RASopathies: a window into the molecular mechanisms underlying neurodevelopmental disorders

Cognitive impairments and congenital structural anomalies are the hallmarks of many genetic syndromes, but the biological links between these various abnormalities is not always obvious. As the cognitive limitations of many individuals with genetic syndromes are being studied with detailed neuropsychological tools, it has become clear that there may be specific patterns of cognitive impairments associated with specific disorders. As the underling molecular pathways that cause specific genetic syndrome are uncovered, their role in specific neurocognitive brain system is being better understood. This can provide us with important insights into the organization and operation of the brain. Noonan syndrome has fascinating genetic underpinnings, being recently identified as part of a constellation of genetic syndromes, known as the RASopathies, which all have a disruption in a common molecular signaling pathway, the RAS-mitogen activated protein kinase (MAPK) signaling pathway. Identification of this pathway has helped us understand how a wide range of mutations in different genes, all which sub-serve different aspects of the same molecular pathway, can cause a variety of overlapping symptoms. Understanding the role of this molecular pathway during various times in development reveals how one pathway can cause multiple abnormalities without obvious connections. Being downstream from the fibroblast growth factor receptor, disruption of the RAS-MAPK pathway during embryonic development disrupts neural crest cell development, causing defects in cardiac, craniofacial, and central nervous system structures. During post-natal life the RAS-MAPK pathway is involved in synaptic function, particularly in GABAergic neurons. While changes in GABAergic function in the hippocampus may lead to changes in memory and learning, disruption of GABAergic projections from the medium spiny neurons in the striatum interrupts feedback inhibition of excitatory glutamatergic and the dopaminergic pathways, leading to cortical inhibitory-excitatory imbalances. Complicating the understanding of the role of the RAS-MAPK pathway in neurodevelopment is the fact that both loss-of-function and gain-of-function mutations are associated with RASopathies and have been shown to have differential effects on brain function in animal models. Animal research has linked RASopathies to dysfunction of inhibitory brain circuits in prefrontal cortex and striatum that regulate attention and executive functions. Pierpont et al. provide empirical support for these basic research findings by comparing measures of attention and executive function between children with Noonan syndrome to their unaffected siblings. The study demonstrates that children with Noonan syndrome have greater impairments in specific aspects of executive and social-emotional function on parental-rated measures and objective measurement of attention and intelligence as compared to unaffected siblings. Interestingly, this study found that objective measures of sustained attention and response inhibition had a much stronger relationship to intelligence in the children with Noonan syndrome than their unaffected siblings, suggesting that the relationship between these two aspects of cognitive function may have developed differently in the children with Noonan syndrome than their siblings. The authors point out that it is important to consider these cognitive difficulties in children with Noonan syndrome and suggest that stimulant medications may be a helpful treatment. Although this represents an excellent study, it does suffer from some limitations which include the lack of objective executive and social functioning measurements, and of a second rater to confirm the parents’ observations. Additional medications besides stimulants may be useful for treating cognitive problems in children with Noonan syndrome. Specifically, animal studies suggest that synaptic dysfunction lies in the GABAergic neurotransmitter with secondary effects on dopamine and glutamate. Agents to manipulate GABAergic and glutamatergic neurotransmission have been applied to neurodevelopmental disorders such as autism and may be effective in children with RASopathies and autism symptomology. Clearly, as we learn more about molecular pathways such as the RASMAPK signaling pathway we can obtain a greater understanding of neurodevelopmental disorders, including other RASopathies, and develop more effective treatments.