Henrik Forsius

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.

Association of LOXL1 gene with Finnish exfoliation syndrome patients

In this study, three single-nucleotide polymorphisms (SNPs) on the lysyl oxidase-like 1 (LOXL1) gene associated with exfoliation syndrome (XFS) and exfoliation glaucoma (XFG) were investigated in the Finnish population. A case–control study of 59 sporadic patients with XFS, 82 with XFG, 71 with primary open-angle glaucoma (POAG) and 26 individuals without these disorders from the southern Finnish population, and a family study of an extended family with 28 patients with XFS or XFG and 92 unaffected relatives from Kökar islands, Southwestern Finnish archipelago, were conducted. Anonymous blood donors (n=404) were studied as population-based controls. Three SNPs, rs1048661 (R141L), rs3825942 (G153D) and rs2165241, of the LOXL1 gene were genotyped by PCR sequencing. Association and linkage analyses were carried out. In both case–control and family materials, significant association for allele G of rs1048661 (P=2.65 × 10−5; P=0.0007), allele G of rs3825942 (P=2.24 × 10−8; P=0.49) and allele T of rs2165241 (P=2.62 × 10−13; P<0.0001) was found in XFS/XFG. However, linkage was not observed for LOXL1 risk alleles. The corresponding three-locus haplotype GGT increased the risk of XFS/ XFG nearly 15-fold relative to low-risk haplotype GAC (odds ratio (OR): 14.9, P=1.6 × 10−16). In conclusion, the earlier reported polymorphisms of the LOXL1 gene showed significant association also in the Finnish population.

Cornea plana congenita gene assigned to the long arm of chromosome 12 by linkage analysis.

We report the mapping of the locus for autosomal recessive cornea plana congenita (CNA2; MIM 217300) by linkage analysis to the approximately 10-cM interval between markers D12S82 and D12S327. The recessively inherited disorder studied here is more severe than dominant forms. Its main manifestations are reduced curvature and hazy limbus of the cornea, opacities in the corneal stroma, and marked corneal arcus at early age. Our results provide a starting point for the positional cloning of CNA2 and the elucidation of the pathogenesis of the disease.

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-Streits 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.

EMBRYOTOXON CORNEAE POSTERIUS IN AN ISOLATED POPULATION.

In 1920, Axenfeld described a narrow, grey-white border on the inner surface of the cornea, adjacent to the limbus, which he had detected in a young man. He called it embryotoxon corneae posterius (ECP). Later, the names peripheral refractile post-corneal rim, dysplasie marginale posterieur and anterior or prominent border-ring of Schwalbe were suggested. ECP occurs either as a physiologically insignificant anomaly, in which case it is detectable only with the slit-lamp as a narrow margin in one or both eyes, as a rule temporally, or as a more prominent border-ring, which often extends further onto the inner surface of the cornea and occasionally completely surrounds the limbus. I t is then frequently observable with the naked eye and has been described in association with many serious ocular anomalies. The occurrence of ECP in connexion with pathological conditions will be discussed in another paper (Forsius & Eriksson). Histologically, ECP consists of collagenous tissue. Fritz (1906), who studied a large number of eyes histologically, detected ECP in 20 per cent of his material. Seefelder (1910), however, observed it in a much smaller proportion of histologically investigated eyes. In 1949, Streiff showed that ECP is a visible anterior border-ring of Schwalbe, a finding which was confirmed by Burian, Braley & Allen in 1955. Streiff estimated the frequency of histologically observable ECP as 20-30 per cent or more. Burian, Braley & Allen detected ECP in 72 out of 600 eyes. Embryologically, ECP is discernible as early as the 6th foetal week (Gasteiger 1939, Streiff 1949). In foetuses measuring 91 mm the incidence of ECP is the same as in adults (Burian, Braley PC Allen).

