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espanolObjetivo: Las distrofias corneales son un grupo de alteraciones hereditarias en las que una acumulacion progresiva de material amiloide, hialino o mixto en las distintas capas corneales produce disminucion de la transparencia corneal. Se describen las caracteristicas clinicas y los estudios moleculares del gen TGFBI en una paciente Mexicana con una distrofia corneal estromal de tipo granular. Metodos: Examen oftalmologico completo, caracterizacion fenotipica de la distrofia corneal, y analisis del gen TGFBI por reaccion en cadena de la polimerasa (PCR) y por secuenciacion nucleotidica, en DNA de la proposita y de un hermano afectado. Resultados: Las lesiones corneales observadas en la paciente fueron compatibles con el diagnostico de distrofia corneal estromal de tipo granular (clasica). No se observaron lesiones en las otras capas corneales. El analisis del gen TGFBI en DNA de la paciente y de un hermano afectado revelo una mutacion puntual, de adenina a guanina, en el exon 14 de TGFBI que origina un cambio de histidina a arginina en el aminoacido 626 (H626R) de la proteina TGFBI. Conclusiones: Este es el primer caso en el que se demuestra que una distrofia corneal granular es causada por la mutacion H626R en TGFBI. Esta mutacion ha sido reportada consistentemente en la distrofia estromal de tipo empalizada, clinicamente diferente a la granular. Nuestros datos indican que existen excepciones en la aparente correlacion genotipo-fenoitipo establecida en el grupo de distrofias corneales asociadas a mutacion en el gen TGFBI. EnglishObjective: To describe the clinical data and the results of molecular analyses of the TGFBI gene in a patient with classic granular stromal corneal dystrophy (type I). Methods: A female patient aged 60-years complaining of a long-standing decrease of visual acuity bilaterally associated with photophobia and foreign body sensation, underwent a complete ophthalmologic examination. Molecular analyses of DNA from the patient and from an affected brother included PCR amplification of exons 4, 11, 12, and 14 of the TGFBI gene and direct automated sequencing of the PCR products. Results: The affected patient showed a pattern of corneal stromal lesions that was compatible with a diagnosis of classic granular dystrophy. No involvement of other corneal layers was evident. Molecular analysis disclosed a point mutation in exon 14 of the TGFBI gene which consisted of an adenine to guanine change at nucleotide position 1924, predicting a substitution of arginine instead of histidine at residue 626 of the TGFBI protein (H626R). An identical mutation was detected in DNA from her affected brother. Conclusions: This is the first time that a case of stromal granular dystrophy has been demonstrated to be caused by the H626R mutation, a molecular defect classically detected in the phenotypically distinct lattice corneal dystrophy. Our data indicate that the same molecular defects in the TGFBI gene lead to different phenotypes in stromal dystrophies, thus expanding the genotypic-phenotypic spectrum in this group of corneal diseases.

A patient with Finnish type familial systemic amyloidosis associated with lattice corneal dystrophy (Meretoja's syndrome) underwent heart transplantation with uneventful postoperative course. Five years later the patient has mild chronic renal failure, normal cardiac allograft function and almost total bilateral blindness.

To describe a large Thai family with lattice corneal dystrophy (LCD) type I and to determine whether this LCD is associated with mutations within the transforming growth factor-β-induced (TGFBI) gene. A six-generation family with LCD type I was identified and diagnosed on the basis of clinical and/or histopathologic evaluation. Visual acuity testing and slit-lamp biomicroscopic evaluation were carried out and corneal photography was documented. All 17 exons and flanking intron sequences of the TGFBI gene were sequenced. Thirty-three participants demonstrated LCD in both eyes, most of which was symmetrical. Age at onset of decreased vision was the mid- to late twenties. Visual acuity varied from 6/6 to no light perception. Two patients, 74 and 42 years of age, demonstrated a thick yellowish plaque covering the corneal surfaces. DNA sequencing revealed a heterozygous mutation in exon 13 (A1762G), changing histidine to arginine at codon 572 (H572R). Ten of 42 clinically unaffected family members, all under 25 years of age, exhibited the same mutation. This is the first report of a molecular analysis of LCD type I in Thai patients. The novel mutation identified is associated with distinct phenotypes and later onset of the disease compared with the more common R124C mutation. Jpn J Ophthalmol 2006;50:403–408 © Japanese Ophthalmological Society 2006

Purpose To compare the therapeutic outcomes after deep lamellar keratoplasty (DLKP) and penetrating keratoplasty (PKP) in patients with lattice corneal dystrophy (LCD) and macular corneal dystrophy (MCD). Design Age-matched control study. Methods We reviewed the clinical records of 84 eyes with LCD or MCD who had DLKP (41 eyes) or PKP (43 eyes). Primary pathology consisted of 60 eyes with LCD and 24 eyes with MCD. DLKP was performed by either removing stromal tissue gradually, or by viscodissection of Descemet’s membrane. Graft clarity, best-corrected visual acuity (BCVA), endothelial density, and complications were compared between DLKP and PKP, as well as between LCD and MCD. Results All 84 eyes showed a postoperative improvement in visual acuity. The median final BCVA was not significantly different between PKP and DLKP groups. Endothelial cell loss rates were similar for DLKP and PKP. While the MCD-DLKP group showed progressive decrease in endothelial density, this was not observed in the LCD-DLKP group after surgery. In the DLKP group, most of the complications occurred intraoperatively or in the early phase, whereas late phase complications such as endothelial rejection and secondary glaucoma were the main complications in the PKP group. Conclusions PKP is no longer an automatic choice for the surgical treatment for LCD and MCD; DLKP seems to be a safe alternative. While DLKP is a favorable method for LCD, MCD may not be a good candidate, as it might show progressive decrease in the corneal endothelium postoperatively.

