Category Archives: Articles of Relevance

IC3D_Class_CornealDystrophies

Laser Revolutionises Corneal Transplants

UGENE, Ore. — (Aug. 25, 2010) — A 13-member research team led by University of Oregon scientist Dr. Albert O. Edwards has found a gene likely responsible for Fuchs corneal dystrophy, an inheritable genetic disorder and leading cause of corneal transplant operations.

Edwards performed a genome-wide analysis comparing patients with and without typical age-related Fuchs, finding an alteration in the transcription-factor-4 gene (TCF4). Fuchs — pronounced FEWKS or FOOKS — generally emerges in middle-aged, roughly age 40, and older people.

The discovery appeared online Aug. 25 ahead of regular publication in the Sept. 9 issue of the New England Journal of Medicine.

Fuchs emerges slowly with blurred or cloudy vision, tiny bumps known as guttae (GOO-tay) on the cornea's surface and, in severe stages, painful blisters on the corneal surface. The disease affects the endothelium, a thin layer of cells that line the back part of the cornea where changes result in swelling of the cornea and thickening and clouding of the cornea. Guttae are found in the corneas of an estimated 5 percent of people in the United States.

Of those diagnosed with Fuchs, only a small percentage go on to require corneal transplants, said lead author Dr. Keith H. Baratz of the Mayo Clinic ophthalmology department in Rochester, Minn. There are about 40,000 corneal transplants — about 10,000 linked to Fuchs — done annually in the United States, according to the Eye Bank Association of America. It is more common in women than in men, according to the Fuchs Corneal Dystrophy Association.

The discovery won't immediately translate into clinical benefits, but "this is the first step in identifying the pathophysiology of the disease," Baratz said. "Right now, we don't have a treatment for Fuchs dystrophy other than transplant surgery when a patient is at the end stages of the disease. The ultimate goal is to find out how the disease occurs and find a treatment to prevent or slow its progression."

Having the TCF4 gene variation has a huge impact on the risk of Fuchs disease, said Edwards, a senior research associate in the University of Oregon's Institute of Molecular Biology. "It vastly exceeds the risk found previously for the complement-factor-H gene in macular degeneration," he said. "If a person has risk variants involving TCF4, that individual is anywhere from several to a couple of hundred times more likely to have Fuchs disease."

Edwards, in 2005, when at the University of Texas Southwestern Medical Center, was lead author of a study published in the journal Science that identified complement factor H in macular degeneration. That gene discovery tied complement factor H to a five-fold increase of risk to developing macular degeneration, accounting possibly for at least 50 percent of the risk of being affected. The risk impact of TCF4 on Fuchs is much stronger, Edwards said.

While the TCF4 gene has been identified, exactly what occurs to cause a defect is not understood. The researchers found evidence that at least one transcription protein, E2-2, needs more scrutiny.  "E2-2 is a transcription factor. It controls gene expression," Edwards said. "The pathway probably contains E2-2 and the protein ZEB1, but we don't really know that yet. We do find variation of expression across this region, so it has something to do with the expression of the gene."

E2-2, important in cellular growth and differentiation, has been implicated in other disease states, including activity that promotes or suppresses cancer. It is expressed in the corneal endothelium. ZEB1, which may be regulated by E2-2, already is thought to contribute to Fuchs.

The study involved the genotyping of 280 Fuchs patients recruited in clinical settings in Minnesota and Michigan. These patients had at least Stage 1 signs of Fuchs or had received corneal replacements as a result of the disease. Their genomes were compared with 410 control patients.

"The real impact of what we've done is to determine the biological underpinnings of the disease," Edwards said. "We've identified a protein that is probably involved, and that will allow us to, hopefully, identify a method to prevent people from losing their vision."

Three other genes previously had been linked to very rare subtypes of Fuchs. In addition, early onset Fuchs has been linked to mutations in yet another gene, COL8A2, but Edwards and colleagues suggest in their paper that this may be a different disease with a different cause.

"This discovery demonstrates the value of excellent clinical phenotyping and a large-scale genetic database of genome-wide association studies (GWAS) to uncover genetic risk factors for many vision-related disorders," said co-author Anand Swaroop, chief of the National Eye Institute (NEI) Neurobiology-Neurodegeneration and Repair Laboratory. "The genetic data used in this study was obtained for GWAS of age-related macular degeneration through a scientific collaboration supported by the NEI."

Co-authors with Edwards, Baratz and Swaroop were: William L. Brown, Katharina E. Schmid-Kubista, Nirubol Tosakulwong, Euijung Ryu and Kent R. Bailey, all of Mayo Clinic; Kari Branham, John R. Heckenlively, Wei Chen and Goncalo Abecasis, all of the University of Michigan; and Khoa D. Tran of the UO Institute of Molecular Biology and Oregon Retina of Eugene.

