Gelatinous Drop-like Dystrophy Research Articles

Gelatinous Drop-Like Corneal Dystrophy in an Acehnese Family: Serial Cases.

Introduction : Gelatinous drop-like dystrophy (GDLD) is a rare type of corneal dystrophy with an autosomal recessive inheritance pattern. Although the prevalence in Japan is approximately 1 in 33,000, it is much less common in other nations. Lamellar or penetrating keratoplasty is needed for most patients to alleviate the symptoms. This case series aims to provide knowledge regarding rare cases of GDLD and its management.
 Case Illustration : Three male siblings from consanguineous marriage were found to have corneal dystrophy, characterized by a white-yellow nodular lesion with a kumquat-like appearance on the corneal surface. The visual acuity of each patient was light perception with good projection. To treat the condition, all patients underwent full-thickness penetrating keratoplasty. One month after the procedure, their visual acuity had improved to 3/60, 2/60, and 2/60, respectively.
 Discussion : GDLD is a genetic disease with gelatinous amyloid deposits in the cornea that typically manifests within the first decades of life. GDLD can present in three different phenotypes, including band keratopathy, mulberry, and kumquat-like appearance. In the case of these siblings, they have developed the severe kumquat-like phenotype. Detection by examining family involvement and the cornea's clinical presentation can help diagnose GDLD. Full-thickness penetrating keratoplasty can be an option for managing severely impaired visual acuity caused by GDLD.
 Conclusion : GDLD is a rare corneal dystrophy that can lead to severe visual impairment. The objective of treating GDLD is to enhance vision and prevent its progression. Vision loss can be alleviated througha surgical procedure such as full-thickness penetrating keratoplasty.

Establishment of a Human Corneal Epithelial Cell Line Lacking the Functional TACSTD2 Gene as an In Vitro Model for Gelatinous Drop-Like Dystrophy

Gelatinous drop-like corneal dystrophy (GDLD) is characterized by subepithelial amyloid deposition that engenders severe vision loss. The exact mechanism of this disease has yet to be elucidated. No fundamental treatment exists. This study was conducted to establish an immortalized corneal epithelial cell line to be used as a GDLD disease model. A corneal tissue specimen was obtained from a GDLD patient during surgery. Corneal epithelial cells were enzymatically separated from the cornea and were dissociated further into single cells. The epithelial cells were immortalized by the lentiviral transduction of the simian virus 40 (SV40) large T antigen and human telomerase reverse transcriptase (hTERT) genes. For the immortalized cells, proliferative kinetics, gene expressions, and functional analyses were performed. The immortalized corneal epithelial cells continued to proliferate despite cumulative population doubling that exceeded 100. The cells showed almost no sign of senescence and displayed strong colony-forming activity. The cells exhibited a low epithelial barrier function as well as decreased expression of tight-junction-related proteins claudin 1 and 7. Using the immortalized corneal epithelial cells derived from a GDLD patient, we tested the possibility of gene therapy. We established an immortalized corneal epithelial cell line from a GDLD patient. The immortalized cells exhibited cellular phenotypes similar to those of in vivo GDLD. The immortalized cells are thought to be useful for the development of new therapies for treating GDLD corneas and for elucidation of the pathophysiology of GDLD.