To investigate the molecular basis of hereditary lattice corneal dystrophy (LCD) type IIIA associated with corneal amyloid deposits afflicting several members of a four-generation family.Histologic, immunohistochemical and biochemical studies were performed on corneal tissue samples obtained after perforating keratoplasty. DNA was extracted from peripheral blood leukocytes. All exons of the keratoepithelin-encoding TGFBI gene were amplified and sequenced. The presence of a mutation was confirmed by digestion of the isolated PCR product with the restriction enzyme AlwNI.The cornea of the index patient (II-1) contained large patchy deposits of amyloid, which were immunoreactive for the C terminus of keratoepithelin. Western blot analysis of the polypeptide chains extracted from the amyloid deposits of paraffin-embedded tissue revealed that these represented mainly fragments of the full-length protein. The smallest fragments were 6.5 and 6.9 kDa. DNA analyses of the TGFBI gene revealed a heterozygous T--C transition at the second position of codon 540 in exon 12, indicating that replacement of phenylalanine by serine (Phe540Ser) leads to dominant disease. The mutation creates a new restriction site for the enzyme AlwNI. Five of the examined family members carried this mutation. Three of them (aged/=41 years) had the disease, two family members (aged20 years) do not yet show any clinical symptoms. An additional inconsequential single-nucleotide polymorphism (T1667C) was found at the third position of the same codon (Phe540Phe) in three unaffected family members.This is the first report of a single-nucleotide mutation at codon 540 of TGFBI leading to LCD, and the first to demonstrate that the amyloid deposits in LCD contain proteolytic fragments of keratoepithelin.

Purpose To evaluate the time period necessary for complete epithelial healing after phototherapeutic keratectomy (o-PTK) carried out for various superficial corneal opacities. Subjects and method A total of 197 eyes were divided into 9 groups: group 1, Cogan dystrophy including recurrences (n = 15); group 2, Reis Bucklers dystrophy including recurrences (n = 12); group 3, granular dystrophy including recurrences (n = 63); group 4, lattice dystrophy including recurrences (n = 19); group 5, macular dystrophy including recurrences (n = 10); group 6, herpetic scars (n = 5); group 7, corneal scars of nonherpetic origin (including scrofulous, traumatic, central keratoconus, post-pterygium surgery) (n = 31); group 8, Salzmann nodular degeneration (n = 22); and group 9, miscellaneous (such as bullous keratopathy, acute chemical burn, corneal degeneration) (n = 20). After o-PTK, patients were examined daily at the slit lamp using fluorescein and blue light. The time period necessary for complete healing of the epithelial defect was compared among these groups. Delayed healing was considered where the epithelium was not closed after 7 days. Result One hundred sixty-one eyes (95%) healed within 7 days. Overall, 63%, 80%, and 85% of epithelial defects were closed within 3, 4, and 5 days, respectively. Out of 9 eyes that had delayed healing, 6 eyes (67%) belonged to lattice dystrophy category. Mean time taken for healing in group 4 (8.6 +/- 8.4 days) was significantly longer than those in group 1 (3.0 +/- 1.5 days, P = 0.009), group 2 (3.7 +/- 3.1 days, P = 0.03), group 3 (3.1 +/- 1.5 days, P = 0.001), group 5 (2.7 +/- 0.8 days, P = 0.01), group 7 (3.6 +/- 2.4 days, P = 0.007), group 8 (3.3 +/- 1.3 days, P = 0.009), and group 9 (3.0 +/- 1.9 days, P = 0.011). Conclusion Eyes with lattice corneal dystrophy suffered from delayed epithelial healing after o-PTK. In addition to adequate counseling, these patients should be followed up closely until complete closure of the epithelium to avoid ulceration, scarring, or even infection. These eyes might need additional treatment such as hyaluronic acid drops, autologous serum drops, simultaneous amniotic membrane patching, or even temporary lateral tarsorrhaphy.

Purpose To report a unique corneal dystrophy characterized by deposits at Bowman's layer and stromal lattice lines associated with the Gly623Asp missense mutation in the transforming growth factor β–induced ( TGFBI ) gene. Design Experimental study. Participants and Controls The proband, 3 affected siblings, 4 unaffected relatives, and 100 control individuals. Methods Slit-lamp examination, photographic documentation, and isolation of genomic DNA from buccal mucosal swabs obtained from each family member examined. Exons 4 and 11 to 14 of the TGFBI gene were amplified and sequenced in these family members and in control individuals. Main Outcome Measures Clinical characteristics of corneal opacification in affected patients and presence of coding region changes in the TGFBI gene. Results Significant phenotypic variability, including polymorphic Bowman's layer opacities and stromal lattice lines, was noted in the 4 affected siblings who were examined. Screening of TGFBI exon 14 in the proband, 3 affected siblings, and a 19-year-old unaffected relative revealed a missense change, Gly623Asp, that was absent in the other 3 unaffected relatives screened and in 200 control chromosomes. Conclusions We report a novel corneal dystrophy phenotype secondary to the Gly623Asp mutation in the TGFBI gene that is associated with clinical features of both lattice corneal dystrophy and a Bowman's layer dystrophy. The presence of clinical features considered atypical for a TGFBI -associated dystrophy in this pedigree, as well as the wide range of phenotypic expressions of the Gly623Asp mutation in affected members, underscore the clinical utility of molecular genetic analysis in the diagnosis of suspected corneal dystrophies.

Purpose To report a phenotypic variant of lattice corneal dystrophy associated with two missense changes, Ala546Asp and Pro551Gln, in the transforming growth factor-β-induced gene ( TGFBI ). Design Experimental study. Methods Genomic DNA was obtained from the proband as well as affected and unaffected family members. Exons 4, 11, 12, and 14 of the TGFBI gene were amplified and sequenced. Additionally, a corneal button excised from the proband was examined by light and transmission electron microscopy. Haplotype analysis was performed on the proband's family and members of a previously identified pedigree with the same TGFBI gene missense changes. Results Bilateral, symmetric, radially arranged, branching refractile lines within and surrounding an area of central anterior stromal haze were noted in the proband. Multiple polymorphic, refractile deposits were noted in the mid and posterior stroma in both the proband and her daughter. Light and electron microscopic analyses demonstrated amyloid and excluded the presence of deposits characteristic of granular corneal dystrophy. Screening of TGFBI exon 12 in the proband and her affected daughter revealed two missense changes, Ala546Asp and Pro551Gln (both absent in 250 control chromosomes). Haplotype analysis suggested that the mutations in this family and in a previously identified pedigree reflect a founder effect, rather than an independent occurrence. Conclusions We present a phenotypic variant of lattice corneal dystrophy associated with the Ala546Asp and Pro551Gln missense changes in exon 12 of the TGFBI gene. A common ancestor appears to account for the missense mutations observed in this pedigree and in a previously reported family.