The National Institutes of Health primarily funded the research. The Foundation Fighting Blindness and the American Health Assistance Foundation, both based in Maryland, and Research to Prevent Blindness and the Max Kade Foundation, both in New York, also provided support.

About the University of Oregon
The University of Oregon is a world-class teaching and research institution and Oregon's flagship public university. The UO is a member of the Association of American Universities (AAU), an organization made up of the 63 leading public and private research institutions in the United States and Canada. The UO is one of only two AAU members in the Pacific Northwest.

About Mayo Clinic
Mayo Clinic is the first and largest integrated, not-for-profit group practice in the world. Doctors from every medical specialty work together to care for patients, joined by common systems and a philosophy of "the needs of the patient come first." More than 3,700 physicians, scientists and researchers, and 50,100 allied health staff work at Mayo Clinic campuses in Rochester, Minn., Jacksonville, Fla., and Scottsdale/Phoenix, Ariz.
 

South African Medical Journal – July 2007 by David Meyer

Modern corneal transplantation is internationally accepted as highly successful and cost effective. The avascularity of the cornea puts it in a relatively immune-privileged position, and complications due to graft rejection can be handled more effectively than in other solid organs.

Modern microsurgery, which has the ability to manage postoperative astigmatism, has turned corneal transplant surgery into a most gratifying procedure as far as visual acuity is concerned. Corneal graft survival is often lifelong, with most patients not needing topical or systemic immunosuppression for longer than several months postoperatively. Patients are frequently given a new lease on life after sight-restoring corneal transplantation.

Nationally obtained corneal tissue in South Africa is harvested and supplied to ophthalmic surgeons via five regional eye banks, the Cape Town-based Eye Bank Foundation of South Africa (which for several decades was the only national eye bank and served the whole of southern Africa), Gauteng Cornea and Eye Bank in Johannesburg, Pretoria Eye Bank, KZN Eye Bank in Durban and the Port Elizabeth Eye Bank.

Unfortunately the availability of corneal tissue in South Africa has recently been severely curtailed. There has been a steady progressive 41% decrease in the total number of corneal transplants performed with tissue supplied by the five South African-based eye banks. This decrease has occurred over the past 4 years, down from 934 in 2003 to 549 in 2006. Several factors have contributed to this unfortunate state of affairs. Legal/administrative issues due to a restriction placed on access to information on deceased persons held at the forensic (medicolegal) mortuaries.

Before June 2006, South African Police Service-controlled forensic mortuaries permitted eye banks access to information on persons who had died of non-natural causes. Management and control of these forensic mortuaries passed to the Department of Health in June 2006. Owing to the confidential nature of the information available at the forensic mortuaries, and the fact that the information is actually privileged information pertaining to a SAPS medicolegal case, the Department of Health have restricted access to all information that could identify or link a deceased body to a specific person and/or the family and next of kin.

The crippling result of this decision has been that eye banks have lost a vital source of access to information that could lead to potential donors. Rising level of infected donors. Tissue from donors positive for hepatitis B or C or HIV cannot be used for transplantation. Fig. 1 illustrates the progressive negative impact of this factor on the number of useable corneas from just one of our national eye banks. Public awareness.

The South African public is not tissue transplant-conscious. Much more needs to be done to instil a nationwide awareness of the need for donor tissue. Ideally at some point in their adult lives every South African should be confronted with the choice to become a willing organ donor (e.g. at the time of application for a driver's licence, identification document, passport, etc.). In countries such as the USA and Sri Lanka the local supply of corneal tissue exceeds national demands, and hence they are able to export worldwide. Donor corneas from the USA are readily available here, but at a cost of around R15 000 are prohibitively expensive for state hospital patients.

However, the corneal disease burden and need for corneal grafting in South Africa is immense. The national waiting list for corneal grafts during the first quarter of 2007 totalled 1 738 adults and 146 children. Many state hospitals do not keep up-to-date waiting lists any more because of the scarcity of tissue. During 2006 in the whole of South Africa only 516 corneal transplants in adults and 33 in children were performed using national eye bank tissue.

Every health care professional in South Africa should be aware of the need for donors of solid organs, skin, bone and corneas. It is our collective responsibility to sensitise government and decision makers to this national challenge, and to encourage our patients to inform next of kin of their intention to be organ donors and to register themselves as willing donors with the Organ Donor Foundation of South Africa (toll free 0800 22 66 11  website www.odf.org.za).

Thanks to Ms Sharon Munnik, Director of the Eye Bank Foundation of South Africa, for her help.

Corresponding author: D Meyer (dm2@sun.ac.za)