PVNH: Could this genetic disorder have a ‘butterfly’ effect?

The butterfly effect is defined as “the sensitive dependence on initial conditions, where a small change at one place in a deterministic nonlinear system can result in large differences to a later state.” In medicine, the identification of a rare disease or a genetic mutation may provide insights that spread well beyond the initial discovery.

And in genetics, scientists are learning just how widespread the effects are for mutations in one gene: filaminA (FLNA).

FLNA is a common cause of periventricular nodular heterotopia (PVNH), a disorder of neuronal migration during brain development. The syndrome was first described by the late Peter Huttenlocher, MD, and the gene was identified by Christopher Walsh, MD, PhD, of Boston Children’s Hospital.

In normal brain development, neurons form in the periventricular region, located around fluid-filled ventricles near the brain’s center, then migrate outward to form six onion-like layers. In PVNH, some neurons fail to migrate to their proper position and instead form clumps of gray matter around the ventricles.

The incidence of PVNH is unknown. While boys with the mutation die early, PVNH usually becomes evident in girls when seizures appear, often during the teenage years; other neurologic findings such as learning disability are not uncommon. Joint, pulmonary and gastrointestinal complications have been reported, but one of the most life-threatening complications for these young patients is cardiovascular disease.

Walsh, director of the Brain Development in Genetics (BrDG) Program, and cardiologist Ming Hui Chen, MD, MSc, have been investigating the genetic and cardiovascular ramifications of PVNH. Married for more than 20 years, they have together revealed more about the disease. “This has become a lifelong passion of ours,” Chen says.

Walsh first described the localization of the PVNH gene to the X chromosome in 1996. (About 50 percent of cases are genetically linked to the X chromosome; the rest are thought to be spontaneous mutations.) In 2005, they jointly published a paper describing PVNH’s clinical association with Ehlers-Danlos Syndrome, a genetic disorder affecting the connective tissue. Chen has further helped analyze the mechanisms for development of congenital heart disease; in 2006, she and Walsh described the cardiac and vascular effects of FLNA mutations in the first mouse model.

Help for patients with PVNH

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

Ming Chen with a patient with PVNH

The clinic recently began accepting patients. A little girl named Sophie, traveling with her family from Washington State, was the first to arrive. She was adeptly diagnosed in utero in 2007 by her local specialists—the nodules around the brain ventricles are often visible on ultrasound—although very little was known about the disease at the time. Her doctors did note that “it could affect any organ at any time,” recounts Sophie’s mother, Amy Joy. “We had a paragraph explaining the disease, and we were encouraged to contact the National Organization for Rare Disease (NORD), but there was very little else they could do for us.”

In fact, at the time, NORD did not have any information on the disease. After scouring the Internet for information, Amy Joy came across Walsh’s paper, which she brought to varied specialists in her area after Sophie was born.

For the first seven years of life, most of Sophie’s symptoms were gastrointestinal, including explosive diarrhea. Most of the specialists who saw Sophie dealt with her symptoms in isolation, because they were unfamiliar with the underlying problem of PVNH, explains Amy Joy. Over the past year, Sophie’s condition started to impact additional organs, causing an enlarged bladder and chronic headaches.

Most recently, she was diagnosed with several heart complications, including borderline dilated aortic root, borderline dilated left ventricle and left ventricle fractional shortening, as well as trivial mitral and bicuspid valve insufficiency. Her parents believed a complete diagnostic work-up and a genetic screen of their daughter and themselves would help inform them about potential complications resulting from PVNH and preventive strategies to minimize cardiac risk.

Walsh and Chen are still at the early stages of understanding the full spectrum of the disease and its varied presentations, as well as the incidence rate of PVNH and its manifestations. Their passionate quest, along with other researchers, may help uncover the extent of this condition’s “butterfly” effect.