PURPOSE To determine the genetic basis for lattice corneal dystrophy (LCD) in an extensively studied family. METHODS Ten affected family members were examined clinically, and three individuals were studied with in vivo confocal microscopy and optical coherence tomography (OCT). Corneal tissues from eight affected family members were examined histopathologically. The status of the transforming growth factor beta-induced gene (TGFBI) gene was determined in each consenting family member (six affected, seven nonaffected) by amplifying, sequencing, and analyzing exons 4 and 12 of TGFBI for mutations. All exons from the entire coding region of TGFBI of one affected person were analyzed for mutations. RESULTS Slit lamp biomicroscopy disclosed the clinical features of LCD in both eyes of affected individuals. In vivo confocal microscopy confirmed the presence of deposits as bright lesions within the corneal stroma. OCT revealed increased reflectivity within the corneal stroma. The corneal stroma in persons undergoing penetrating keratoplasty contained amyloid. Affected members of the family were found to have two heterozygous single-nucleotide mutations in exon 12 of the TGFBI gene (C1637A and C1652A) leading to predicted amino acid substitutions in the encoded TGFbeta-induced protein (A546D and P551Q). Mutations were not detected in exon 4. In addition, an inconsequential single-nucleotide polymorphism T1620C (F540F) was found in some affected and nonaffected family members. CONCLUSIONS Two mutations in the TGFBI gene (A546D and P551Q) cosegregated with LCD in an extensively studied family that lacked the R124C mutation that frequently accompanies this form of corneal amyloidosis.

OBJECTIVE To quantify the distribution and size of deposits in granular and lattice corneal dystrophies and to estimate the impact of these findings on the potential benefit of phototherapeutic keratectomy (PTK) as primary treatment in these corneal disorders. METHODS Central histologic sections of consecutive corneal buttons (34 granular dystrophy specimens of 27 patients (mean age 53 +/- 12 years) and 20 lattice dystrophy specimens of 20 patients (mean age 50 +/- 17 years) obtained from central penetrating keratoplasty were examined by light microscopy using Masson trichrome and Congo Red stains. Localization and anterioposterior diameter of the most superficial, the deepest, and the largest deposits were quantified in the central and the two peripheral thirds of the specimens. Bowman layer status and thickness of the epithelium were recorded. The clear central corneal zone size before and after a hypothetical superficial PTK (100-microm ablation) was calculated. RESULTS Central deposits in granular dystrophy were mostly superficial (mean distance from the epithelium 28 +/- 19 microm) and associated with Bowman layer and epithelial changes. In lattice dystrophy, deposits were mostly midstromal (mean distance from the epithelium 79 +/- 54 microm, P < 0.001) with a larger scatter, showing minor superficial involvement. After a fictitious PTK, a significant increase in mean clear central zone was achieved (P = 0.004). This increase in mean clear central zone was more pronounced in granular (from 484 +/- 389 microm to 1451 +/- 1954 microm) than in lattice (from 258 +/- 183 microm to 846 +/- 784 microm) dystrophy (P = 0.004). Deposits were completely removed in 22% of the granular dystrophy samples. In both dystrophies, a clear central "pinhole" greater than 1 mm in diameter was achieved in around one third of corneas. CONCLUSION According to the histopathologic corneal deposit size and distribution, PTK may be an effective treatment to increase visual acuity in patients with granular dystrophy more than in those with lattice dystrophy, to delay or even avoid penetrating keratoplasty.

6 páginas, 3 figuras, 2 tablas.-- et al., [Aims]: To report a Bangladeshi family displaying intrafamilial phenotypic heterogeneity of lattice corneal dystrophy type I (LCDI) and to identify the causative mutation. [Methods]: Molecular genetic analysis was performed on DNA extracted from all members of the family. Exons of BIGH3gene were amplified by polymerase chain reaction. Gene mutation and polymorphisms were identified by heteroduplex and sequence analyses. Segregation of the mutation in the family was confirmed by restriction digestion of amplified gene fragments. [Results]: A heterozygous C T transition at the first nucleotide position of codon 124 of the BIGH3gene was detected in the three affected members and not in the unaffected members of the family. [Conclusions]: This is the first report of BIGH3gene mutation in a Bangladeshi family with phenotypic heterogeneity. This study confirms that BIGH3gene screening should be undertaken for proper classification of corneal dystrophy, especially in the absence of histopathological examination.

Lattice corneal dystrophy type I (LCDI) is a relatively common corneal dystrophy which can cause severe visual impairment. Recent studies have suggested a genetic localisation for the disease to chromosome 5q. Independent genetic linkage analysis in a six generation LCDI pedigree confirmed linkage to the 5q region bounded by marker loci IL9 and D5S436 suggesting genetic homogeneity. A maximum two point lod score of 7.51 (theta = 0.03) was obtained with marker D5S393. Multipoint and haplotype data positioned the disease between loci D5S393 and D5S396 corresponding to a genetic distance of 2cM, thus refining linkage sufficiently to allow for physical mapping of this disorder.

