Detecting a Stealthy Genetic Disease

UNC-CH researchers have taken the first step toward clinical screening for neurofibromatosis, a genetic disorder affecting an estimated 100,000 Americans.

Neurofibromatosis targets the skin and other tissues, with symptoms ranging from freckles to larger areas of pigmentation called cafe-au-lait spots to benign nerve tumors to mental retardation. The disease is difficult to diagnose because the symptoms vary widely and may not emerge until adolescence. In addition, nearly 50 percent of the cases occur de novo--the patient's parents are neither affected nor carriers and cannot be predicted by family histories.

However, a technique that holds promise as a future diagnostic test was identified by Ruth Heim, formerly a post-doctoral fellow in Larry Silverman's laboratory in the Department of Pathology. In collaboration with Mike Luce, a scientist previously at the biotechnology company LabCorp, Heim showed that a "protein truncation test" identified mutations in two-thirds of the clinically diagnosed patients who were tested. This success rate is a large improvement over genetic screening techniques, which identify neurofibromatosis mutations only one-fifth of the time.

The neurofibromatosis gene is immense--ten to twenty times larger than many human genes--so genetic tests, which search an entire gene for mutations, are impractical. The more efficient protein truncation test, developed by researchers in the Netherlands to look at another huge gene, screens the protein instead of the gene. The test identifies abnormally short versions of the protein, with the protein's length providing a clue to the location of the mutation. Heim realized that many neurofibromatosis mutations lead to such truncated proteins.

The next step toward a clinical test is to correlate the locations of the mutations with the severity of the illness. Silverman and Rosann Farber, an associate professor of pathology, will work with Arthur Aylsworth and Robert Greenwood, co-directors of the Neurocutaneous Disorders Clinic, to establish that connection.

If they succeed, doctors may be able to predict the type and the acuteness of symptoms. Such a test could lead to earlier intervention, which would ameliorate some effects, particularly learning difficulties.

Heim thinks clinical screening could change the definition of the disease by including patients whose symptoms are not yet recognized as neurofibromatosis.

Heim was funded by the Texas Neurofibermatosis Foundation and the North Carolina Biotechnology Center.

-- Elizabeth Zubritsky