Identification of the gene that, when mutated, causes the human obesity syndrome BBS4.

Bardet-Biedl syndrome (BBS, MIM 209900) is a heterogeneous autosomal recessive disorder characterized by obesity, pigmentary retinopathy, polydactyly, renal malformations, mental retardation, and hypogenitalism. The disorder is also associated with diabetes mellitus, hypertension, and congenital heart disease. Six distinct BBS loci map to 11q13 (BBS1), 16q21 (BBS2), 3p13-p12 (BBS3), 15q22.3-q23 (BBS4), 2q31 (BBS5), and 20p12 (BBS6). Although BBS is rare in the general population (<1/100,000), there is considerable interest in identifying the genes causing BBS because components of the phenotype, such as obesity and diabetes, are common. We and others have demonstrated that BBS6 is caused by mutations in the gene MKKS (refs. 12,13), mutation of which also causes McKusick-Kaufman syndrome (hydrometrocolpos, post-axial polydactyly, and congenital heart defects). MKKS has sequence homology to the alpha subunit of a prokaryotic chaperonin in the thermosome Thermoplasma acidophilum. We recently identified a novel gene that causes BBS2. The BBS2 protein has no significant similarity to other chaperonins or known proteins. Here we report the positional cloning and identification of mutations in BBS patients in a novel gene designated BBS4.

Rieger syndrome is associated with PAX6 deletion.

PURPOSE: Rieger syndrome is an autosomal dominant condition defined by anterior segment dysgenesis in combination with facial, dental, skeletal and umbilical abnormalities. To date Rieger syndrome has been associated with mutations in the PITX2 gene at chromosome 4q25 and a second locus has been found at chromosome 13q14. METHODS: We describe a Rieger syndrome case with all the typical dysmorphic features and the molecular genetic finding by use of FISH analysis of the PAX6 gene. RESULTS: An eight-year-old girl had iris stroma hypoplasia, corectopia and iridogoniodysgenesis. She had an underdeveloped premaxilla and a congenital absence of nine teeth in the maxilla. The front teeth in the mandible were peg-shaped and all teeth were small. There was failure of involution of the periumbilical skin. FISH analysis using probes for the PAX6 gene showed a small deletion for the PAX6 gene on one homologue of chromosome 11. CONCLUSION: Rieger syndrome can -- in addition to PITX2 gene mutations and abnormalities at chromosome 13q14 -- be associated with PAX6 gene abnormalities.

Intrafamilial variation of the phenotype in Bardet-Biedl syndrome.

AIMS: To describe the variation of the phenotype within families with several individuals with Bardet-Biedl syndrome. METHODS: The phenotypes of affected siblings in 11 Scandinavian families with two or more members who had at least three of the features: retinal dystrophy, polydactyly, obesity, hypogenitalism, and mental retardation, were compared [corrected]. Individuals without retinal dystrophy were excluded. RESULTS: Intrafamilial variation of expressivity of the features obesity, polydactyly, abnormal radiograms of the extremities, hypogenitalism, short stature, paraplegia, and dental abnormalities was found. The retinal dystrophy varied with respect to both the onset of symptoms and the course of the disease. The morphology of the fundus, however, was consistent within the families. The disorder showed statistically significant genetic linkage to the BBS4 locus on chromosome 15 in the affected siblings in two of the families, but the clinical features in these patients did not differ from the other cases of Bardet-Biedl syndrome. CONCLUSION: Comparison of siblings with the Bardet-Biedl syndrome showed variation of the typical features. In addition, the course of retinal dystrophy varied. No distinctive clinical features were found to separate the BBS4 phenotype from the remaining patients.

Linkage mapping in 29 Bardet-Biedl syndrome families confirms loci in chromosomal regions 11q13, 15q22.3-q23, and 16q21.