Purpose To report the utility of genetic testing in the diagnosis and management of patients with suspected corneal dystrophies. Design Case report. Methods A 58-year-old man with a history of recurrent corneal erosions was diagnosed with bilateral anterior basement membrane dystrophy and unilateral lattice corneal dystrophy. All 17 exons of the TGFBI gene were screened for mutations previously associated with lattice corneal dystrophy as well as novel coding region changes. Results No mutations were found in the 17 exons of the TGFBI gene. A nucleotide change in exon 6 (651C>G) did not result in a change in the encoded amino acid (Leu217Leu). Conclusions In cases of suspected TGFBI corneal dystrophies, genetic testing is a useful tool to confirm the clinical diagnosis. In this case of suspected unilateral lattice corneal dystrophy, screening of the TGFBI gene ruled out the diagnosis, raising the possibility that the corneal changes were related to the coexistent anterior basement membrane dystrophy.

Amyloid diseases are secondary protein structure diseases in which insoluble protein fibrils accumulate extracellularly. Twenty different types of fibrils have been described in human amyloidosis, each with a different clinical picture. Amyloidosis can be generalised, affecting multiple organ systems, or localised and can affect almost any organ of the body. In the eye amyloid is the material commonly seen in lattice corneal dystrophy. Cases of localised corneal amyloidosis have been reported in literature but are quite rare.1–4 We report a case of localised corneal amyloidosis presenting as a large raised gelatinous vascularised lesion in a patient with long standing herpetic keratitis. A fit and healthy 34 year old woman was a tertiary …

Keratoconus is an idiopathic, progressive, non-inflammatory ectasia of the axial cornea. Its association of other systemic disorders or ocular disease have been reported, but its specific origin remains unknown. Recently, Munier and associates detected that four types of autosomal dominant corneal dystrophy result from mutation in the human transforming growth factor β induced gene (βigH3), the product of which has shown to be the protein keratoepithelin (R555W for granular corneal dystrophy, R555Q mutation for Reis-Buckler’s corneal dystrophy, R124C mutation for lattice corneal dystrophy type I, and R124H mutation for Avellino corneal dystrophy).1 Molecular genetic analysis of various corneal dystrophies, which had previously presented an insuperable challenge to clinical diagnosis, now clearly demonstrates the distinct phenotypes.2 We report a rare case of bilateral keratoconus in association with Avellino corneal …

Purpose To report a penetrating corneal transplant in which there was inadvertent inversion of the corneal button. Design Interventional case report. Methods A 48-year-old man with lattice corneal dystrophy had a third penetrating keratoplasty in the right eye 3 years after the second procedure and 2 years following renal transplantation. Results Histologic examination of the corneal button from the second penetrating keratoplasty disclosed inadvertent corneal graft inversion. Survival epithelium from the donor in the anterior chamber may be explained by the ocular anterior chamber–associated immune deviation or by the patient’s systemic cyclosporine A (CsA) treatment after renal transplantation. Conclusions Histologically proven corneal button inversion is a rare cause of corneal graft failure.

Purpose: To assess the involvement of BIGH3 in corneal dystrophies (CD) with an autosomal dominant trait, in patients referred to a hospital in the Kyushu district of Japan. Methods: Forty-five CD patients from 44 families were studied. Genomic DNA was extracted from peripheral blood, and exons 4 and 12 of the BIGH3 gene were amplified by polymerase chain reaction followed by direct sequencing. Results: In exon 4, an R124H mutation associated with Avellino corneal dystrophy (ACD) was found in 39/44 families (86.4%) and an R124C mutation associated with lattice corneal dystrophy type 1 (LCD1) was detected in 2/44 families (4.5%). In exon 12, an R555W mutation associated with granular corneal dystrophy (GCD) was detected in 4/44 families (9.1%). Conclusions: Codons R124 and R555 of the BIGH3 gene represent mutational hotspots in the genomes of Japanese patients with autosomal-dominant CD.

PURPOSE To present a patient with a genotype usually associated with lattice corneal dystrophy but with clinical and histopathologic features of advanced Avellino corneal dystrophy. METHODS Penetrating keratoplasty was performed with subsequent histopathologic analysis. For genetic testing, a 5-mL blood sample was taken after informed consent. Genetic sequencing was performed by the John and Marcia Carver Laboratory of the University of Iowa. The mutation was identified by direct sequencing through the positions of the coding sequences of the TGFBI gene that have been previously reported to have genetic variations (exons 4 and 11-14). RESULTS Corneal examination revealed bilateral lattice and multiple confluent subepithelial and anterior stromal granular opacities. Histopathologic examination showed amyloid deposits by Congo red stain and hyaline deposits by Masson trichrome stain, consistent with a diagnosis of Avellino dystrophy. Automated DNA sequencing revealed a heterozygous Arg124Cys (R124C) mutation in the coding sequence of the TGFBI gene on chromosome 5q31. Recurrent granular deposits developed in the corneal graft 14 months after surgery. CONCLUSIONS Our case presented with clinical and histopathologic findings consistent with a diagnosis of Avellino dystrophy and exhibited a genotype with R124C mutation. Avellino dystrophy has not previously been reported to be associated with the R124C mutation, which is usually associated with lattice corneal dystrophy. This also raises the issue as to whether classification of the corneal stromal dystrophies should be based primarily on phenotype/histopathology or on genotyping.

Transforming growth factor β induced protein (TGFBIp) is an extracellular matrix protein that has been linked to several types of corneal dystrophies. Nearly fifty percent of the mutations leading to corneal dystrophies affect two major single residue hotspots, namely R124 and R555, located in the first and the fourth FAS1 like domain of TGFBIp, respectively (1). The remaining mutations are primarily located in the fourth FAS1 like domain (FAS1-4). Three mutations in the FAS1-4 domain of TGFBIp are investigated in the present study: R555W, leading to granular corneal dystrophy; R555Q, leading to Thiel-Behnke corneal dystrophy; and A546T, leading to lattice corneal dystrophy. Of the three mutations, A546T is the only one resulting in deposits of amyloid fibrils in vivo and in vitro. The aim of this study is to investigate whether or not the three pathogenic mutations give rise to distinct association poses discerning between amorphous and amyloid phenotypes. Protein-Protein docking calculations have been performed using the docking algorithm DOCK/PIERR (2). Two highly abundant poses involving direct contact between the suspected fibrillating core regions of the FAS1-4 domain have been identified. Runager et al. has shown the A546T mutant to be the least stable of the three mutants (3). Combining the decreased stability with the docking poses could give an explanation to the amyloidogenic nature of the A546T mutant.1. Munier et al. Invest. Ophthalmol. Vis. Sci. 2002, 4, 949-954.2. Ravikant et al. Proteins 2010, 2, 400-419.3. Runager et al. J. Biol. Chem 2011, 7, 4951-4958.

