Mutations in KERA, encoding keratocan, cause cornea plana.

Specialized collagens and small leucine-rich proteoglycans (SLRPs) interact to produce the transparent corneal structure. In cornea plana, the forward convex curvature is flattened, leading to a decrease in refraction. A more severe, recessively inherited form (CNA2; MIM 217300) and a milder, dominantly inherited form (CNA1; MIM 121400) exist. CNA2 is a rare disorder with a worldwide distribution, but a high prevalence in the Finnish population. The gene mutated in CNA2 was assigned by linkage analysis to 12q (refs 4, 5), where there is a cluster of several SLRP genes. We cloned two additional SLRP genes highly expressed in cornea: KERA (encoding keratocan) in 12q and OGN (encoding osteoglycin) in 9q. Here we report mutations in KERA in 47 CNA2 patients: 46 Finnish patients are homozygous for a founder missense mutation, leading to the substitution of a highly conserved amino acid; and one American patient is homozygous for a mutation leading to a premature stop codon that truncates the KERA protein. Our data establish that mutations in KERA cause CNA2. CNA1 patients had no mutations in these proteoglycan genes.

Abnormal crossing of the optic fibres shown by evoked magnetic fields in patients with ocular albinism with a novel mutation in the OA1 gene.

AIM: To perform genealogical and clinical studies in Finnish families with X linked ocular albinism (OA1), including characterisation of the potential misrouting of optic fibres by evaluating visual evoked magnetic fields (VEFs), and to determine the mutation behind the disease. METHODS: Three families with OA1 were clinically examined. VEFs were measured in two affected males and in one female carrier to characterise the cortical activation pattern after monocular visual stimulation. The neuronal sources of the VEFs were modelled with equivalent current dipoles (ECDs) in a spherical head model. All coding exons of the OA1 gene were screened for mutations by single strand conformation analysis and direct polymerase chain reaction sequencing. RESULTS: Genealogical studies revealed that the three families were all related. The affected males had foveal hypoplasia with reduced visual acuity varying from 20/200 to 20/50, variable nystagmus, iris transillumination, and hypopigmentation of the retinal pigment epithelium. The ECD locations corresponding to the VEFs revealed abnormal crossing of the optic fibres in both affected males, but not in the carrier female. A novel point mutation, leading to a STOP codon, was identified in the fifth exon of the OA1 gene. CONCLUSIONS: The data indicate that the novel mutation 640C>T in the OA1 gene is the primary cause of the eye disease in the family studied. VEFs with ECD analysis was successfully used to demonstrate abnormal crossing of the optic fibres.

Three widespread founder mutations contribute to high incidence of X-linked juvenile retinoschisis in Finland.

X-linked juvenile retinoschisis (RS) is a recessively inherited disorder causing progressive vitreoretinal degeneration in males. The gene defective in retinoschisis, XLRS1, has recently been identified and characterised. This gene consists of six exons encoding a protein with a putative role in cell-cell adhesion and phospholipid binding. Juvenile retinoschisis has been actively studied in Finland over the past 30 years, with over 300 diagnosed RS patients. Based on genealogical studies, approximately 70% of the Finnish RS patients originate from Western Finland and 20% from Northern Finland. In this study, one third of the known Finnish RS patients were screened for mutations of the XLRS1 gene. Haplotype analysis, using nine microsatellite markers spanning 1 cM in Xp22.2, suggested the segregation of eight different mutations in these families. To identify mutations, the six exons were amplified by PCR and analysed by single strand conformation analysis, followed by direct sequencing of the PCR products. We identified seven distinct missense mutations, all in exons 4 and 6. The mutations in exon 4, 214G > A and 221G > T, are accountable for RS in Western Finland. A third mutation in exon 4, 325G > C, gives rise to RS in Northern Finland. These three founder mutations are the predominant cause of RS in Finland and their existence explains the high incidence of the disease. The identification of mutations common in genetically isolated populations, such as Finland, allows the diagnosis of patients with an atypical RS phenotype and enables nationwide carrier testing and improved genetic counselling.

Autosomal recessive cornea plana: in vivo corneal morphology and corneal sensitivity.

