Boston Children’s Is Leading a Rare Genetic Syndrome Study

Boston Children’s Hospital will take the lead in a new study that will look at three rare genetic syndromes related to autism spectrum disorder (ASD) and intellectual disability (ID). The study will be a large collaboration between 10 medical centers, funded through a five-year, $6 million grant from the National Institutes of Health (NIH).

The rare genetic syndrome study’s ultimate goal, according to a report from Boston Children’s, is “to launch clinical trials of new treatments and develop ‘biomarkers’ that can be used to monitor treatment effectiveness—for the three rare syndromes and possibly for broader groups of ASD/ID patients.”

Through the grant, the 10 centers formed what they are calling the “Developmental Synaptopathies Consortium.” In addition to the NIH and Boston Children’s, the Consortium includes: Cincinnati Children’s Hospital Medical Center; Cleveland Clinic; Icahn School of Medicine at Mount Sinai; Rush University Medical Center; Stanford University; University of Alabama at Birmingham; University of California at Los Angeles; and University of Texas at Houston.

Boston Children’s outlines in a report the specific reasons why studying these genetic syndromes is important:

While both ASD and ID have a variety of known genetic causes, some of them have been shown to impair similar cellular pathways in the brain. The three conditions to be studied by the Consortium—tuberous sclerosis complex (caused by mutations in the TSC1 and TSC2 genes), Phelan-McDermid syndrome (caused by SHANK3 mutations) and PTEN Hamartoma Tumor Syndrome (caused by PTEN mutations)—seem to affect certain shared pathways influencing the development of brain connections, or synapses.

“To date, genetic studies indicate that there are about 500 to 1,000 genes that make people susceptible to ASD and ID,” says Mustafa Sahin, MD, PhD, a pediatric neurologist at Boston Children’s Hospital and the Consortium Director. “While it’s very unlikely that a single therapy could treat disorders with so many distinct causes, we may be able to find certain groups of patients who share defects in similar biochemical pathways and may respond to treatment with the same agents.”

For example, the finding that tuberous sclerosis complex results from disruption of the mTOR pathway have led Sahin and colleagues to test whether mTOR inhibitors can improve patients’ neurocognition. The Consortium investigators now plan to begin testing mTOR inhibitors in PTEN patients, since mTOR has also been implicated in their disease.

The study, which is expected to begin in the spring of 2015, will enroll 100 patients with tuberous sclerosis, 90 with Phelan-McDermid syndrome and 140 with PTEN mutations. Participants will be ages 3 to 21, and they will be followed for three to five years with physical examinations, neuropsychological testing, and advanced brain imaging. Boston Children’s notes that advocacy groups for each condition helped design the studies and are providing additional funding. These groups will notify their communities when the studies are opening enrollment. The groups are: the Tuberous Sclerosis Alliance; Phelan McDermid Syndrome Foundation; PTEN World; PTEN Life; and The Beatrice and Samuel A. Seaver Foundation.

“Through comparative analysis of pathology caused by multiple genes, we may find that treatments developed for one disorder might be applicable to others,” Sahin said in a statement. “A deeper understanding of this shared biology may also be a gateway to understanding the broader mechanisms of ASD and ID.”