Cardiology research translated to the bedside: C-BrDG clinic

Periventricular nodular heterotopia (PVNH), a neuronal migration disorder characterized by misplaced gray matter nodules in the brain, is commonly caused by mutations in the filaminA gene (FLNA). The syndrome was first described by the late Peter Huttenlocher, MD, and the gene identified by Christopher Walsh, MD, PhD, of Boston Children’s Hospital. Although neurologic findings such as learning disability and seizures are not uncommon, one of the most life-threatening complications for these young patients is cardiovascular disease. Joint, pulmonary and gastrointestinal complications also have been described.

For the last 20 years, two physicians from Boston Children’s, neurologist and geneticist Walsh, director of the BrDG (Brain Development in Genetics) Program, and cardiologist Ming Hui Chen, MD, MSc, have been investigating the genetics and clinical cardiovascular ramifications of PVNH. With the Walsh team, Chen has described PNVH’s clinical association with Ehlers-Danlos Syndrome in the literature and has further helped analyze the mechanisms for development of congenital heart disease.

While affected individuals are predominantly heterozygous females, males show early lethality. About 50 percent of affected females inherit the gene mutation from their mother and at least 50 percent have a de novo mutation. For women with X-linked PVNH, the risk of passing the mutation to each child is 50 percent. Because of the high rate of prenatal lethality in males, most sons born to women with X-linked PVNH are unaffected. Prenatal diagnosis by molecular genetic testing is possible if the disease-causing mutation has been identified in an affected relative. The periventricular nodules can be visualized by ultrasound examination as early as 24 weeks of gestation, but the sensitivity of this finding is unknown.

To serve as a comprehensive cardiovascular resource for PVNH patients who also frequently have multi-systemic disease, Chen recently founded and become the director of the cardiology clinic for the BrDG program, called C-BrDG (pronounced C-Bridge).

C-BrDG recently began accepting patients, the first of whom was a family traveling from Washington State to undergo genetic testing and clinical consultation by Walsh, Chen and their colleagues. Their daughter, Sophie, was adeptly diagnosed in utero in 2007 by her local specialists—when very little was known about the disease. Since birth, Sophie has had multiple complications to her different organs, and her parents believed a complete screen of their daughter and themselves would help inform them about potential complications resulting from PVNH and preventive strategies to minimize cardiac risk.

Still at the early stages of understanding the full spectrum of disease and its varied presentations, Boston’s Children’s BrDG Program uses a comprehensive, multidisciplinary approach, aligning genetics, neurology, cardiology, other medical specialists, genetic counseling and research to diagnose and advance management of patients with PVNH.