Classification of Secondary Corneal Amyloidosis and Involvement of Lactoferrin

To classify secondary corneal amyloidosis (SCA) by its clinical appearance, to analyze the demographics of the patients, and to determine the involvement of lactoferrin. Retrospective, observational, noncomparative, multicenter study. Twenty-nine eyes of 29 patients diagnosed with SCA by corneal specialists at 9 ophthalmologic institutions in Japan were studied. The clinical appearance of SCA was determined by slit-lamp biomicroscopy and was classified into 3 types. The demographics of the patients, for example, age, gender, and the duration of the basic disease (trichiasis, keratoconus, and unknown), were determined for each clinical type. Surgically excised tissues were stained with Congo red and antilactoferrin antibody. The postoperative prognosis also was determined. Clinical appearance of the 3 types of SCA, along with the gender, age, and duration of the basic diseases were determined. Classification of SCA into 3 types based on clinical appearance found 21 cases with gelatinous drop-like dystrophy (GDLD)-like appearance (GDLD type), 3 cases with lattice corneal dystrophy (LCD)-like appearance (LCD type), and 5 cases with the combined type. Patients with the GDLD type were younger (average age: 40.9 years for the GDLD type, 74.3 years for the LCD type, and 46.8 years for the combined type), predominantly women (85.7% for the GDLD type, 33.3% for the LCD type, and 60% for the combined type), and had the basic disease over a longer time (average duration: 22.1 years for the GDLD type, 14.0 for the LCD type, and 11.4 for the combined type). The distribution of the basic diseases (trichiasis vs. keratoconus vs. unknown) was not significantly different for each type. Surgical treatments, for example, phototherapeutic keratectomy, lamellar keratoplasty, and simple keratectomy, resulted in a good resolution in all surgically treated cases. One subject dropped out of the study. Spontaneous resolution was seen in one subject after epilation of the cilia. Amorphous materials in the excised tissues showed positive staining results by Congo red and by antilactoferrin antibody. Secondary corneal amyloidosis can be classified into 3 clinical types based on its clinical appearance. Larger numbers of females and lactoferrin expression were seen in all 3 types. The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Gelatinous drop like dystrophy (GDLD) in a Sudanese patient

AbstractPurpose Gelatinous drop‐like corneal dystrophy (GDLD) (OMIM #204870) is an early‐ onset, autosomal recessive corneal dystrophy, reported globally. It presents in the first decade of life with bilateral, mulberry‐like or gelatinous lesions, due to amyloid deposition in the superficial cornea.Methods A 50 year old Sudanese patient was diagnosed for GDLD. The patient had penetrating keratoplasty in the right eye. The tissue was processed for light and electron microscopy. A DNA sample was screened for 333 sequence variants in 13 corneal dystrophy genes by Asper Ophthalmics Ltd, followed by confirmatory sequencing.Results The GDLD cornea contained deposits of amyloid fibrils at the sub‐epithelial region and in various parts of stroma. The deposits were Congo red positive and showed apple green birefringence under polarized light. The growth of amyloid fibrils was associated with large splits between lamellae, a reduced diameter of collagen fibrils and degeneration of keratocytes. A homozygous c.355T>A mutation in exon 1 of the TACSTD2 (M1S1) gene was identified, not present in dbSNP, predicted to cause a pathogenic amino acid change (p.Cysl19Ser in NCBI entry NP_002344.2).Conclusion The cornea of this GDLD patient with a novel c.355T>A mutation in exon 1 of TACSTD2 showed degeneration of the corneal epithelium, Bowman’s layer, stroma and keratocytes. Deposits of amyloid were found in the sub‐epithelium region, Bowman’s layer, and stroma. Acknowledgement: Supported by National Plan for Science and Technology, KSU, Riyadh.

Simultaneous deep anterior lamellar keratoplasty and limbal allograft in bilateral limbal stem cell deficiency

To report the efficacy of simultaneous keratolimbal allograft (KLAL) surgery and deep anterior lamellar keratoplasty (DALK) for limbal stem cell deficiency (LSCD). We conducted a retrospective, interventional case series of six consecutive eyes of five patients with LSCD and stromal opacity due to gelatinous drop-like dystrophy (two eyes), Stevens-Johnson syndrome (SJS, two eyes), or aniridia (two eyes). Only patients with normal lid anatomy and Schirmer test values greater than 3 mm were enrolled. DALK was performed by viscodissection followed by a thin, 360° KLAL designed by using an artificial anterior chamber. KLAL sutures were removed after 2 weeks. DALK and KLAL were successfully performed in all eyes, which were followed for an average of 17.2 ± 10.8 months. All eyes recovered a smooth corneal epithelium, although one SJS patient developed a persistent epithelial defect (PED) leading to opacification of the central cornea. Visual acuity improved by more than 2 lines in all eyes except that of the SJS patient with PED. No other complications were observed. Simultaneous DALK and thin-section KLAL is an effective treatment for ocular surface disease in patients with residual tear function and normal lid anatomy.