PURPOSE: Autosomal recessive corneal plana (RCP) is a rare corneal anomaly with unknown pathogenesis and a high incidence in Finland. The aim was to examine corneal sensitivity and the morphology of different corneal layers and subbasal nerves in RCP patients. METHODS: Three patients with a diagnosed autosomal recessive cornea plana were examined. Corneal sensitivity to different modalities of stimulation was tested in four corneas using noncontact esthesiometry. Tissue morphology of three corneas was evaluated, and in two corneas thickness of corneal layers was measured using in vivo confocal microscopy. RESULTS: Corneas of RCP patients appear to have mechanosensory, polymodal, and cold-sensitive nerve terminals. RCP patients had normal sensation thresholds for chemical, heat, and cold stimulation but a high threshold for mechanical stimulation. Their capacity to discriminate increasing intensities of stimulus was reduced, except for cold stimuli. Thickness of the epithelial layer was reduced, whereas total corneal and stromal thicknesses were slightly reduced or close to normal values. In all cases Bowman's layer was absent. Subbasal nerves had abnormal branching patterns. The arrangement of anterior keratocytes was altered, showing clustered and irregularly shaped nuclei. Increased backscattering of light in confocal microscopy through focusing (CMTF) profiles was observed throughout the stroma. Epithelial and endothelial cells appeared to be regular in shape. CONCLUSIONS: The present study revealed qualitative and quantitative alterations in corneal sensitivity, cellular morphology, and the thickness of corneal layers in RCP patients.

Pseudoinflammatory fundus dystrophy with autosomal recessive inheritance.

A family in southwest Finland with bilateral hemorrhagic degeneration of the retina and choroid was followed up for more than 16 years. The maculas showed subretinal hemorrhages, glial cicatrization of the outer retinal layers, and profound choroidal atrophy, particularly in the advanced stages of the disease. Fluorescein angiography demonstrated leakage through the pigment layer in the retinal tissue. The age of onset varied from the second to the fourth decade. The clinical pattern was similar to Sorsby's pseudoinflammatory dominant fundus dystrophy, except that the disorder appeared earlier in this Finnish family, the members of which show secondary dyschromatopsia, many deep hyaloid bodies in the retina, disturbed dark adaptation (1 to 4 log units), subnormal light-peak/dark-trough ratios, progressive myopia, and a mode of inheritance which is probably autosomal recessive. The affected parents are consanguineous in many ways and each of their eight children is affected.

Autosomal dominant cornea plana: clinical findings in a Cuban family and a review of the literature.

Cornea plana may occur in connection with malformations of the eye or of other parts of the body. As an isolated ocular anomaly, it may be inherited in an autosomal recessive or in an autosomal dominant fashion. We have previously mapped genes for both forms of the disease to 12q21. We studied 36 members of three generations of a Black Cuban family with autosomal dominant cornea plana. Three affected males and 11 affected females were examined. Corneal refraction varied between 37.50 and 42.75 diopters. Horizontal corneal diameter ranged from 8.75 to 11.25 mm. The cornea was clear and the limbal zone only occasionally widened. A marked arcus senilis was present in six patients aged 30 to 58 years, but in none of their healthy relatives. The anterior chamber was shallow in those affected, varying in depth from 1.68 to 2.38 mm. One woman was blind from closed-angle glaucoma. The axial length was within normal limits in all patients.

Changes of the eye caused by the climate in Rwanda, Africa.

Rwanda is a small but densely populated country, situated at the watershed between East and West Africa, close to the equator. The mean elevation is around 1500 m. We studied 114 males (mean age 28.42 years) and 111 females (mean age 29.84 years) at the ophthalmological outpatient department of the Centre Hospitalier in Kigali. Changes to the eye caused by the climate were fewer than expected. Only 10 patients (5 males, 5 females) with pterygium (mean age 33.0 years), and four males and two females with climatic droplet keratopathy (mean age 47.5 years) were observed. However, the size of the pinguecula was marked. Corneal thickness, measured with Haag-Streit's device, averaged 0.524 mm in 38 males and 0.521 mm in 38 females. The Rwandans showed a normal chamber depth, a mean of 2.98 mm being noted in 107 males and a mean of 2.80 mm in 106 females.

Exfoliation syndrome in various ethnic populations.

