Learning Disability in RASopathies

Abstract

Learning disabilities are relatively common conditions in pediatric population. The incidence of learning disability ranges from 1% to 17%, reflecting that learning disability may be not a single clinical entity but a wide distribution of cognitive traits in the population. As reported by the American Association on Intellectual and Developmental Disabilities (AAIDD), among the prenatal learning disability causes, chromosomal disorders, genetic syndromes, and inborn errors of metabolism must be taken into account. In this chapter, we will focus the attention on RASopathies, genetic disorders characterized by germline mutations in the RAS-MAPK pathway whose role is crucial in the regulation of the cell cycle, differentiation, growth, and cell senescence. This group of disorders includes Noonan syndrome, neurofibromatosis type 1, Costello syndrome (CS), Legius syndrome, Noonan syndrome with multiple lentigines, and cardiofaciocutaneous syndrome. Mutations in RAS-MAPK pathways lead to impairments in synaptic plasticity, necessary for normal brain function, especially for learning and memory. Variation across the RAS/ MAPK pathway syndromes suggests that different gene mutations affecting this pathway can have markedly different developmental effects.

Neuron type-specific expression of a mutant KRAS impairs hippocampal-dependent learning and memory

“…Common features of RASopathies are growth delay, congenital heart defects, and short stature 3 – 6 . Patients with RASopathies also show a wide range of cognitive deficits from mild learning defects to severe intellectual disabilities 4 , 7 , 8 .…”