THE DAZZLING TEST IN DISEASES OF THE RETINA

When the eye is suddenly exposed to a strong light, a transient impairment of vision results. The degree of dazzling is dependent on the strength and duration of the illumination. Individual differences are great. It may be mentioned that some patients are dazzled by skiascopy to such a degree that their visual acuity cannot be determined for quite a while. From a practical standpoint these phenomena are very important owing to the dazzling effect of motorcar headlights, and interest in research in this field is increasing. Baillart (1954) proposed a useful method for detecting diseases of the macula, which consists in dazzling the macula by exposure to the light of the ophthalmoscope. His method has been later used by Chilaris and Pountzas (1955) and by Chilaris (1962). In central serous retinopathy the effect of dazzling is particularly strong. The influence of macular processes on adaptation and colour discrimination has been studied by Oguchi (1922), among others. McDonald & Adler (1940) observed a local disturbance of the adaptive processes in central retinopathy and macular degeneration. Jaeger & Nover (1951), who studied cases of central serous retinopathy with the aid of adaptometry, observed a marked delay in adaptation up to 15 minutes. In 1960, Magder found that in central serous retinopathy 15 seconds’ illumination with the ophthalmoscope dazzled the eye to such an extent that normal visual acuity was sometimes only recovered after a long interval, while a normal eye rapidly recovers its function. In addition, he published case reports and stated that the delayed dazzling effect was only seen in the disease in question and not in other macular processes. In a previous paper we described 10 typical cases of central serous retino-

DAZZLING TEST IN CENTRAL SEROUS RETINOPATHY

The effect of macular processes on the function of the eye, and on adaptation and colour vision in particular, has been the subject of many clinical studies. In central serous retinopathy Oguchi (1922) observed a central scotoma, which was by nature positive or negative depending on the illumination and the stage of the disease. In the same disease Kitahara (1936) found that impaired discrimination of red and green was correlated with elevated threshold values as measured with Nagels adaptometer. Central retinopathy and macular degeneration cause local disturbances of the adaptive processes (McDonald & Adler 1940). Jaeger & Nover (1951), who examined cases of central serous retinopathy, reported that the immediate adaptation was disturbed, the end values occasionally being reduced to as little as 1/32 of the normal values. Rod adaptation did not deviate appreciably from the normal. Magder (1960) described a simple dazzling test which, according to him, enables differential diagnosis between central serous retinopathy and other pathological processes in the macula. He stated that the test results are pathognomonic of the firstmenitioned disease. The recovery time after dazzling has even been proposed by Baillart (1954) and by Chilaris (1962). Elenius (1962) reported a case in which protanomaly had persisted for half a year afiter normalization of both foveal adaptation and central vision. The typical ophthalmoscopic picture in central serous retinopathy is a welldemarcated local swelling of the macula. The latter appears to be elevated; it is somewhat yellowish and exhibits small yellowish exudative dots. The subjective complaints consist in micropsia, metamorphopsia and chromatopsia. In addition, there may be a central scotoma, which is more readily detected in weak illumination. The disease is usually unilateral, the duration is from some weeks to some months, and there is a clear tendency towards recurrence.

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

Abstract 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 Åand 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 serveral 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 Ålandic 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 quasidominant 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. The incidence in Scandinavia seems to be among the highest ever noted. At least this is true for Åland (about 1/2000) and south Norway.

INFLUENCE OF AGE ON THE POSITION AND SIZE OF THE IRIS FRILL AND THE PUPIL

At the end of the second embryonic month the mesodermal anterior layer of the iris grows out in front of the lens and forms the irido-pupillary membrane. In the fourth month the posterior layer of the iris and a double pigment layer grow out from the base of the iris. This structure attains its ultimate size in the sixth month. At this time the anterior iris layer overlying the pupil and the pupillary margin begins to atrophy and is gradually resorbed from this area. By the eighth month the pupil is free of mesodermal tissue. The edge of the remaining tissue is seen as a small circular prominence of the anterior surface of the iris (cf. Fig. 1). This prominence is called the iris frill, iris ripple or collarette (German: Iriskrause). At birth, the iris frill and the iris crypts which also result from the resorption of the mesoderm are entirely rudimentary (Weninger, 1934). Ritter, 1960, believes that the iris frill is fully developed by the end of the second year of life. Giirtler, 1954, thought that it may move farther away from the pupil up to the eighth year. Ziegelmayer, 1954 a, stated that this may occur until adult age. According to Waardenburg, 1955, the distance from the pupillary margin to the iris frill is 1-1.5 mm in pupils of normal size. In the ageing iris degenerative changes occur in all layers. The iris thins and rigidifies. The sphincter pupillae contracts and senile miosis develops.

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.