An 87-year-old woman visited our clinic for a scheduled cataract surgery. At the time of preoperative evaluation, slit lamp examination showed lattice-shaped and granular deposits with asymmetrical patterns in the stroma of both corneas. Genomic DNA samples of the patient, amplified by polymerase chain reaction, showed a single nucleotide substitution, c. 1580T>G (p.L527R), in the transforming growth factor-β-induced TGFBI gene. We also found two additional SNP mutations, c.1620T>C (p.F540F) and c.1678+23G>A, along with the well-known L527R mutation. This is the first report of lattice corneal dystrophy type IV with an L527R mutation outside of Japan, and could challenge the idea that L527R is caused by a mutation from a single Japanese ancestor.

Lattice corneal dystrophy (LCD) type I is one of the five dominant TGFBI (transformimg growth factor β induced; formerly designated as bigh3 or keratoepithelin)-related corneal dystrophies with characteristic lattice-like refractile lines in the corneal stroma.1 Other than this common-type LCD, there have also been reported several minor-type LCDs caused by different mutations of the TGFBI gene.2 An 85-year-old man presented with complaints of bilateral blurred vision. His best-corrected visual acuity was 0.1 in OD and HM/30 cm in OS. He had bilateral corneal haze and cataract. The corneal haze contained many isolated or fused refractile opacities, most of them being dot-like, and some being lattice-like (figure 1A). The opacities were found at all depths of the corneal stroma, but mainly involved the deep stromal layer. The degree of corneal haze was severe in his left eye, but relatively mild in his right eye. His wife and two sons did not show any corneal opacity in their eyes. Cataract surgery was performed on his left eye, but his best-corrected visual acuity in that eye was improved …

Familial amyloidosis, Finnish (FAF), is an autosomal dominant form of systemic amyloidosis with lattice corneal dystrophy and progressive cranial neuropathy as principal clinical manifestations. We have shown that the novel amyloid fibril protein found in these patients is an internal degradation fragment of gelsolin, an actin-binding protein, and that it contains an amino acid substitution, asparagine for aspartic acid at position 15, that is due to a guanine-to-adenine transversion corresponding to codon 187 of human plasma gelsolin cDNA. To test that this mutation cosegregates with the disease high-molecular-weight genomic DNA was isolated from autopsied tissues or lymphocytes of 23 patients, 6 healthy relatives and 20 unrelated healthy control persons. Specific fragments were amplified with the polymerase chain reaction for oligonucleotide hybridization analysis using the slot-blot technique. The guanine-to-adenine transversion was found in all FAF patients tested, but in none of the control subjects. Our results show that the mutation (G to A) cosegregates with the disease phenotype, and that the slot-blot analysis can be used as a diagnostic assay, including prenatal evaluation.

PURPOSE: To evaluate the incidence of BIGH3 gene mutations in 164 unrelated Japanese patients with corneal stromal dystrophies with an autosomal dominant trait. METHODS: Data were collected at two major institutions in the eastern and western parts of Japan, where molecular genetic analysis was performed for diagnostic purpose. RESULTS: The incidence of mutations was ranked as follows: 118 patients (72%), the R124H mutation associated with Avellino corneal dystrophy; 23 patients (14%), the R124C mutation associated with lattice corneal dystrophy type 1; and 10 patients (6%), the P501T mutation associated with lattice corneal dystrophy type 3A. CONCLUSION: Avellino corneal dystrophy associated with the R124H mutation is the most common form of corneal stromal dystrophy in Japan. This dystrophy, which is diagnosed histopathologically, has also been called granular corneal dystrophy in Japan. The classification of these diseases according to genetic pathogenesis may be more appropriate than is the use of clinical or histological findings.

AIM—To report a Japanese family diagnosed clinically as having lattice corneal dystrophy type I (LCDI) in which a Leu518Pro mutation in the βig-h3 gene and not the R124C mutation reported previously was found. METHODS—Molecular genetic analysis was performed on DNA extracted from peripheral leucocytes from four members (three affected and one unaffected) of a family. Exon 4 of the βig-h3 gene was amplified by PCR and directly sequenced. Histopathological study was performed on the corneal tissue from the proband obtained during deep lamellar keratoplasty. RESULTS—All the affected members were clinically diagnosed as having LCDI, and the pedigree indicated an autosomal dominant inheritance. A heterozygous single base pair transition (CTG to CCG, leucine to proline) was detected in codon 518 of the βig-h3 gene in the three affected members, and not in the unaffected member. No mutation was found in codon 124. Amyloid deposits were observed between the collagen bundles of the corneal stroma and were seen to extend deep into the stroma. CONCLUSION—The Leu518Pro mutated βig-h3 forms amyloidogeneic intermediates which precipitate in the cornea and gives rise to a clinical appearance of LCDI.

