RASopathies Research

What are the Rasopathies?

Much of Dr. Pierpont's research focuses on a group of genetically related genetic syndromes known as the "Rasopathies." These genetic syndromes are all caused by gene mutations affecting the RAS-MAPK pathway, which is a cellular signaling pathway important for a variety of developmental processes. The Rasopathies include Noonan syndrome, cardiofaciocutaneous (CFC) syndrome, Costello syndrome, neurofibromatosis type 1 (NF1) and more. A key journal article describing the genetics of the RAS-MAPK and the syndromes that result from mutations in this pathway can be found here.

All Rasopathy syndromes affect multiple systems of the body. Among the Rasopathies, features such as cardiac disease, growth deficits, facial characteristics, bone and skin abnormalities, and learning and behavior problems are common. However, there is incredible variation in the ways that individuals with Rasopathies develop. Some individuals experience life-altering neurological effects of their syndrome that impact almost every aspect of their daily lives. Other individuals with Rasopathies have such a mild form that their syndrome may not be detected until adulthood! Researchers are just beginning to learn how the specific molecular genetic characteristics of these syndromes interact with environmental variables to affect development and functioning of the body and brain. These are just some of the many reasons that the Rasopathies are exciting to study!

Noonan syndrome research

Much of the Rasopathies research Dr. Pierpont has completed to date examines the neuropsychological features of Noonan syndrome (NS). NS is a genetic syndrome characterized by short stature, cardiac disease, skeletal and skin anomalies, and variable learning disabilities. Mutations in the PTPN11, SOS1, KRAS, NRAS, RAF1, SHOC2, CBL, MEK1, and BRAF genes account for 60-80% of cases of clinically diagnosed NS. More genes are continually being discovered! Intellectual functioning in Noonan syndrome is generally within the average range, although there is a heightened risk for intellectual disability (ID). In one study, we found that children with mutations in the SOS1 gene typically did not demonstrate impairments in intellectual functioning. Individuals with mutations in PTPN11 and unknown mutations were a significantly higher risk for intellectual deficits, although the range of cognitive abilities in these individuals varied from moderately impaired to above average. The figure below shows the distributions of scores on a test of intellectual functioning among patients with different mutations.

Pierpont, et al. (2009) Genes, Brain & Behavior

In this study, we also found that children with NS who had better verbal intellectual functioning also tended to have better fine motor dexterity, better hearing ability on audiological testing, and parents with higher levels of education. Interestingly, while congenital heart disease was present among many patients in the sample, the severity of children's cardiac disease did not predict cognitive ability.

We have also conducted studies examining language abilities in children with Noonan syndrome. We found that children with NS are at higher risk for language impairments than the general population. Below is a pie chart depicting performance of a group of 66 children with Noonan syndrome on a standardized language test that is frequently used in clinical settings:

Mean standard score = 88.9, standard deviation = 20.3, range = 44 to 120

We found that language ability in NS was significantly correlated with nonverbal cognitive ability, articulation, hearing loss, manual motor skill and phonological memory. Therefore, children with language problems were more likely to have difficulties in other areas of development.

In study that was recently published in the American Journal of Medical Genetics, we investigated learning and memory abilities in children with Noonan syndrome. This study found that children with NS tend to have better recognition memory (i.e., the ability to recognize information they have previously seen when provided with choices) as compared to recall memory (i.e., the ability to retrieve information stored in memory in an organized way). This finding is significant both because it provides information regarding possible underlying brain regions that may be affected by NS, and also because it suggests that children with NS may better be able to demonstrate learning when tested in a recognition rather than a recall format. Intriguingly, another research group reported a similar finding of impaired recall memory relative to recognition memory in Costello syndrome. This suggests that brain development may be impacted in similar ways across the Rasopathies! Indeed, avenues for educational interventions relevant to NS may also be relevant to other genetically similar syndromes.

Our study of learning and memory provided other insights into learning differences in NS as well. First, we found that verbal memory was, on average, stronger than nonverbal (visual) memory and working memory. Working memory is the ability to hold information in mind for short periods while using it. Children with NS generally performed more poorly compared to the normative population on working memory tests. We also found that children with NS remembered information better when it was provided in a contextual format (e.g., stories) than when it was presented in a rote format (e.g., a list of unrelated words). Performance of children with NS on the standardized battery of memory and learning tasks is depicted below.

Performance of 29 children and adolescents with NS on subtests of the Wide Range Assessment of Memory and Learning, Second Edition (WRAML2).

If you are interested in learning more about neuropsychological functioning in individuals with Noonan syndrome, you may be interested in this review article! You can download it free from the publisher website.

Cardiofaciocutaneous syndrome research

Cardiofaciocutaneous syndrome (CFC), a rare RASopathy, is characterized by anomalies in the heart (cardio-), face (facio-) and skin (-cutaneous), as well as other bodily systems. Neurological impairments (e.g., hypotonia, seizures, macrocephaly) are common in CFC syndrome, as well as intellectual disability. Four different genes have been found to be associated with CFC (BRAF, MEK1, MEK2, and KRAS). The large majority of individuals with CFC (80-90%) have a mutation in the BRAFgene. Some of our past research on adaptive behavior in the RASopathies has included data pertaining to individuals with CFC syndrome.

There is a great need to better characterize the range of neuropsychological and behavioral functioning in CFC syndrome. In particular, little is know regarding social and emotional skills and challenges. In collaboration with Melinda Wolford at Youngstown State University, Dr. Pierpont recently conducted a study to investigate risk and protective factors that contribute to behavioral outcomes in this population. This study found that behavioral concerns in children with CFC, such as problems with focus/attention, withdrawn behaviors, aggressive behaviors or symptoms of anxiety, were highly related to problems with sensory modulation. In other words, children with CFC may engage in a number of behaviors to fulfill a sensory need or to avoid certain sensations that are overwhelming to them. This study also examined the relationship between behavioral and communication challenges and caregiver stress/well-being. Our results support a need for interventions to help families address functional communication barriers and concerns related to behavioral health.

Neurofibromatosis Type 1 research

Children and adolescents with neurofibromatosis type 1 (NF1) are at heightened risk for learning disabilities, attention difficulties and social-emotional challenges relative to same-aged peers. Our research group is currently conducting a study of social development in individuals with NF1 and Noonan syndrome. In particular, we are trying to understand which characteristics or behaviors contribute to poorer social competence in these populations and to design interventions to support better psychosocial adjustment in affected children. Dr. Pierpont and Dr. Hudock are developing an intervention curriculum for parents/caregivers of children with NF1 to help support families in coping with social-emotional concerns. We hope to make this intervention available to interested families in the near future!