Behavior and learning publications

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Behaviour and learning publications

Behavioral Profile in RASopathies

Paolo Alfieri,Giorgia Piccini, Cristina Caciolo, Francesca Perrino, Maria Luigia Gambardella, Maria Mallardi, Laura Cesarini, Chiara Leoni, Daniela Leone, Chiara Fossati, Angelo Selicorni, Maria Cristina Digilio, Marco Tartaglia, Eugenio Mercuri, Giuseppe Zampino, and Stefano Vicari Dipartimento di Neuroscienze, Bambino Gesu` Children’s Hospital, IRCCS, Rome, Italy 2L.U.M.S.A. Libera Universita` Maria SS. Assunta, Rome, Italy 3Dipartimento per la Tutela della Salute della Donna della Vita Nascente del Bambino e dell’Adolescente, Catholic University, Rome, Italy Dipartimento di Pediatria, Neurologia e Psichiatria Infantile, Catholic University, Rome, Italy 5Ambulatorio di Genetica Clinica Pediatrica, Fondazione MBBM, A.O. San Gerardo, Monza, Italy Dipartimento di Genetica Medica, Bambino Gesu` Children’s Hospital, IRCCS, Rome, Italy Dipartimento di Ematologia, Oncologia e Medicina Molecolare, Istituto Superiore di Sanita`, Rome, Italy


Here, we describe neurobehavioral features in patients with RASopathies (i.e., Noonan syndrome, LEOPARD syndrome, Costello syndrome, and cardiofaciocutaneous syndrome), developmental disorders caused by mutations in genes coding transducers participating in the RAS-MAPK signaling cascade.

Parents of 70 individuals with a RASopathy were asked to fill out the following questionnaires: Child Behavior Checklist (CBCL), Social Communication Questionnaire version lifetime (SCQ-L), and Modified Checklist for Autism in toddlers (MCHAT). Data analysis indicated high rates of internalizing (37%) and externalizing problems (31%) on CBCL. Scores over the cutoff were documented in 64% of patients with cardiofaciocutaneous syndrome, 44% with Costello syndrome, and 12% with Noonan syndrome on SCQ-L/M-CHAT.

Our findings indicate that mutations promoting dysregulation of the RAS-MAPK cascade mark an increased psychopathological risk and highlight that autistic-like behavior could be underdiagnosed in patients with RASopathies.

Verbal Memory Functioning in Adolescents and Young Adults With Costello Syndrome: Evidence for Relative Preservation in Recognition Memory

David D. Schwartz,1* Jennifer M. Katzenstein,2 Elisabeth Hopkins,3 Deborah L. Stabley,4 Katia Sol-Church,4 Karen W. Gripp,3 and Marni E. Axelrad1

1 Section of Psychology, Department of Pediatrics, Baylor College of Medicine/Texas Children’s Hospital, Houston, Texas

2 Section of Neuropsychology, Department of Neurology, Indiana University School of Medicine, Indianapolis, Indiana

3 Division of Medical Genetics, A. I. duPont Hospital for Children, Wilmington, Delaware

4 Department of Biomedical Research, A. I. duPont Hospital for Children, Wilmington, Delaware

Costello syndrome (CS) is a rare genetic disorder caused by germline mutations in the HRAS proto-oncogene which belongs to the family of syndromes called rasopathies. HRAS plays a key role in synaptic long-term potentiation (LTP) and memory formation. Prior research has found impaired recall memory in CS despite enhancement in LTP that would predict memory preservation. Based on findings in other rasopathies, we hypothesized that the memory deficit in CS would be specific to recall, and that recognition memory would show relative preservation. Memory was tested using word-list learning and story memory tasks with both recall and recognition trials, a design that allowed us to examine these processes separately. Participants were 11 adolescents and young adultswith molecularly confirmed CS, all of whom fell in the mild to moderate range of intellectual disability. Results indicated a clear dissociation between verbal recall, which was impaired (M ¼ 69 14), and recognition memory, which was relatively intact (M ¼ 86 14).

Story recognition was highly correlated with listening comprehension (r ¼ 0.986), which also fell in the low-average range (M ¼ 80  12.9). Performance on other measures of linguistic ability and academic skills was impaired. The findings suggest relatively preserved recognition memory that also provides some support for verbal comprehension. This is the first report of relatively normal performance in a cognitive domain in CS. Further research is needed to better understand the mechanisms by which altered RAS-MAPK signaling affects neuronal plasticity and memory processes in the brain.

