2016
Gatlinburg Conference Symposium
SS‐14 Symposium Title: Can Rare Disorders Pave the Way to Targeted Interventions for Autism Spectrum Disorders (ASD) and Intellectual Disability (ID)? Insights Gained from Fragile X Syndrome, Tuberous Sclerosis Complex, and Dup15q Syndrome Chair: Shafali S. Jeste1 2 Discussant: Julian Martinez1 Overview: Precipitated by rapid advances in diagnostic methods, from the chromosomal microarray to whole exome sequencing, routine clinical genetic testing is now recommended for the etiological evaluation of all children with new diagnoses of neurodevelopmental disorders, including global developmental delay, Intellectual Disability (ID) and Autism Spectrum Disorder (ASD) (Shevell et al, 2003; de Vries et al., 2005; Schaefer et al, 2013; Moeschler et al, 2014). This surge in genetic testing has facilitated the identification of causative rare genetic variants and, with the ascertainment of subgroups of individuals with shared variants, the identification of clinically meaningful genetic syndromes (Jeste and Geschwind, 2014). To date, detailed developmental and behavioral characterization of these syndromes has lagged behind the genetic diagnoses, leaving considerable uncertainty at the time of diagnosis regarding developmental trajectories, prognosis and recommended treatment options. Interventions remain broad in focus, targeting the neurodevelopmental diagnoses (such as ASD or ID) rather than specific features of cognition or social communication that may define a particular syndrome. This considerable dissociation between the precision of genetic testing and the imprecision of clinical treatment may be addressable and represents a critical challenge in neurodevelopmental disorders. Improved and precise behavioral characterization of genetic syndromes associated with ID and ASD can inform not only prognosis, but also treatment, with the ultimate goal of facilitating the discovery of targeted, mechanism‐based interventions that may improve individual outcomes. Paper 1 of 3 Paper Title: The Comorbidity of Fragile X Syndrome and Autism Spectrum Disorder: Failed and Potential Insights Authors: Len Abbeduto3 4, Andrea McDuffie3 4, Angela J. Thurman3 4 Introduction: More than half of individuals with fragile X syndrome (FXS) also meet diagnostic criteria for autism spectrum disorder (ASD). This high rate of comorbidity has led to claims that because FXS is an etiologically "simpler" (i.e., a single‐gene) disorder, it provides a ready window into the more etiologically complex nonsyndromic ASD (Belmonte & Bourgeron, 2006). Moreover, the high comorbidity has led to the claim that targeted pharmaceutical treatments that are efficacious for core symptoms of FXS are likely to be beneficial for nonsyndromic ASD as well (Berry‐Kravis et al., 2012). Arguably, however, few insights into nonsyndromic ASD have yet to come from research on FXS, and no pharmaceutical treatments developed for FXS have had documented benefit for core symptoms of ASD. In part, the failure of research on FXS to advance the understanding and treatment of ASD reflects the fact that although the comorbidity of the two disorders was first recognized over 30 years ago (Brown et al., 1982), there is still much that we do not understand about the comorbidity. In fact, many of the claims about the potential for synergy between research on FXS and nonsyndromic ASD derive from the assumption that ASD symptoms reflect the same underlying psychological and neurobiological impairments in both disorders. Methods: In the proposed presentation, we will argue that this assumption is probably not correct. We will present evidence from published and unpublished findings from our laboratory that strongly suggest that ASD symptoms in FXS and in 1
University of California, Los Angeles Center for Autism Research and Treatment 3
University of California, Davis 4
UC Davis MIND Institute 2
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Gatlinburg Conference Symposium
SS‐14 nonsyndromic ASD reflect at least partly different underlying impairments. We will summarize four sets of findings relevant to understanding the FXS‐ASD comorbidity. Results: First, we will present data on the symptoms that lead to the diagnosis of ASD in FXS and the nonsyndromic case, thereby providing evidence of differences in the symptom profiles "earning" affected individuals the diagnosis. Second, we will present data on behaviors and impairments that, although not diagnostic of ASD, are nonetheless correlated with the diagnosis or correlated with ASD symptom severity, which again point to important differences between FXS and nonsyndromic ASD. Third, we will present data on differences in the developmental trajectories of ASD symptoms in FXS and nonsyndromic ASD. Fourth, we will present data on the symptoms and correlates that distinguish individuals with FXS who receive an ASD diagnosis from those with FXS who do not receive the diagnosis. Discussion: Together, these data suggest that although there are similarities between the ASD symptoms and profiles of FXS and nonsyndromic ASD, there are numerous clinically important differences as well. We will conclude the presentation by suggesting that use of the categorical diagnosis of ASD in FXS obscures important differences within the syndrome and between the syndrome and nonsyndromic ASD and is thus, a barrier to scientific progress and to the development of effective treatments. Instead, we favor focusing on individual symptoms or constellations of symptoms in future research, including studies designed to evaluate treatment efficacy. References/Citations:  Belmonte, M. K. & Bourgeron, T. (2006). Fragile X syndrome and autism at the intersection of genetic and neural networks. Nature Neuroscience, 9(10), 1221‐1225.  