PURPOSE This study was undertaken to identify beta ig-h3 gene mutations in Japanese patients with granular corneal dystrophy (GCD), Avellino corneal dystrophy (ACD), lattice corneal dystrophy (LCD), and Reis-Bucklers' corneal dystrophy (RBCD). R124H, R124C, R555W, and R555Q mutations have been reported in Europe to cause ACD, LCD type I, GCD, and RBCD, respectively. METHODS In total, 91 Japanese patients who had been clinically diagnosed with GCD, LCD, or RBCD were investigated to determine whether they had mutations in the beta ig-h3 gene. Genomic DNA was amplified using the polymerase chain reaction and analyzed using single-strand conformation polymorphism techniques. Mutations were identified using the direct sequencing method. RESULTS In 68 unrelated patients who had been diagnosed with GCD, 62 patients (91%) were found to have the R124H mutation, which has been reported to cause ACD, whereas only six patients (9%) had the R555W mutation. In LCD patients, 10 patients with type I disease had the R124C mutation, and 10 patients with type IIIA disease had a P501T mutation. One patient with atypical LCD had an L527R mutation. In two patients with RBCD, one had an R555Q mutation and the other patient with geographic opacities was found to have an R124L mutation. CONCLUSIONS Depending on the specific mutation in the beta ig-h3 gene, the phenotypes of corneal dystrophy may differ. Our results indicate that assay of mutations in the beta ig-h3 gene is required to establish a correct diagnosis.

AIMS To establish a clinical and molecular diagnosis in a family with late onset lattice corneal dystrophy. METHODS Linkage analysis, single strand conformation polymorphism (SSCP) analysis, and direct sequencing of genomic DNA were performed. A review of the patients9 clinical symptoms and signs was undertaken. RESULTS Linkage to chromosome 9q34 was established and a mutation in the gelsolin gene was found in affected individuals. Numerous symptoms experienced by the patients were attributable to this mutation. CONCLUSION A diagnosis of amyloidosis type V (familial amyloidosis, Finnish type, FAF/Meretoja syndrome/gelsolin related amyloidosis) was made. This is the first case of amyloidosis type V described in the UK. This emphasises the importance of recognition of the extraocular manifestations of eye disease both in the diagnosis and management of the patient. In addition, these findings can help molecular geneticists in their search for disease-causing mutations.

PURPOSE: To characterize the βig-h3 gene defect in a French family affected with lattice corneal dystrophy type IIIA (LCDIIIA). METHODS: Histologic examination was performed from corneal buttons of two patients. Genomic DNA was extracted from leukocytes, and exons of the βig-h3 gene were amplified by polymerase chain reaction to be directly sequenced. RESULTS: Numerous deposits were evident in the stroma and beneath the Bowman membrane, which had all the features of amyloid deposits. Analysis of exon 12 revealed a heterozygous G to A transition on codon 546. CONCLUSION: In contrast to Japanese patients, these French patients affected with LCDIIIA carry a distinct mutation of the βig-h3 gene (A546T instead of P501T). Therefore, it is unclear whether different mutations could result in the same dystrophy or whether we are dealing with clinical heterogeneity of LCDIIIA.

The purpose of this study was to report the association of phenotypic features characteristic of lattice corneal dystrophy (LCD) with a monoclonal gammopathy of undetermined significance (MGUS) after exclusion of a coding region mutation in transforming growth factor beta-induced (TGFBI) gene.Case report.Slit-lamp examination and collection of DNA for TGFBI screening were performed. A systemic evaluation was also performed to evaluate for conditions associated with systemic amyloidosis.A 65-year-old man demonstrated bilateral linear branching corneal stromal opacities characteristic of classic LCD. No mutations were found in any of the 17 exons of TGFBI or in the intron-exon boundary regions. Four previously described single nucleotide polymorphisms were identified: c.698CG (p.Leu217Leu; rs1442), c.1028AG (p.Val327Val; rs1054124), c.1416CT (p.Leu472Leu; rs1133170), and c.1667TC (p.Phe540Phe; rs4669). Serum protein electrophoresis revealed the presence of a monoclonal spike, and based on the results of additional investigations, the patient was diagnosed with MGUS.Although the presence of bilateral thin branching lattice lines in the corneal stroma is characteristic of classic LCD, this distinctive phenotype may not be associated with a TGFBI coding region mutation but instead with a myeloproliferative disorder such as MGUS. Therefore, appropriate genetic and serologic testing should be performed in patients with a late-onset LCD phenotype in the absence of a positive family history.

PURPOSE Subepithelial recurrences in the graft are well known after conventional penetrating keratoplasties in granular and lattice dystrophies. In contrast to what is still written in most textbooks, both dystrophies have their origin in the epithelium, which originates from the limbal stem cells. The aim of this study, therefore, is to investigate whether recurrences can be avoided or minimized by simultaneous transplantation of healthy donor limbus by means of a homologous central limbokeratoplasty. METHODS Since October 1995, five patients with granular and four patients with lattice dystrophies were treated with homologous penetrating central limbokeratoplasties. Approximately 40% of the graft's circumference contained limbal donor stem cells. After surgery, cyclosporin A was administered for at least 6 months to protect the limbal stem cells from immunologic destruction. RESULTS During a follow-up period of 12-35 months, one recurrence was observed, probably because of an immune reaction against the transplanted limbal stem cells after tapering off the immune prophylaxis. CONCLUSION These first results are in agreement with our expectations. More patients, however, must be operated on in this way. Follow-up must occur for many years before we will definitely know under which conditions long-term survival of donor stem cells occurs to such an extent that subepithelial recurrences in granular and lattice dystrophies stop being a major problem after keratoplasty in these patients.

To characterize severe lattice corneal dystrophy, we analyzed the βig-h3 gene, clinical features, histological findings, and genotype-phenotype correlation in an affected Japanese family. Deoxyribonucleic acid was extracted from leukocytes in 16 members (12 affected and 4 unaffected) of a Japanese family with lattice corneal dystrophy type I. Exon 4 of the βig-h3 gene was amplified and analyzed using molecular biological methods. Clinical and pathological data were also collected. We found a heterozygous point mutation that causes the disease phenotype. It was a single base-pair transition leading to an amino acid substitution (CGC→TGC, Arg124Cys). The phenotypic variation within families was not recognized. The affected members in the pedigree demonstrated severe visual disturbance in the third decade and required keratoplasty. Histopathological examination revealed amyloid deposits consisting of short and thin amyloid fibers and lattice corneal dystrophy type I. The heterozygous Arg124Cys mutation reported in Caucasian lattice corneal dystrophy caused severe lattice corneal dystrophy consisting of short and thin amyloid fibers in a Japanese family. Based on our study of many members of the family, we are able to construct the natural course of this disorder from its earliest clinical findings through its late manifestations.