Autism traits in the RASopathies

Brigid Adviento,1,2 Iris L Corbin,1,2,3 Felicia Widjaja,1 Guillaume Desachy,1,2 Nicole Enrique,4 Tena Rosser,5 Susan Risi,1 Elysa J Marco,6 Robert L Hendren,1 Carrie E Bearden,4,7 Katherine A Rauen,2,8 Lauren A Weiss1,2


Background Mutations in Ras/mitogen-activated protein kinase (Ras/MAPK) pathway genes lead to a class of disorders known as RASopathies, including neurofibromatosis type 1 (NF1), Noonan syndrome (NS), Costello syndrome (CS), and cardio-facio-cutaneous syndrome (CFC). Previous work has suggested potential genetic and phenotypic overlap between dysregulation of Ras/MAPK signalling and autism spectrum disorders (ASD). Although the literature offers conflicting evidence for association of NF1 and autism, there has been no systematic evaluation of autism traits in the RASopathies as a class to support a role for germline Ras/MAPK activation in ASDs. Methods We examined the association of autism traits with NF1, NS, CS and CFC, comparing affected probands with unaffected sibling controls and subjects with idiopathic ASDs using the qualitative Social Communication Questionnaire (SCQ) and the quantitative Social Responsiveness Scale (SRS). 

Results Each of the four major RASopathies showed evidence for increased qualitative and quantitative autism traits compared with sibling controls. Further, each RASopathy exhibited a distinct distribution of 

quantitative social impairment. Levels of social responsiveness show some evidence of correlation between sibling pairs, and autism-like impairment showed a male bias similar to idiopathic ASDs. Conclusions Higher prevalence and severity of autism traits in RASopathies compared to unaffected siblings suggests that dysregulation of Ras/MAPK signalling during development may be implicated in ASD risk. Evidence for sex bias and potential sibling correlation suggests that autism traits in the RASopathies share characteristics with autism traits in the general population and clinical ASD population and can shed light on idiopathic ASDs.

Longitudinal Course of Cognitive, Adaptive, and Behavioral Characteristics in Costello Syndrome

Marni E. Axelrad,1 David D. Schwartz,1 Julie E. Fehlis,1 Elizabeth Hopkins,2 Deborah L. Stabley,3 Katia Sol-Church,3 and Karen W. Gripp2*

1 Psychology Service, Department of Pediatrics, Texas Children’s Hospital, Psychology Section, Pediatrics, Baylor College of Medicine, Houston, Texas

2 Division of Medical Genetics, A. I. duPont Hospital for Children/Nemours Childrens’ Clinic, Wilmington, Delaware

3 Department of Biomedical Research, A. I. duPont Hospital for Children/Nemours Childrens’ Clinic, Wilmington, Delaware

Costello syndrome is a rare rasopathy caused by germline mutations in the oncogene HRAS resulting in increased signal transduction through the Ras/mitogen-activated protein kinase pathway. In contrast to the more common rasopathies, such as neurofibromatosis type 1 and Noonan syndrome, limited information is available on standardized cognitive testing in this cohort. Past research indicated a mean average IQ in the mild mental retardation range, with strengths in fluid reasoning (FR) and weakness in expressive language, as well as static skills over time.

Here we report on standardized IQ and adaptive functioning in 18 individuals with Costello syndrome, nine males and nine females, and longitudinal development for 11 who had previous testing. The overall IQ, ranging from severe mental retardation to the average range, with a mean in the mildly mentally retarded range, was again found to be stable, but an interesting pattern in the development of nonverbal FR was identified. Participants showed an improvement in nonverbal FR, followed by stable skills thereafter, suggesting a ‘‘late bloomer’’ effect in late childhood/early adolescence. Overall adaptive functioning fell into the range of Intellectual Disability for 70% of subjects, with Socialization as a relative strength and Daily Living Skills an area of relative difficulty. Interestingly, females were found to be higher functioning than males in all domains, including Communication, Daily Living Skills and Socialization. Caregivers reported significantly more behavioral concerns in males, including internalizing, externalizing, and other maladaptive behaviors. In contrast, no gender differences were found in cognitive or visuomotor functioning.

Neurocognitive, Adaptive, and Behavioral Functioning of Individuals With Costello Syndrome: A Review


Costello syndrome is a rare rasopathy resulting from germline mutations of the proto-oncogene HRAS. Its phenotype includes severe failure-to-thrive, cardiac abnormalities, a predisposition to benign and malignant tumors, hypotonia, and developmental delay. Costello syndrome is associated with cognitive impairment, including intellectual functioning generally in the mild to moderate range of disability, ommensurate adaptive functioning, and increased anxiety. Relative strengths have been found for nonverbal fluid reasoning (FR).

Gender effects have been reported, with females showing better adaptive functioning across domains. Developmentally, nonverbal skills plateau in late childhood/early adolescence, whereas the rate of vocabulary acquisition may increase in adolescence into early adulthood. Here we review the literature assessing cognitive, adaptive, and behavioral functioning in Costello syndrome, and weprovide data from an ongoing longitudinal study. Severity of cognitive impairment may depend upon the specific HRAS mutation, as three individuals with the p.G13C change showed average nonverbal FR skills and borderline-to-low average overall nonverbal IQ. Further, separation anxiety is more common in Costello syndrome than in the general population, affecting 39% of this cohort, and males are more often overly anxious than females. Interrelations between anxiety and cognitive and adaptive functioning were found, pointing to functional difficulties as a likely source of stress and anxiety. Taking into account data from animal models, cognitive and behavioral changes likely originate from abnormal differentiation of neuronal precursor cells, which result in structural and functional brain differences.