Researchers Identify Genetic Defects Causing North Carolina Macular Dystrophy

January 08, 2016

For Kent Small, M.D., the formidable, 28-year search for the gene mutations causing the rare retinal disease known as North Carolina macular dystrophy (NCMD) was highly personal and career-defining.

“My first academic position after leaving Duke did not work out so well because, against the wishes of my chairman, I went to Marshfield, Wisconsin, for two weeks to learn genetic testing methods from Dr. James Weber to help find the NCMD genes,” recalls Dr. Small. “I made a commitment to the families with NCMD and became too deeply entrenched in the pursuit of this disease to ever give up. It consumed me sometimes at considerable cost personally, emotionally and financially.”

But thanks to his collaboration with 12 affected families and 20 researchers — including Ed Stone, M.D., Ph.D., at the University of Iowa, who provided powerful, state-of-the-art genetic discovery technologies for the effort — Dr. Small finally got his answer. Mutations involving the genes PRDM13 and IRX1 were identified as the culprit. The first mutations in both genes were difficult to find, because they were located outside of genetic regions known as exons, which code for proteins and are where disease-causing defects are most likely to occur. Results of the long-standing research project were published recently in the journal Ophthalmology.

Dr. Small saw his first case of NCMD in 1987 as a resident at the Veterans Administration hospital in Asheville, North Carolina, on rotation from Duke University. “I had recently connected with Ed Stone, and he expressed a commitment to me to throw enough energy and resources at the problem,” says Dr. Small. “He and his lab, especially Dr. Adam DeLuca, met the challenge with swift and effective bioinformatics.”

NCMD is an inherited form of macular degeneration, which can cause widely varying levels of central vision loss, even within the same family. The disease is generally not progressive, meaning it doesn’t get worse over time. Rather, it causes problems with development of the central region of the retina known as the macula. It can be diagnosed in adults as well as young children, even infants.

NCMD is an autosomal dominant condition, which means that an affected person has a 50-percent chance of passing it along to a child. While the disease affects people around the world, it got its name because the first large family diagnosed was from North Carolina.

NCMD is similar in several respects to age-related macular degeneration (AMD). Both conditions can cause drusen, toxic waste products, which accumulate underneath the retina. Also, both diseases cause central vision loss. Dr. Small says that research into NCMD is helping to better understand and treat AMD, and vice versa.

Dr. Stone adds that the NCMD gene discovery will help scientists learn how the macula develops so they can reconstruct a damaged macula using retinal tissue derived from induced pluripotent stem cells (iPSCs). Dr. Stone’s collaborator, Budd Tucker, Ph.D., produces iPSCs by taking blood and skin samples from patients and turning back the clock so they revert to a stem-cell state. The iPSC are then coaxed to become retinal cells, which can be used to study diseases and develop therapies.

Dr. Small says that his obsession with NCMD has enabled him to develop rewarding collaborations and make many good friends. “There are many people I can thank, but I will always especially be grateful to Drs. Margaret Pericak-Vance and Jeffrey Vance who are now at the University of Miami, for helping me get my first grant at Duke and for being such outstanding examples of true scientists.”

Dr. Small is a solo retina specialist in Glendale, California, and affiliated with Cedars-Sinai Board of Governors Regenerative Medicine Institute in Los Angeles.