Tumor-Associated Calcium Signal Transducer 2 Is Required for the Proper Subcellular Localization of Claudin 1 and 7: Implications in the Pathogenesis of Gelatinous Drop-Like Corneal Dystrophy

Gelatinous drop-like dystrophy (GDLD) is a rare autosomal recessive form of corneal dystrophy characterized by subepithelial amyloid depositions on the cornea. Previous clinical and laboratory observations have strongly suggested that epithelial barrier function is significantly decreased in GDLD. Despite the decade-old identification of the tumor-associated calcium signal transducer 2 (TACSTD2) gene as a causative gene for GDLD, the mechanism by which the loss of function of this causative gene leads to the pathological consequence of this disease remains unknown. In this study, we investigated the functional relationship between the TACSTD2 gene and epithelial barrier function. Through the use of immunoprecipitation and a proximity ligation assay, we obtained evidence that the TACSTD2 protein directly binds to claudin 1 and 7 proteins. In addition, the loss of function of the TACSTD2 gene leads to decreased expression and change in the subcellular localization of tight junction-related proteins, including claudin 1, 4, 7, and ZO1 and occludin, both in diseased cornea and cultured corneal epithelial cells. These results indicate that loss of function of the TACSTD2 gene impairs epithelial barrier function through decreased expression and altered subcellular localization of tight junction-related proteins in GDLD corneas.

Corneal Wound Healing from the Perspective of Keratoplasty Specimens With Special Reference to the Function of the Bowman Layer and Descemet Membrane

To review corneal wound healing with special reference to the function of the Bowman layer and Descemet membrane. Corneal specimens were obtained from keratoplasties, including regrafted cases. Recipient corneal buttons were evaluated histopathologically with attention to 5 layers of corneal structure: 3 cellular layers consisting of epithelial cells, keratocytes, and endothelial cells and 2 acellular layers consisting of the Bowman layer and Descemet membrane. Subepithelial fibrosis was found in advanced bullous keratopathy. The possible source of subepithelial fibrosis was either conjunctival stroma or corneal stroma through disruption of the Bowman layer. Subepithelial fibrosis was observed in the area of the Bowman layer disruption at the host-graft junction in regrafted cases. The Bowman layer was disrupted in eyes with not only keratoconus but also corneal dystrophy such as macular dystrophy and gelatinous drop-like dystrophy. Newly formed, thin Descemet membrane was found in keratoconic eyes of patients with acute hydrops. Retrocorneal membranes were observed in eyes with advanced bullous keratopathy and graft failure. Abnormal wound healing of Descemet membrane such as override and separation was found in the host-graft interface of regrafted eyes, causing stromal overgrowth. The Bowman layer and Descemet membrane seem to serve as barriers to separate 3 cellular layers of epithelium, stroma, and endothelium. Disruption of the Bowman layer forms a new epithelial-stromal interaction and may cause cellular proliferative response. Separation of Descemet membrane can provide the trigger for emanating stromal tissue from the wound edge.

A novel missense mutation in a Japanese patient with gelatinous droplike corneal dystrophy

To report a novel missense mutation in TACSTD2 gene, L186P, responsible for gelatinous droplike dystrophy (GDLD). Case report and experimental study. A 10-year-old Japanese boy suffering from typical GDLD was studied. A 1.1-kb DNA fragment of the TACSTD2 gene was amplified and analyzed using a molecular biological method. cDNA from the patient's cornea was also analyzed to determine which allele was expressed in the patient's corneal epithelium. Sequence analysis revealed that the patient is a compound heterozygote for the Q118X mutation and the L186P, the first missense mutation found in Japanese GDLD. Polymerase chain reaction-restriction fragment length polymorphism analysis from cDNA of patient's cornea revealed that the L186P missense mutation allele is expressed in the patient's corneal epithelium. We describe a novel mutation in one case of Japanese GDLD. The results confirm that the missense mutation L186P in the TACSTD2 gene is also responsible for the GDLD phenotype.

Frequency, distribution, and outcome of keratoplasty for corneal dystrophies at a tertiary eye care center in South India.