Berry‐Kravis, E. M., Hessl, D., Rathmell, B., Zarevics, P., Cherubini, M., Walton‐Bowen, K., ... Hagerman, R. J. (2012). Effects of STX209 (Arbaclofen) on neurobehavioral function in children and adults with fragile X syndrome: A randomized, controlled, phase 2 trial. Science in Translational Medicine, 4, 152ra127.  Brown, W.T., Friedman, E., Jenkins, E.C., Brooks, J., Wisniewski, K., Raguthu, S., French, J.H. 1982). Association of fragile X syndrome with autism. Lancet, 9, 100. Paper 2 of 3 Paper Title: Characterizing Early Developmental Trajectories and Social Communication Profiles in Tuberous Sclerosis Complex Authors: Kandice Varcin5 6, Shafali S. Jeste1 2, Amanda Gulsrud1 2, Charles Nelson5 6 Introduction: Tuberous Sclerosis Complex (TSC) is an autosomal dominant genetic disorder resulting from a TSC1/TSC2 mutation. This genetic disorder confers a high risk for neurodevelopmental disorders, including autism spectrum disorder (ASD) and intellectual disability (ID) (Curatolo, 2015). Up to 80% of children with TSC will experience cognitive delay and up to 60% will meet criteria for ASD (Jeste, 2008). Importantly, ID and ASD often co‐occur in this population, posing challenges for diagnosis, intervention targets and treatment selection. The high rate of ASD and ID, combined with the fact that TSC is often diagnosed prior to the onset of any social communication or cognitive delays, has led to TSC being studied as a "model system" for neurodevelopmental disorders in both animal and human research. However, despite hypotheses about the role of epilepsy, cortical pathology, and co‐occurring genetic mutations in predicting neurodevelopmental outcomes in TSC, no single clinical factor has been identified as a consistent predictor of atypical neurodevelopment. Moreover, beyond prevalence rates, we know relatively little about the cognitive and phenotypic profiles of children with TSC and the degree to which these profiles show 5
6
Boston Children's Hospital Harvard Medical School Page 2 of 5 2016
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SS‐14 convergence with non‐syndromic ASD. In this context, we recently conducted the first prospective, longitudinal study of early development in infants with TSC (Jeste, 2014). We aimed to (1) characterize early developmental trajectories in TSC, (2) identify prospective risk factors of ASD and ID that would allow us to define the timing and emergence of developmental delays, and (3) compare cognitive and behavioral profiles in TSC to non‐syndromic ASD and typical development. Collectively, we aimed to move beyond diagnostic categorization to a deeper and more fine‐grained characterization of early development in this high‐risk group in order to inform intervention targets. Methods: Infants with TSC were recruited as early as 3‐6 months of age and followed longitudinally until 36 months of age. We took a multi‐modal approach to characterize behavioral, neurophysiological and clinical changes in early development. Data gathered at each time point included detailed seizure history, developmental testing using the Mullen Scales of Early Learning (MSEL), social‐communication assessments including the Autism Observation Scale of Infancy (at 6, 9 and 12 months) and the Autism Diagnostic Observation Schedule (ADOS) at 18, 24 and 36 months. We also collected eye tracking data in response to faces and electroencephalographic (EEG) data in baseline and event‐related conditions. Results: Infants with TSC show delays in cognitive development and social communication skills, particularly in the non‐verbal domain, as early as 6 months of age. Infants with TSC who develop ASD show the greatest cognitive impairment from 12 months age and a slowing of non‐verbal skills development between 12 to 36 months of age compared to infants with TSC without ASD (Jeste et al., 2014). Using EEG, we have demonstrated that non‐verbal delays do not appear to be rooted in deficits in low‐level visual processing and may instead represent impairments in networks associated with higher‐level cognitive processes (Varcin, 2015). Through a profile analysis, comparing individual item‐scores on the ADOS, we have identified a pattern of impairment in social communication and restrictive and repetitive behaviors in toddlers with TSC and ASD that closely maps that of toddlers with non‐syndromic ASD. Discussion: Our research to date has unveiled a developmental profile in TSC that is marked by prominent and early delays in non‐verbal skills, particularly in infants with TSC and ASD. Despite the prominence of intellectual disability and seizures, infants with TSC and ASD show a profile of social communication impairment that has almost complete convergence to that of children with non‐syndromic ASD. These results have laid the foundation for the first trial of early behavioral intervention in TSC. References/Citations:  Curatolo P, Moavero R, de Vries PJ. Neurological and neuropsychiatric aspects of tuberous sclerosis complex. Lancet Neurol. 2015 Jul;14(7):733‐45.  Jeste SS, Sahin M, Bolton P, Ploubidis GB, & Humphrey A (2008). Characterization of autism in young children with tuberous sclerosis complex. J Child Neurol.; 23(5):520‐5.  Jeste SS, Wu JY, Senturk D, Varcin K, Ko J, McCarthy B, Shimizu C, Dies K, Vogel‐Farley V, Sahin M, Nelson CA 3rd. Early developmental trajectories associated with ASD in infants with tuberous sclerosis complex. Neurology. 2014 Jul 8;83(2):160‐8.  Varcin KJ, Nelson CA 3rd, Ko J, Sahin M, Wu JY, Jeste SS.Visual Evoked Potentials as a Readout of Cortical Function in Infants With Tuberous Sclerosis Complex. J Child Neurol. 2015 May 26. Epub ahead of print. Page 3 of 5 2016