Corneal dystrophies have traditionally been defined as bilateral, symmetric disorders that, with a few notable exceptions, are associated with autosomal dominant inheritance and complete penetrance. The characteristic clinical phenotype of each dystrophy typically allows unambiguous distinction between different corneal dystrophies and between dystrophic and non-dystrophic corneal disorders. However, cases of unilateral and markedly asymmetric dystrophic deposits have been reported,1–4 as have affected individuals without a family history who have been shown to possess spontaneous mutations in TGFBI .5 Additionally, significant inter- and even intra-familial phenotypic variability between individuals sharing the same TGFBI mutation have also been reported, challenging the ability of the clinician to rely upon the clinical phenotype to diagnose and classify such dystrophies.6 Thus, molecular genetic analysis is particularly helpful to confirm or refute the diagnosis of a presumed TGFBI dystrophy in cases associated with atypical clinical features, such as the delayed development of corneal deposits, unilateral or asymmetric involvement, deposits demonstrating unusual morphological features, or a negative family history.7 We report …

PURPOSE: To discover if βig-h3 is mutated in gelatinous drop-like corneal dystrophy, as has been suggested. METHODS: Genomic DNA was isolated from unrelated individuals with lattice corneal dystrophy type I (n = 3), Avellino corneal dystrophy (n = 3), and gelatinous drop-like corneal dystrophy (n = 3) and used as a template for polymerase chain reaction to amplify all exons in βig-h3. The polymerase chain reaction product was then sequenced. RESULTS: βig-h3 is mutated in lattice corneal dystrophy type I (Arg124Cys) and Avellino corneal dystrophy (Arg124His). In gelatinous drop-like corneal dystrophy, on the other hand, no mutation was detected in the entire coding region of βig-h3 (all 17 exons). CONCLUSION: Unlike the amyloidotic corneal dystrophies lattice type I and Avellino, gelatinous drop-like corneal dystrophy is not likely to be caused by a mutation in βig-h3.

To compare the time necessary for complete epithelial healing after penetrating keratoplasty carried out for various corneal dystrophies.In a retrospective single-center study, 679 eyes that underwent nonmechanical keratoplasty were evaluated concerning postoperative epithelial healing time. On the basis of corneal pathology, the eyes were divided into 5 groups: group 1, lattice dystrophy (n = 9); group 2, macular dystrophy (n = 16); group 3, Fuchs dystrophy (n = 207); group 4, granular dystrophy (n = 13); group 5, keratoconus (n = 434). After keratoplasty, the time necessary for complete healing of the epithelial defect was compared among the groups.In lattice dystrophy, 22% showed delayed healing, in contrast to 0% in granular dystrophy. Mean time necessary for healing in group 1 (8.8 +/- 9.4 days) was significantly longer than in group 2 (2.5 +/- 2.5 days, P = 0.003), group 3 (4.4 +/- 4.1 days, P = 0.09), group 4 (2.2 +/- 1.4 days, P = 0.003), and group 5 (3.1 +/- 2.7 days, P = 0.005).In patients with lattice dystrophy, delayed epithelial healing after penetrating keratoplasty may be anticipated. Patients should be counseled accordingly.

In the light of recent studies into lattice corneal dystrophies, with particular reference to gelsolin immunoreactivity, the authors set out to determine the ultrastructural localization of gelsolin molecules in lattice corneal dystrophy type I. Immunoelectron microscopy with a monoclonal antibody against the COOH-terminal of the native gelsolin molecule (clone GS-2C4) was used to compare antigelsolin reactivity in normal and dystrophic corneas. A gelsolin-like protein was observed at the level of the rough endoplasmic reticulum in both epithelial and endothelial cells, together with mild positive staining in stromal keratocytes of normal corneas; increased keratocytic immunoreactivity with positive staining within and/or around corneal amyloid deposits was revealed in dystrophic corneas. Observed intra- and extracellular immunoreactivity suggests that amyloid deposition may induce gelsolin synthesis; this actin-related protein could be involved in the rearrangement of corneal stroma in lattice corneal dystrophy.

Purpose To investigate whether corneal epithelial cells of individuals with lattice corneal dystrophy (LCD) possess an intrinsic defect. Design Retrospective case-control study. Methods The medical charts of nine individuals with LCD and those of 14 patients with keratoconus and 11 patients with corneal leukoma (controls), all of whom underwent penetrating keratoplasty (PKP) in one eye at Yamaguchi University Hospital between February 1998 and November 2001, were examined for the time for epithelial resurfacing after surgery. Results The time required for resurfacing of the corneal epithelium after PKP was significantly greater in LCD patients (8.56 ± 4.95 days, mean ± SD) than in patients with either keratoconus (1.71 ± 0.91 days, P = .006) or corneal leukoma (3.00 ± 1.95 days, P = .03). Conclusions Corneal epithelial wound healing was delayed in LCD patients after PKP, suggesting that the keratoepithelin gene mutations responsible for this condition affect corneal epithelial cells.

Lattice corneal dystrophy (LCD) is a bilateral, local amyloidosis, characterized by variation in the corneal manifestations, clinical course, and genetics.1 LCD has been attributed to TGFBI (transforming growth factor, beta-induced) gene on human chromosome 5q31 (OMIM No. 601692). LCD type II is associated with secondary open-angle glaucoma in the context of familial amyloidosis, Finnish (FAF).2 We report a case with the corneal findings of LCD type II but without any systemic involvement, in a patient with juvenile glaucoma.