Bardet-Biedl syndrome (BBS) is a clinically and genetically heterogeneous autosomal recessive disorder characterized by retinitis pigmentosa, polydactyly, obesity, hypogenitalism, mental retardation, and renal anomalies. To detect linkage to BBS loci, 29 BBS families, of mixed but predominantly European ethnic origin, were typed with 37 microsatellite markers on chromosomes 2, 3, 11, 15, 16, and 17. The results show that an estimated 36-56% of the families are linked to the 11q13 chromosomal site (BBS1) previously described by M. Leppert et al. (1994, Nature Genet. 7, 108-112), with the gene order cen-D11S480-5 cM-BBS1-3 cM-D11S913/D11S987-qter. A further 32-35% of the families are linked to the BBS4 locus, reported by R. Carmi et al. (1995, Hum. Mol. Genet. 4, 9-13) in chromosomal region 15q22.3-q23, with the gene order cen-D15S125-5 cM-BBS4-2 cM-D15S131/D15S204-qter. Three consanguineous BBS families are homozygous for three adjacent chromosome 15 markers, consistent with identity by descent for this region. In one of these families haplotype analysis supports a localization for BBS4 between D15S131 and D15S114, a distance of about 2 cM. Weak evidence of linkage to the 16q21 (BBS2) region reported by A. E. Kwitek-Black et al. (1993, Nature Genet. 5, 392-396) was observed in 24-27% of families with the gene order cen-D16S408-2 cM-BBS2-5 cM-D16S400. A fourth group of families, estimated at 8%, are unlinked to all three of the above loci, showing that at least one other BBS locus remains to be found. No evidence of linkage was found to markers on chromosome 3, corresponding to the BBS3 locus, reported by V. C. Sheffield et al. (1994, Hum. Mol. Genet. 3, 1331-1335), or on chromosome 2 or 17, arguing against the involvement of a BBS locus in a patient with a t(2;17) translocation.

Ocular findings in the Laurence-Moon-Bardet-Biedl syndrome.

PURPOSE: To improve the description of the ocular part of the Laurence-Moon-Bardet-Biedl syndrome. METHODS: We examined 44 Scandinavian individuals who all had retinal dystrophy plus at least 2 more of the traditional cardinal signs of the syndrome: obesity, hypogenitalism, polydactyly and mental retardation. RESULTS: Full-field electroretinograms were obtained in 36 of the individuals and were abnormal in all. The dark adaptation thresholds were elevated by on average 3.5 log units. Symptoms of night blindness were observed at a mean age of 4 years and visual problems at daytime at 6-7 years. No one exceeding the age of 16 had a best corrected visual acuity of more than 0.1. In the fundus attenuated vessels were noted at all ages while macular pigmentations and a wax-pale optic disc appeared at age 6-7 years. Pigmentary changes in the midperiphery were noted at the earliest at 13 years of age and appeared mainly as bone spicules, however, in a minority of cases the pigmentations were atypical. Ten of the participants had been followed through a period of 9 years. Their visual acuity was reduced by on average 0.3 line (decimals) and the angle of visual fields by approximate 3 degrees (Goldmann standard object V:4e) per year through the adolescence. CONCLUSION: The ocular disease in Laurence-Mood-Bardet-Biedl syndrome presents early, the prognosis for visual function is poor and the fundus features are atypical and varying.

Full-field electroretinograms in individuals with the Laurence-Mood-Bardet-Biedl syndrome.

PURPOSE: To evaluate rod and cone function in individuals with the Laurence-Moon-Bardet-Biedl syndrome. METHODS: We obtained a full-field electroretinograms in 36 patients. If responses less than 10 microV were recorded with single white flashes a special techniques with narrow band filter and computer averaging was used. RESULTS: No rod responses to dim blue light could be obtained in any of the patients. Residual cone flicker responses were measurable in 28 of the individuals. Those with amplitudes < 0.05 microV were significantly older than those with amplitudes > 1.00 microV. The ERG pattern was consistent within affected pairs of siblings in 8 families. CONCLUSION: The retinal dystrophy in Laurence-Moon-Bardet-Biedl syndrome is primarily a rod-cone dystrophy, but even cone flicker amplitudes are severely reduced with further progression with age. There is no intrafamilial variability of the electroretinograms in affected siblings.

Skeletal abnormalities of hands and feet in Laurence-Moon-Bardet-Biedl (LMBB) syndrome: a radiographic study.

