglycan 2 (IMPG2) have been shown to underlie recessive childhood-onset rod-cone dystrophy with early macular involvement in several families. In other families, heterozygous IMPG2 mutations have been associated with dominant vitelliform macular dystrophy. To date, the retinal phenotype of heterozygotes from families with recessive IMPG2-related retinal dystrophy has not been assessed. This study documents the genotypes and phenotypes observed in both homozygotes and available heterozygotes from additional families with IMPG2-related recessive rod-cone dystrophy.

Methods: Retrospective case series (2016–2018).

Results: Four families were identified. All were first-cousin marriages and had no known relation to each other. Individuals with biallelic pathogenic variants (7 individuals) had childhood-onset rod-cone dystrophy. Families 1 and 2 harboured the same novel homozygous mutation c.189dup;p.Gln64Thrfs*9 (5 individuals, 4–17 years old). Family 3 harboured the novel homozygous mutation c.533 + 4_533 + 7del;p.? (1 individual, 17 years old), and Family 4 harboured the previously reported homozygous mutation c.3262C>T;p.Arg1088* (1 individual, 45 years old). The 3 available carriers were genetically confirmed (both parents from Family 1 and the father from Family 3) and had macular focal retinal pigment epithelium thickening by optical coherence tomography (OCT). The father from Family 3 also had unilateral sectoral pigmentary retinopathy.

Conclusions: Childhood-onset recessive rod-cone dystrophy with early macular involvement should prompt examination of the parents for macular focal retinal pigment epithelium thickening on OCT. If present the possibility of biallelic IMPG2 mutations in the proband should be considered. Young affected relatives of the proband can show multimodal imaging abnormalities before they are overtly symptomatic.     

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.     

Childhood blindness in Lebanon.

A survey in the Lebanese schools for the blind revealed that 77% of childhood blindness in the country was genetically determined. Two thirds of the hereditary blindness cases were due to autosomal recessive conditions; the high frequency of consanguineous marriages in Lebanon was the underlying cause of this finding. There is marked similarity in the etiology of childhood blindness in Cyprus and Lebanon, for both countries are somewhere between the highly developed countries.     

Ocular findings in a new heritable syndrome of brain, eye, and urogenital abnormalities

We studied the clinical and histopathologic ocular findings in four related males with a newly recognized syndrome consisting of microphthalmos, microencephaly, mental retardation, agenesis of the corpus callosum, hypospadius, and cryptorchidism with X-linked recessive inheritance. The ocular abnormalities include microphthalmos, corneal pannus and hypoplasia, cataracts, uveal hypoplasia, retinal dysplasia, optic nerve hypoplasia, and congenital blepharoptosis. In case 4, a female twin who died in utero (at 15 weeks' gestation) showed none of the ocular abnormalities.     

Therapeutical and genetical aspects of congenital glaucomas

Therapy for congenital glaucoma is primarily surgical. We have investigated 249 cases who have undergone trabeculectomy. There was a 79% success rate as regards to control of the IOP. Vision could be saved among the patients who had applied relatively early. At the end of the follow up which was 5 years IOP remained normal in the successful group. All the patients and their families were analysed genetically by their pedigrees and caryotypes. An autosomal recessive pattern with variable penetrance was found. The majority of the patients came from families with consanguineous marriages giving a rate of 66.6%. It was suggested that the course of the disease is highly affected by and related to parental consanguinity. An early age of onset and an accelerated clinical course could be well correlated.