This introductory lecture to the epidemiological session in the Workshop on the Exfoliation Syndrome (ES) gathers together figures for the prevalence of ES around the world. Prevalence figures from published reports are shown in the text separately for each country. Four ways of comparing the prevalences are used. 1) Prevalences in people over 60 years of age, 2) Percentages of glaucoma in persons with ES, 3) Percentages of ES in patients with glaucoma or ocular hypertension, with separate statistics for the proportion of capsular glaucoma in patients treated with laser trabeculoplasty (LTP), 4) Prevalence of ES in patients with cataract. The major differences in prevalence can partly be explained by the different techniques used in the investigations. Very few authors have studied people in different countries, which is the best way of obtaining comparable results. The author has personally studied Finns, Lapps, Eskimos in Greenland, Canada and Alaska, Icelanders, populations in Tunis, India and Peru and four populations in the USSR by the same technique. The prevalences vary from 0% in Eskimos to 21% in Finns over 60 years of age, and are at the same high level in Lapps, Finns, Russians in Novosibirsk and Icelanders, but significantly lower in all the others. The results support the opinion that ES is not uniformly distributed in all countries, and this is confirmed by many reports from different countries in this workshop.

Seasonal variations in retinal detachment in Northern Finland and Novosibirsk.

Retinal detachments have a tendency to occur more commonly in spring and summer than in winter. Two new series are presented here, the first collected in Northern Finland at latitudes 64 degrees-70 degrees and the second from Novosibirsk, at a much lower latitude, 55 degrees N, but with an equally long winter. A statistically significant seasonal variation is found in both. The highest incidence peak is seen in June in Oulu and in July in Novosibirsk, the difference between the prevalence curves was, however, not statistically significant. The Oulu series shows a statistically highly significant seasonal variation in low refractive errors but no seasonal difference in high myopia and aphakia.

[Treatment of obesity in children and adolescents]. / Behandling av obesitet hos barn och ungdomar.

Weight development was compared in 48 obese children, 6-15 years of age, who during a 12-month period underwent treatment either individually, in groups, or as part of the school health services. Those treated intensively by groups or individually manifested a relative weight reduction of 10-14 per cent at the 12-month follow-up, as compared with seven per cent in those treated by the school health services, but at five-year follow-up relative weight reduction was much the same in all three categories. Thus, group treatment of childhood obesity would appear to be the best alternative as it yields fairly rapid relative weight reduction with beneficial metabolic changes, and entails less investment in personnel resources.

Increase in type I and type IV collagenolytic activity in primary cultures of keratoconus cornea.

The collagenolytic activities were assayed in fibroblast cultures established from ten keratoconus and six control corneal explants. The assays included those for both type I and type IV collagenase. The amount of free, directly assayable type I collagenase was highly increased in the media of keratoconus primary cell cultures. Also the activity of type IV collagenase was increased significantly in these cultures but was detectable only after proteolytic activation. The total hydroxyproline content of keratoconus corneas was decreased when compared to controls. However the activity of the prolyl-4-hydroxylase, reflecting the biosynthesis of collagen, was higher in the keratoconus corneal tissue, either expressed per DNA, soluble protein or hydroxyproline content of corneas. The enhancement in collagenolytic processes could explain the pathological tissue destruction in keratoconus corneas and this enhancement is maintained still in primary cultures of keratoconus corneal fibroblasts.

Juvenile cataract with autosomal recessive inheritance. A study from the Aland Islands, Finland.

Juvenile (including congenital and infantile) cataract occurs commonly as part of a more generalized or systematic condition, or as a component of a syndrome. Isolated juvenile cataract is a relatively rare disorder and the mode of inheritance is often autosomal dominant. Autosomal recessive transmission of isolated juvenile cataract is rare. The present paper is a report of 15 cases of juvenile cataract on the Aland Islands (Finland) with about 23,000 inhabitants. Twelve belong to 7 sibships of two different pedigrees and 3 cases are sporadic, of which we have found no genealogical connections in the last 6-10 generations to the two cataracta pedigrees. One of the sporadic cases presented an operated cleft palate and a chromosomal anomaly. In another sporadic case the mother probably had been infected with rubella during early gestation. In the third sporadic case the cataract was combined with partial aniridia, but he has several genealogical connections to one of the cataract pedigrees. Consanguinity between the parents was detected in 5 of the 7 sibships, in some even on various ancestral levels. Apart from the cataracts, all patients were healthy, with normal intellect, behavior, hearing, growth and development. They were neurologically intact and there were no ocular lesions apart from cataract. In the Alandic familial cases the cataracts appear to be an autosomal recessive trait. A family branch originating from southwestern Sweden and south Norway showed transmission of the cataract in three successive generations. The possibility of quasi-dominant inheritance is discussed against the background that autosomal recessive juvenile cataract may not be so rare as the small number of recorded cases would suggest.(ABSTRACT TRUNCATED AT 250 WORDS)