Enrollment Begins For Study Linking Rare Diseases to Autism Spectrum Disorders
Cincinnati Children’s Hospital Medical Center is a primary site for a large, five-year study that represents a crucial step forward in the treatment of autism spectrum disorder and intellectual disability. The study will enroll patients ages 3 to 21 with tuberous sclerosis complex (TSC), Phelan-McDermid syndrome and PTEN Hammertoma syndrome who also have an autism spectrum disorder and/or intellectual disability. These three rare genetic conditions exhibit similar clinical features—as well as similar biochemical pathways that seem to influence synaptic development.
The five-year study is funded by the National Institute of Neurological Disorders and Stroke. Participating medical centers are seeking to enroll 100 patients with TSC, 90 with Phelan-McDermid syndrome and 140 with PTEN Hammertoma syndrome mutations. Each site will operate independently, but use similar methodology that will allow researchers to compare data across all patient groups.
Darcy Krueger, MD PhD, director of the Tuberous Sclerosis Complex Clinic at Cincinnati Children’s, is principal investigator for the TSC component of the study, titled “Autism Spectrum Disorder and Intellectual Disability Determinants in Tuberous Sclerosis Complex.” Cincinnati Children’s opened enrollment to patients with TSC in April 2015.
“The traditional approach to studying autism spectrum disorder and intellectual disability is to focus on idiopathic forms, which tend to be highly variable in terms of severity and symptom patterns,” Dr. Krueger says. “In contrast, our strategy focuses on TSC as a model—50 percent of affected individuals develop autism spectrum disorder and intellectual disability.”
Recent studies have made significant progress in identifying the underlying genetic, molecular and cellular basis of TSC, and have resulted in recent clinical approval of molecular-based treatments for several TSC disease manifestations. “The connection between TSC and the mTOR signaling pathway is well established,” Dr. Krueger explains. “mTOR regulation also is important for Phelan-McDermid and PTEN Hammertoma, so we hope this study will help researchers better understand how that pathway affects neuron maturation and synapses in these diseases, all of which correlate to a high incidence of autism spectrum disorder and intellectual disability.”
Children participating in the TSC study will be evaluated longitudinally at baseline, 6 months, 12 months, 18 months and 24 months. At each time point, they will undergo standardized observational assessments using cognitive and adaptive measures for autism spectrum disorder and intellectual disability. Investigators will collect clinical data, including medication use, seizure history, interventional therapies and medical comorbidities, to determine if specific clinical factors independently modify the course of autism spectrum disorder and intellectual disability development in TSC.
“At least once a year, patients will undergo magnetic resonance imaging with advanced diffusion tensor imaging,” Dr. Krueger says. “We hypothesize that longitudinal assessment of brain connectivity with advanced MR imaging focusing on white matter and the cerebellum can be used as a surrogate marker of neurodevelopmental deficits. If so, it is possible that cerebellum is involved with brain functionality, as well as with movement as classically thought.”
This study expands areas of investigation in the underlying mechanisms of autism disorder spectrum and intellectual disability, which utilized the same advanced MRI and EEG technology and comprehensive autism and cognitive assessment tools in patients with TSC. This includes studies sponsored by the TSC Autism Center of Excellence Network, which is still recruiting TSC patients between 3-12 months of age.
To learn about eligibility requirements for the autism-TSC study, please contact Dr. Krueger by email.