Mid-Atlantic Consortium Newsletter Summer 2013

Breakthrough for Sturge-Weber syndrome

Children with the Sturge-Weber Syndrome

Children with the Sturge–Weber Syndrome have “port-wine” birthmarks, as illustrated in the top photographs, as well as characteristic types of brain pathology, as seen in the bottom MRI scans (axial views). The neuropathology can affect the membranes surrounding the brain (seen as leptomeningeal enhancement – yellow arrows), internal structures involved in production of cerebrospinal fluid (seen as enlarged and enhanced choroid plexus – red arrow), and brain volume (seen as evidence of hemispheric atrophy – white arrows). Figure reproduced with permission of The New England Journal of Medicine.

A team of scientists  led by faculty of the IDDRC at the Kennedy Krieger Institute and Johns Hopkins University have discovered the gene mutation that causes Sturge-Weber syndrome, a rare condition with symptoms that may include impaired intelligence and related mental abilities, seizures, severe headaches, glaucoma and “port wine” colored birthmarks on the face. Identification of the altered gene, on chromosome 9, represents a major step toward development of new treatments, according to investigators.

“We have been working towards this crucial breakthrough for many years,” said Anne Comi, M.D., Director of the Hunter Nelson Sturge-Weber Center at Kennedy Krieger and co-senior author of a report of the  research in the New England Journal of Medicine.

A key observation was made by Matthew Shirley while working  in the laboratory of the co-senior investigator, Jonathan Pevsner, Ph.D., and the team included researchers at Duke University Medical Center and  the Medical College of Wisconsin, as well as people  at Kennedy Krieger and Johns Hopkins University. Identification of the mutation came through analyses of data collected by using whole genome sequencing, a technology that allows the billions of nucleotide pairs that form DNA to be examined. The DNA of affected and unaffected tissue was compared to find differences related to the disease, and in this case over  700 billion base pairs of DNA were analyzed, derived from just three pairs of affected/unaffected samples.

The research team predicted that affected individuals might have a mutation occurring during prenatal development. This would result in a condition called “somatic mosaicism,” in which some cells have the mutation causing the condition, while others do not. If their view were correct, then  affected and  unaffected tissue within the same individual should only differ with respect to disease-associated genes, although  some minimal level of random variation and background error always has to be ruled out of consideration.

By examining  affected and unaffected cells from three people with Sturge- Weber syndrome,1,294 candidate gene variants were identified, and sophisticated bioinformatics analyses eventually led to the identification of just one variant that was present in all  abnormal cells  and absent in unaffected cells. This “single-nucleotide”variant was in the GNAQ gene located on chromosome 9q21. The team’s subsequent findings confirmed that this mutation indeed causes Sturge-Weber syndrome and is also responsible for commonly occurring port-wine stain birth- marks.  The team identified the protein encoded by this gene. Such knowledge offers a strong foundation for future research targeting possible interventions and treatments.

Comi summarized the importance of these findings in a video posted on Kennedy Krieger’s website: “We have real hope in the next five to 10 years, perhaps sooner, perhaps a little later, that there will be new treatments for Sturge-Weber syndrome.” She referred to these new findings as a “game changer.”

Pevsner says whole genome sequencing technology, only recently available, “allows us to examine genetic variation at exquisite resolution. Moving forward, it is likely that we can apply this approach to other neurodevelopmental disorders wherever the underlying cause remains unclear.” Whole genome sequencing and other “high-throughput” methods are already being used in studies of these conditions, including intellectual disability and severe self-injurious behaviors, seen in many children in the Neurobehavioral Unit (NBU) at Kennedy Krieger.

Pevsner and his colleagues say they are planning to examine the DNA of these children to see if they can find genetic variants likely to be involved. In a pre- liminary study of just 14 affected children and their parents using microarray analyses, four individuals were found to have genetic mutations that have never been described previously. Normally, the DNA in each human chromosome is present in two complementary copies, one inherited from the father and one from the mother, the only exception being that males have only one “X” chromosome and one “Y” chromosome. Sometimes, though, an anomaly occurs and either extra DNA is present or some is missing. This type of mutation, present in these four individuals, is called a “copy number variation,” and one in partuclar, in which only a singled copy is present of a segment of chromososme 1 that includes several dozen key genes, was previously thought  to cause such severe consequences that survival would be impossible.

These data suggest that as many as 25-30% of children with intellectual disability and problem behaviors due to unknown causes have a still-unidentified mutation likely to be contributing to their severe disability, Pevsner and the team say. Thus, genetic studies of this population have great potential, and the research team plans to expand efforts to study many more affected children and their parents using next-generation sequencing methods.

While it’s always hard to predict the future, said Pevsner, this research ultimately could determine the pathways involved, and, eventually, contribute information that can guide the
development of new and more effective treatments.

Comments are closed.