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SS‐14 Paper 3 of 3 Paper Title: Recent Advances in 15q11.2‐Q13.1 Duplications (Dup15q Syndrome): Identification of Symptom Profiles Within the ID and ASD Spectrum Authors: Shafali S. Jeste1 2, Charlotte DiStefano1 2, Amanda Gulsrud1 2, Larry Reiter7, Ronald Thibert8, Edwin Cook9 Introduction: Several chromosomal disorders, copy number variant (CNV) syndromes and single nucleotide variants have been associated with autism spectrum disorder (ASD) and Intellectual Disability (ID), with the number increasing recently at a relatively rapid rate (Schaefer, 2013; Moeschler, 2014). Duplications of the 15q11.2‐q13 region of maternal origin (Dup15q syndrome) were first associated with ASD and ID over 15 years ago, and now these duplications are amongst the most common CNV's associated with ASD and related neurodevelopmental disorders (Hogart, 2010). Through collaborative efforts facilitated by a national Dup15q alliance, studies have identified neurobiological, developmental and behavioral features of Dup15q syndrome that will guide targeted treatments, both behavioral and pharmacological. In the last year, we have been studying the behavioral and electrophysiological characteristics of children with Dup15q syndrome compared to IQ matched children with non‐
syndromic ASD in order to determine if there are distinctive features of the social‐ communication deficits and overall developmental profiles of children with Dup15q syndrome. Our study is driven by the hypothesis that there will be a distinctive developmental phenotype in children with Dup15q syndrome that will vary in severity across mutation size and location, and that this phenotype will be defined by expressive language and motor impairment with relatively preserved non‐verbal social abilities. We frame these findings in the context of larger, retrospective studies of the clinical symptom profile of children with Dup15q syndrome. Methods: The Dup15q Alliance has been collecting a registry of patients, with 425 patients in the registry and 212 with complete clinical records. From the registry, 142 children have isodicentric 15q duplications, 30 have interstitial duplications, 14 have mosaic isodicentric duplications, and 26 have "edge" duplications either at q11.2 or q13.3. We recruited a cohort of children from the UCLA Dup15q clinic for a comprehensive, developmentally targeted behavioral evaluation and compared them to an IQ and age matched cohort of children with ASD. Participants were assessed for verbal and non‐verbal cognition, ASD characteristics based on the Autism Diagnostic Observation Schedule (ADOS) and adaptive function based on the Vineland Adaptive Behavior Scales (VABS). Group comparisons were performed between Dup15q and ASD participants, as well as within the Dup15q group based on duplication type and epilepsy status. Results: Participants included 13 children with Dup15q syndrome and 13 children with non‐syndromic ASD, ages 22 months ‐ 12 years. Of the children with Dup15q syndrome, 10 participants had isodicentric and 3 had interstitial duplications. Four children had active epilepsy (all with isodicentric duplications). All children with Dup15q syndrome met criteria for ASD, but ASD severity scores were significantly lower than children in the non‐syndromic ASD group. ADOS profiles demonstrated a relative strength in items related to social interest. Children with Dup15q syndrome also demonstrated significantly more impairment in motor and daily living skills. Within the Dup15q group, children with epilepsy demonstrated significantly lower cognitive and adaptive function than those without epilepsy. Conclusions: The relative strength observed in social interest and responsiveness in the context of impaired motor skills represents an important avenue for intervention, including aggressive treatment of epilepsy, early and consistent focus on motor skills, and intervention targeting joint attention and language within a play context, in order to build on social interest to further develop social communication abilities. Longitudinal research beginning in early development will elucidate the temporal relationships between developmental domains and neurological comorbidities in these children at high risk for 7
University of Memphis Massachusetts General Hospital 9
University of Illinois Chicago 8
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SS‐14 neurodevelopmental disorders. Translational research, linking electrophysiological and behavioral phenotypes in mouse models to patients will facilitate the identification of the specific genetic mechanisms underlying the neurodevelopmental symptom profile in children with Dup15q syndrome. References/Citations:  Schaefer GB, Mendelsohn NJ: Clinical genetics evaluation in identifying the etiology of autism spectrum disorders: 2013 guideline revisions. Genet Med 2013, 15:399‐407.  Moeschler JB, Shevell M, COMMITTEE ON GENETICS: Comprehensive Evaluation of the Child with Intellectual Disability or Global Developmental Delays. PEDIATRICS 2014, 134:e903‐e918.  Hogart A, Wu D, LaSalle JM, Schanen NC: The comorbidity of autism with the genomic disorders of chromosome 15q11.2‐q13. Neurobiology of Disease 2010, 38:181‐191. Page 5 of 5