OBJECTIVE: To identify radiological changes of the hands and feet in a large group of patients with Laurence-Moon-Bardet-Biedl syndrome. DESIGN: Postero-anterior views of hands and feet were obtained and analysed. PATIENTS: The material consists of 43 Scandinavian patients with the syndrome (24 males and 19 females; age 3 weeks to 57 years, median 23 years at the time of radiological examination). RESULTS AND CONCLUSIONS: Polydactyly of the hands and feet is one of the main criteria. This was noted clinically in 33 of 43 patients, but all but 3 had been operated on before this radiological study. Remnants of the extirpated finger or toe noted as exostoses, additional joint surfaces of duplication were found in half the hands and feet, while the remainder showed no radiological changes. Other features found were short, broad bones and flat joint surfaces of the metacarpophalangeal or metatarsophalangeal joints. We also found a high frequency of short or long ulna in relation to the radius and Madelung deformity of the wrist in several patients. Thus, the radiographs showed several non-specific normal variations besides remnants or postoperative changes after polydactyly.

Anomalies in the permanent dentition and other oral findings in 29 individuals with Laurence-Moon-Bardet-Biedl syndrome.

This paper reports a clinical and roentgenological examination of the teeth, jaws and saliva of 29 Scandinavian individuals with Laurence-Moon-Bardet-Biedl (LMBB) syndrome, whose cardinal signs are retinal dystrophy, polydactyly, obesity, hypogenitalism and mental retardation. All subjects had at least three of these signs, including retinal dystrophy. Compared with normal subjects, the group had statistically significantly higher frequencies of hypodontia, small teeth and short roots. In addition, the saliva showed a buffering capacity higher than normal. In conclusion, there seem to exist disturbances of both dental and skeletal formation in the LMBB syndrome.

The cause of death in Laurence-Moon-Bardet-Biedl syndrome.

The certificates of death of 14 deceased patients with Laurence-Moon-Bardet-Biedl (LMBB) syndrome, in which retinal dystrophy is dominant feature, were review. Death occurred at a considerably younger age than in the general population. Renal disease was noted as primary or contributing cause of death in 7 cases with the diagnoses: cyst of the kidney, renal sclerosis, renal failure, proteinuria, renal disease unspecified and malignant hypertension with renal involvement. It is concluded that renal involvement is characteristic of individuals with LMBB syndrome and seems to reduce life expectancy considerably.

Incidence of registered visual impairment in the Nordic child population.

A collaborative, population based, prospective register study on the incidence of visual impairment in children during the year 1993 was carried out in five Nordic countries with a total population of 17 million inhabitants. The child population was 3.8 million individuals aged 0-17 years. The following variables were taken into account: nationality, age, sex, diagnoses, aetiology, degree of visual impairment, and additional impairments. Classification routines from an earlier prevalence study were used. The present study included 304 children corresponding to an incidence of notification of 8/100,000 children, varying from 5.7 to 11.1 in the five countries. Fifty per cent of the visually impaired children were reported before they were 3 years of age. In approximately 45% of the children, visual impairment was due to various brain disorders, with cerebral amblyopia and secondary optic atrophy as the two leading causes. The relative impact of retinopathy of prematurity had decreased from the third most frequent cause (10%) in the prevalence study to seventh place (4%) in the incidence study. Two thirds of the children had additional impairments and these children also suffered from the most severe visual impairments. Among aetiological factors the majority (64%) were prenatal. The overall male:female ratio of 1.4:1 was identical to the sex ratio of the prevalence study.

[Ophthalmological services to mentally retarded persons. A review and recommendations]. / Ojenhelsetjeneste til personer med psykisk udviklingshaemning. Oversigt og anbefalinger.

This is a survey of Nordic contributions to the study of the development of vision, visual impairment, and ocular disorders in people with developmental delay. Visual impairment and ocular pathology are frequently observed in these individuals. We give examples of various combinations of ocular and cerebral disorders. We underline the central role of the ophthalmologist in the diagnostic, therapeutic, and counselling procedures, and stress that the quality and accessibility of eye health services have definite medical, educational and social consequences for this group of people. We suggest that our countries monitor vision and eye disease in all individuals with developmental delay at the following periods of life: 1) At the first assessment of developmental delay. 2) At 2-3 years of age. 3) At the beginning and end of school. 4) At 45 years of age and every five years thereafter. 5) People with Down's syndrome should be monitored for cataract at the ages of one month, one year, 30 years, and later as the rest of the patients.

Visual impairment in Nordic children. V. X-linked juvenile retinoschisis.

