Cognitive profile of disorders associated with dysregulation of the RAS/MAPK signaling cascade

Abstract

Mutations in genes coding for transducers participating in the RAS/MAPK pathway have been identified as the molecular cause underlying a group of clinically related developmental disorders with cognitive deficits of variable severity. To determine the spectrum of cognitive defects associated with dysregulation of this signal cascade, we studied the profile of cognitive abilities in patients with mutations affecting the PTPN11, SOS1, HRAS, KRAS, BRAF, RAF1, and MEK1 genes and phenotype-genotype correlations. Our findings support the observation that heterogeneity in cognitive abilities can be at least partially ascribed to the individual affected genes and type of mutation involved. While mutations affecting transducers upstream of RAS were less frequently associated with mental retardation, mutations in downstream components of the pathway were generally associated with a more severe cognitive impairment. Among patients with a heterozygous PTPN11 mutation, the T468M substitution was associated with a mean IQ significantly higher compared to that of individuals carrying the N308D change. Our study provides insights on the range of cognitive abilities in patients with gene mutations causing dysregulation of RAS signaling suggesting that the presence and severity of cognitive involvement can be predicted in part by the gene involved.

Neuropsychological Functioning in Individuals with Noonan Syndrome: a Systematic Literature Review with Educational and Treatment Recommendations

“…In one study, intellectual functioning of children with SOS1 mutations was found to be significantly higher than those with PTPN11 mutations, as well as those with unknown mutations (Pierpont et al 2009), although the sample size of the SOS1 mutation group was relatively small. This finding is consistent with other reports suggesting that, in the absence of complicating neurological features such as seizures, most people with SOS1 mutations have intellect within the average range and attend regular education classrooms (Tartaglia et al 2007;Cesarini et al 2009). In general, behavioral and adaptive functioning of children with SOS1 mutations tends to be consistent with those with PTPN11 mutations and those of other children with a clinical diagnosis of NS (Pierpont et al 2010b;Pierpont et al 2015;Alfieri et al 2014).…”

“…A number of studies have shown that mutations in genes acting more downstream in the RAS-MAPK pathway (e.g., BRAF, MEK 1, MEK2, HRAS), which typically cause CFC syndrome and Costello syndrome, tend to be associated with greater impairments in neurological, intellectual, and adaptive functioning than mutations in genes encoding components or regulators that act more upstream in the pathway (e.g., NF1, PTPN11, SOS1, RAF1), which cause NF1 and NS (Cesarini et al 2009;Pierpont et al 2010b;Yoon et al 2007). Individuals with gene mutations acting downstream in the pathway (especially those diagnosed with CFC syndrome) also tend to have a higher prevalence of autisticlike traits (Adviento et al 2014;Alfieri et al 2014).…”

“…Studies reporting on individuals with RAF1 mutations typically find that intellectual and adaptive functioning is commensurate with individuals with other NS gene mutations (Cesarini et al 2009;Pierpont et al 2010b;Alfieri et al 2014). Neuropsychological functioning in individuals with NRAS, CBL, and RIT1 mutations is largely unknown.…”

“…Neuropsychological functioning in individuals with NRAS, CBL, and RIT1 mutations is largely unknown. There is some evidence to suggest that individuals with KRAS and SHOC2 mutations may experience greater severity of neurological deficits and developmental delay compared to other children with a diagnosis of NS, with intellectual disability being relatively common (Lee et al 2011;Cesarini et al 2009;Alfieri et al 2014;Gripp et al 2013).…”

“…Further, understanding the similarities and differences between NS and other distinct RASopathies (e.g., NF1) can also bring us to a better understanding of the variable clinical manifestations of RAS pathway anomalies. Only a handful of articles have evaluated individuals with multiple different RASopathies within the same study (e.g., Alfieri et al 2014;Adviento et al 2014;Pierpont et al 2010b;Cesarini et al 2009). This type of neuropsychological research can be challenging, as measures that are used to study one population may not easily be applied to other groups due to differences in phenotypic presentation and neurological involvement.…”