BACKGROUND: The capability of the 193-nm excimer laser to ablate the cornea and to remove opacities and various other corneal diseases in a procedure called phototherapeutic keratectomy (PTK) has been demonstrated. In this study we evaluated the long-term results of PTK for treatment of granular and lattice corneal dystrophies. METHODS: Four eyes with granular or lattice corneal dystrophy were treated with a mean followup of 47.8 months (range, 36 to 58 months). Focal ablations of the central cornea with an ablation zone of 5.5 to 6.0 mm were performed. Ablation depth was 110 µt? in three eyes and 140 /on in one eye. RESULTS: Removal of corneal opacities allowed for improvement in corrected visual acuity in all patients. Mean corneal thickness in the area of pathology decreased from 0.583 mm before surgery to 0.449 mm after surgery. Spherical equivalent of the manifest refraction measurements increased by a mean of +5.09 D. There were no major complications, but all patients developed slight haze. There was a hyperopic shift in three eyes. CONCLUSION: Our long-term results suggest that PTK is a safe and effective alternative to penetrating and lamellar keratoplasty in patients with granular or lattice corneal dystrophies. [J Refract Surg 1996;12:795-800]

Background: Finnish-type familial amyloidosis (FAP-IV) is an autosomal, dominantly inherited disorder characterized by progressive polyneuropathy and lattice corneal dystrophy type II. The vast majority of families with this disorder originated from Finland. Only two families, in neighboring districts, have been reported in Japan previously. Methods: The authors report two additional Japanese patients with FAF-IV. The proband, a 70-year-old man, had decreased perspiration and abnormal facial muscle movement. Results of neurologic examination showed bilateral facial and hypoglossal nerve palsies, and an autonomic disturbance, including orthostatic hypotension and dysfunction of perspiration. Histochemical, immunohistological, and DNA studies confirmed the diagnosis of FAP-IV. Results: Results of ophthalmologic examination showed asymptomatic lattice corneal dystrophy of both eyes, but the appearance of the cornea was different from that described in the patients from Finland. Lattice lines in the authors' patient were very fine, short, and glassy and could be observed with indirect retroillumination, but might be missed with direct illumination by the slit-lamp microscope. The proband's younger half-sister, a 68-year-old woman, showed clinical findings and laboratory data similar to those of the proband. Conclusion: The authors report two Japanese patients with lattice corneal dystrophy type II related to FAP-IV. This is the third Japanese family with this disorder, and there is no familial relationship to the two previously reported families in Japan.

Familial amyloidosis, Finnish type (FAP-IV) was identified clinically in an American kindred with Scandinavian ancestry. A polymerase chain reaction (PCR)-based DNA diagnostic assay was used to identify a G-to-A mutation at position 654 of the gelsolin cDNA (G654A) in this family. Molecular diagnostic testing demonstrated the mutation in individuals in three generations--the clinically affected proband, here deceased clinically affected father, and her presumably affected presymptomatic child. This report represents a rare example of FAP IV and the G654A mutation identified in a family outside Finland. The disease-associated haplotype was similar to that observed in Finnish FAP IV families (suggesting common distant ancestry).

Three stromal corneal dystrophies (granular, lattice type l, and Avellino) were recently mapped to a single locus on chromosome 5. This study was conducted to determine if there is histologic evidence to support the allelic relationship suggested by the genetic studies. We examined 23 corneal buttons from the two families with lattice dystrophy and 13 corneal buttons from the two families with granular dystrophy who were involved in the chromosomal linkage studies. In the two families with clinically typical granular dystrophy, one corneal button also contained focal amyloid deposits. In both families with clinically typical lattice dystrophy type 1, we found evidence of granular deposits. The genetic linkage studies demonstrate only that the disease-causing mutations for these three stromal dystrophies share the same genetic locus. However, the evidence of histologic overlap strongly suggests that these dystrophies are caused by mutations within the same gene.

A 69-year-old Japanese woman with non-familial amyloidosis had polyneuropathy and profound autonomic neuropathy, and kappa chain monoclonal gammopathy. Immunohistopathological examination showed protein AA and protein AP in the amyloid deposits. She showed involvement of the vestibulocochlear nerve and lattice dystrophy of the cornea. Vestibulocochleopathy and corneal lattice dystrophy have been reported in familial amyloid polyneuropathy type IV, Finnish type, but never in non-familial amyloidosis.

Avellino corneal dystrophy has rarely been reported in literature. It consists of a combination of granular and lattice dystrophy. Patients may complain of glare and decreased night vision with or without decreased visual acuity, depending on the degree of corneal involvement. Current treatment for this dystrophy includes bandage contact lenses for the erosions or corneal transplant in the case of decreased visual acuity. We describe the first patient with Avellino corneal dystrophy to have been treated with phototherapeutic keratectomy.

Purpose Specific components of transforming growth factor-beta-induced protein (TGFBIp) responsible for amyloid deposits in lattice corneal dystrophy (LCD) have not been delineated. LCD has been associated with various TGFBIp mutations such as R124C, L518P, and L527R. Using recombinant TGFBIp, this study was undertaken to identify TGFBIp components potentially contributing to the protein deposits in LCD. Methods Recombinant wild-type (WT) TGFBIp and four mutants (R124C, R124H, L518P, and L527R) were generated in HEK293FT cells. WT and mutant TGFBIp were collected from crude cell lysates or purified from culture media. Immunoblot analyses were performed with four different anti-TGFBIp antibodies raised against various regions of TGFBIp. Results Consistent with the authors' previous findings, purified recombinant proteins are more prone to polymerize than crude cell lysates. As expected, all monomers and polymers of TGFBIp WT and mutants were detected by these antibodies. However, the authors noted WT and TGFBIp mutants showed differential reactivities with these antibodies. A 47-kDa band was detected in purified 2-tag proteins of L518P by all four antibodies. A unique 43-kDa band was detected in both 1-tag cell lysates and purified proteins of R124C by the authors' custom-made antibody (KE50) and a commercial anti-TGFBIp. Conclusions Based on its universal reactivity with various antibodies, the authors surmise that the 47-kDa protein is a ubiquitous TGFBIp fragment derived from the N-terminus of the L518P mutant. The fact that the 43-kDa protein fragment was present primarily in R124C and R124H but not in WT implicates its potential role in the protein deposits of LCD.