To report the frequency, outcome, and atypical histology in corneal dystrophies. Corneal buttons of patients diagnosed with corneal dystrophy as noted in the records of the ophthalmic pathology register over a period of 6 years were included in this study. The sections from formalin-fixed, paraffin-embedded tissues were reviewed specifically for the type of deposits, associated degenerations such as amyloid and spheroidal deposits, inflammation, and vascularization. Special stains including Masson trichrome, Congo red, and Alcian blue staining were used whenever required. The medical records were evaluated for demographics, clinical presentation, history of consanguinity, family medical history, and clinical outcome of keratoplasty, which was recorded as clear, recurrence of dystrophy, or graft failure. A clinicopathologic correlation was attempted. A total of 144 patients contributed 181 buttons, accounting for 8.1% of keratoplasties performed during the study period. The mean age of the patients was 34 +/- 19 years (range 3-72 years) with a male:female ratio of 1.6 (89):1 (55). Consanguineous parentage was noted in 26% of cases. History of a similar problem in siblings and other family members was elicited in 33 (22%) and 14 (9.7%), respectively. Dystrophies included macular (29.3%), congenital hereditary endothelial dystrophy (34.8%), Fuchs (16.6%), and lattice (15%); the remaining 11% included granular, gelatinous drop-like, Reis-Bucklers, and posterior polymorphous dystrophy. Associated histologic changes were degenerations (15%), vascularization (4%), and inflammation (2%). At a mean follow-up of 42 months, the graft remained clear in 148 eyes (81.7%), failed in 33 eyes (18.2%), and recurred in 5 eyes (2.8%). Graft survival for all dystrophies at the end of 1 year was 94.3 +/- 1.7%, and at the end of 5 years was 74.4 +/- 4.5%. Atypical histologic features did not affect graft survival. Consanguineous marriages possibly contributed to the increase in macular dystrophy and CHED in South India. The degenerative changes seen could possibly be related to late presentation or unknown environmental factors and do not have an effect on the ultimate graft outcome.

Corneal dystrophies in the light of modern molecular genetic research

Modern methods of molecular genetics have resulted in new insights into the pathogenesis of corneal dystrophies which now require a new classification. Clinical evidence, the results of histopathological and electron-microscopical examinations, especially in cases of recurrence which reflect early disease, and the immunohistochemical analysis of the deposits have already aroused the suspicion that the "old" classification dividing the dystrophies into those of the epithelium, of the so-called anterior membrane, of the stroma and of the endothelium may no longer be adequate. The detection of the BIGH 3 gene which is mainly expressed in the corneal epithelium, and its gene product keratoepithelin, have led to the insight that the so-called anterior membrane dystrophies (Reis-Bücklers, Thiel-Behnke) as well as the more common "classical" stromal dystrophies (granular dystrophies Types I and II, lattice dystrophies Types I and IIIA) are caused by different mutations of the above mentioned BIGH3 gene and are thus to be regarded as epithelial in origin. Lattice dystrophy Type II is part of the Meretoja syndrome, a systemic amyloidosis, and is caused by a mutation of the gelsoline gene on chromosome 9 (9q34). Gelsoline is also predominantly expressed in the corneal epithelium. In addition, the responsible genes, their gene-products and the mutations are known for Meesmann's epithelial dystrophy and for the so-called gelatinous drop-like dystrophy, while in other dystrophies only the location on a certain chromosome can be given, namely: 16q22 for the macular dystrophy, 1p36 for the central crystalline dystrophy of Schnyder and 20p11.2-q11.2 for the congenital hereditary endothelial and for Schlichting's posterior polymorphous dystrophies. As the production rate of new results in molecular genetics is very fast, the proposed new classification can only be of preliminary character.