In a study on 2,527 visually impaired children from four Nordic countries X-linked juvenile retinoschisis was diagnosed in 35 male children. Striking differences in frequency between the four countries were found, with 26 cases reported from Finland, 5 cases from Denmark, and 4 cases from Norway. None was reported from Iceland. The corresponding age and sex-specific prevalence rates of X-linked juvenile retinoschisis (N:1,000,000) were 44.5 in Finland, 8.8 in Denmark, and 7.9 in Norway. The uneven geographical distribution is possibly attributed to a 'founder effect' due to the settlements in Finland by European immigrants in the 17th century. The visual impairment of the registered cases was usually mild with 91.4% falling into WHO category 1. However, one child was totally blind, demonstrating large phenotypic heterogeneity. None of our cases had additional impairments. The majority were more than five years old, indicating a progressive course during childhood. Nevertheless, two children were diagnosed at the age of one. The most common age at registration was seven years, coinciding with the beginning of school attendance.

Nordic registers of visually impaired children.

A Nordic study group, NORDSYN, consisting of ophthalmologists from Denmark (Thomas Rosenberg), Finland (Sirkka-Liisa Rudanko), Iceland (Gudmundur Viggosson), Norway (Tor Flage, Egill Hansen, Ruth Riise) and Sweden (Kristina Tornqvist), has compiled data from registers in Denmark, Finland, Iceland and Norway of 2527 visually impaired children. The Swedish register was established later in 1990. Each record contains the following information: sex, year of birth, year of registration, classification of visual impairment, ocular diagnosis, systemic diagnosis, aetiology and evt. additional impairments. The ocular diagnoses were compiled into groups among which congenital malformations and neuro-ophthalmological diseases were the most dominating. A coding system for aetiology was developed. It was demonstrated, that prenatal factors, including genetic aetiologies, were involved in a large proportion (66%) of the cases. The sex distribution revealed a dominance of males compared to the general population at the same age. The age-specific national prevalences for registration of childhood blindness (WHO-definition: best corrected visual acuity in the best eye less than 3/60 or visual field less than 10 degrees around fixation for the ages 0-15 years) were (N/100,000): Denmark 41, Finland 15, Iceland 19 and Norway 15. The differences were primarily presumed to be due to varying efficiency in registration. A coding system for additional impairments was developed. The proportion of visually impaired children with an additional mobility, hearing or mental impairment was between one third and one half of the national materials thus indicating the need for interdisciplinary tracing of and care for the visually impaired child.

Visual impairment due to retinopathy of prematurity in Nordic children.

The registers of visually impaired children in Denmark, Finland, Iceland and Norway have been compiled into a common database by a Nordic study group of ophthalmologists, NORDSYN. The database contains information on 2527 children aged 0-17 years. The total number of children with visual impairment due to retinopathy of prematurity (ROP) is 247. ROP is the 3rd most common single diagnosis in the database. The age-specific national prevalence of registration (N/100 000) of visual impairment due to ROP varies from 12 in Denmark to 5 in Finland and Norway and 4 in Iceland. The differences can partly be explained by varying efficiency of registration. The age-distribution indicates that visual impairment due to ROP is not decreasing. Of the 247 children 175 had a visual acuity less than 1/60 and 58 had one or more additional impairments. Incidence studies on visual impairment in Nordic children are being prepared.

Visual impairment in Nordic children. III. Diagnoses.

The diagnoses, according to type and site and the degree of visual impairment, responsible for severe visual impairment in children below the age of 18, were analyzed in a material compiled from the national registers of visually impaired in Denmark, Finland, Iceland and Norway. Among 2527 children the predominant causes of visual impairment are ascribed to congenital malformations, neuro-ophthalmological diseases and retinal diseases. Optic atrophy is the leading single cause of severe visual impairment when all diagnoses are compared, and this also applies when all categories of visual impairment are included. Retinopathy of prematurity is the second principal cause of severe visual impairment, while cerebral amblyopia rates as the third most significant cause. Congenital cataract is also of considerable importance when all categories of visual impairment are compared. The differences registered between the Nordic countries were found to be within reasonable limits, except for a preponderance of neuro-ophthalmological diseases in the Danish material. This could be explained by a better medical supervision of mentally retarded patients in Denmark. Additional impairments occur in a large percentage of patients, but are unevenly distributed in the disease groups. A high frequency of additional impairments are found in the neuro-ophthalmological group and in the groups with congenital malformations, emphasizing the importance of a multidisciplinary evaluation when dealing with the visually impaired child.