Authors :
Presenting Author: Carin Papendorp, PhD – Brown University
Brian Kavanaugh, PsyD – Assistant Professor, Child and Adolescent Psychiatry, Bradley Hospital; Carrie Best, MPH – Project Coordinator, Developmental Disorders Genetics Research Program, Bradley Hospital; Jennifer Elacio, BS – Brown University; Duyu Nie, MD/PhD – Hasbro Children's Hospital; Judy Liu, MD/PhD – Associate Professor, Molecular Biology, Cell Biology and Biochemistry, Brown University
Rationale:
Absent, small, or homeotic-like (ASH1L) is a highly penetrant gene associated with neurodevelopmental disease (NDD), including epilepsy, autism, and intellectual disability. Despite the clear link between ASH1L mutations and NDD, ASH1L-related NDD is poorly understood because thorough and longitudinal clinical characterization of humans with ASH1L-related NDD has never been done. A major goal of our laboratory is to perform human clinical trials to improve the lives of children with ASH1L mutations. Before investigational drug trials can begin, however, researchers must first understand the baseline symptoms and clinical course of ASH1L mutations. The FDA has stated that “data... from a natural history study may provide an untreated, external control group for... an investigational drug trial,” obviating the need for a placebo group in later clinical trials. In the case of rare NDDs like ASH1L, the relatively small affected population makes it especially undesirable to randomize half of the participants to a placebo group. Overall, a natural history study is a crucial first step towards understanding and ameliorating ASH1L-related NDD.
Methods:
The design of this study is a prospective observational natural history study. Participants receive neuropsychological testing to measure symptoms of autism, adaptive functioning, and verbal and non-verbal intelligence, and we perform a neurological examination. During the study visit, participants also undergo electroencephalography to detect seizures and measure resting-state brain rhythms. Along with the measures performed during study visits to Brown, we review all past medical records.
Results:
About fifty percent of humans with ASH1L mutations (eight out of seventeen) had seizures. Clinical EEGs show ~3Hz generalized spike and wave discharges accompanied by behavioral pausing characteristic of atypical absence epilepsy. Most children have hyperventilation-induced seizures. Similar to the phenotype we have identified in a mouse model of ASH1L, some patients have had abnormal spiking activity and background slowing without overt seizures. In some cases, spiking activity appeared to precede the development of seizures by a few years. Possible sex differences exist in the prevalence of autism and epilepsy, with girls more likely to have epilepsy without autism and boys more likely to have autism without epilepsy.
Conclusions:
This study is the first to define the clinical phenotype of children with ASH1L mutations. A clear description of the ASH1L clinical phenotype will help families know what to expect when their child is diagnosed with a mutation in ASH1L. Baseline natural history data will pave the way for investigational drug trials to decrease seizure burden and improve the lives of children with ASH1L mutations. Finally, understanding which symptoms children and families find most difficult will allow researchers to prioritize research into those symptoms and select the best outcome measures for future clinical trials. Although this project pertains to a rare genetic cause of NDD, insights from this project may be extended to other epigenetic proteins whose mutations lead to NDD.
Funding: Autism Science Foundation Pre-Doctoral Fellowship