Two brothers with gelatinous drop-like dystrophy at different stages of the disease: role of mutational analysis

PURPOSE: A report of two Japanese brothers with gelatinous drop-like corneal dystrophy, one with and one without the typical gelatinous drop-like region. DESIGN: Interventional case report and observational case report. METHODS: After penetrating keratoplasty, the corneal button, right eye, of the elder brother, 39 years of age, was stained and examined by microscopy. The M1S1 and BIGH3 genes were examined for mutations using the polymerase chain reaction and direct sequencing. Corneal abnormalities in the younger brother, 37 years of age, were observed. RESULTS: The elder brother had bilateral gelatinous prominences and band-shaped corneal opacities, whereas the younger brother had only bilateral band-shaped opacities. Histologically, corneal deposits beneath the epithelium stained with Congo red. Molecular genetic analysis revealed that M1S1 was homozygously mutated in both brothers (Q118X). CONCLUSION: The Q118X mutation of the M1S1 gene can produce either a gelatinous drop-like region or band-shaped opacities.

Clinical and Histopathologic Features of Corneal Dystrophies in Japan

To examine retrospectively the frequency of various corneal dystrophies among Japanese patients who underwent keratoplasty or keratectomy at the authors' institution over a 34-year period, and to compare the histopathologic features of these disorders in the Japanese population with those reported in the Western literature. Corneal specimens obtained during keratectomy or keratoplasty (lamellar and penetrating) performed at the authors' institution from 1959 through 1992 were reviewed. Immunohistochemical studies were performed using monoclonal antibodies to keratan sulfate and gelsolin, as well as two lectins (concanavalin A and wheat germ agglutinin). Of 1259 corneal specimens, 159 (12.6%) specimens from a total of 80 patients showed corneal dystrophy. Virtually all were non-Fuchs dystrophies; only one case of primary Fuchs dystrophy was identified histologically. Granular dystrophy and gelatinous drop-like dystrophy were the most common dystrophies identified in the specimens, largely because of multiple specimens from individual patients with recurrent disease. These two disorders accounted for 86 of the 159 specimens. In terms of numbers of patients, lattice dystrophy was the most common (26 patients, 32.5%), followed by macular dystrophy (16 patients, 20%), gelatinous drop-like dystrophy (15 patients, 18.8%), granular dystrophy (14 patients, 17.5%), and Avellino dystrophy (3 patients, 3.75%). Dystrophies represented by only one or two patients included congenital hereditary endothelial dystrophy, primary spheroidal keratopathy, posterior polymorphous dystrophy, Schnyder crystalline dystrophy, and Fuchs dystrophy. This histopathologic study showed a very low incidence of Fuchs dystrophy in the authors' Japanese patient population, compared with the incidences seen in studies of populations in Western countries. Of the non-Fuchs dystrophies, lattice dystrophy was the most common among the patients, although there were large numbers of specimens with granular dystrophy and gelatinous drop-like dystrophy due to their recurrent character. The causes of clinical and histopathologic differences and similarities among the Japanese patients and the patients described in the Western literature are likely related to genetic factors, but a complete understanding of their specific mechanisms awaits future molecular biologic and genetic elucidation.

Spheroidal Keratopathy Associated with Subepithelial Corneal Amyloidosis: A Clinicopathologic Case Report and a Proposed New Classification for Spheroidal Keratopathy

An unusual case of primary spheroidal degeneration associated with subepithelial corneal amyloidosis is described clinically and histopathologically, and a new classification for spheroidal keratopathy is proposed. The corneal button obtained by lamellar keratoplasty was examined by light and transmission electron microscopy. Amyloid deposits were evaluated further by means of the thioflavin T fluorescence technique, the potassium permanganate reaction, and immunohistochemical studies using antibodies against immunoglobulin light chains and proteins AA and AP. Spheroidal droplets were observed in basement membrane, Bowman's layer, and anterior stroma, and exhibited characteristic staining with Verhoeff's iron hematoxylin. Amyloid deposits were found beneath the epithelium, almost exclusively in the central area of the corneal button. The deposits showed no immunohistochemical staining with antibodies to amyloid proteins AA and AP or kappa and lambda light chains. The histochemical properties of the spheroidal droplets in this case were similar to those observed by other authors and suggested a sulfur-rich protein other than keratin. The combination of clinical and pathologic findings permitted the differential diagnosis of subepithelial amyloidosis and distinguished this condition from that of gelatinous drop-like dystrophy. To the authors' knowledge, this is the first description of primary spheroidal keratopathy associated with secondary subepithelial corneal amyloidosis in an eye that had not undergone previous keratoplasty.