Intellectual Difficulties in Noonan Syndrome
Brett | Mar. 18, 2018
Noonan Syndrome (NS) is one of many RASopathies -a group of conditions caused by mutations in genes coding for molecules in the RAS pathway. This pathway is responsible for and involved in many cellular functions and processes such as neural activity and plasticity which can unfortunately can lead to impairments in some areas of intellectual function. The RAS/MAPK cascade is involved in essential cell division, development and differentiation during nervous system development so it is logical that some intellectual or neurological issues may be present in people with mutations affecting this cascade. At present, the exact mechanisms responsible for learning difficulties in NS are still unknown.
However it must be remembered that the range of cognitive abilities in individuals with NS are large – from moderate intellectual disability at one extreme to superior intellectual abilities on the other! It is also worth noting that studies have consistently shown approximately 50-66% of NS individuals have average or above average intellect.
Two leading theories regarding NS and intellectual diffcutlies are that the RAS pathway mutations disrupt hemispheric brain function or hippocampus and prefrontal networks. This is because recall is more difficult for people with NS than recogniton and the former is performed in the hippocampus/prefrontal region and the latter in temporal cortical regions. Hippocampus dysfunction was also found in mouse models with NS that have shown memory and learning deficits caused by RAS-ERK mutations.
Thankfully the majority of people with NS (50-66%) perform at the average or above-average range on IQ tests. However there are particular cognitive and intellectual domains in which people with NS may have difficulty. Approximately 6% of people with NS will be diagnosed with intellectual disability and approximately 25% will have below average IQ.
Cognitive Difficulties Present in NS
A wide variety of cognitive difficulties have been recognised within the NS community. The RAS-ERK signaling pathways that are affected by the various genetic mutations responsible for NS have been identified in visual processing, verbal long term memory, language, learning, social emotional functioning and spatial awareness processes. NS is known to adversely affect memory, attention, visual processing, communication and executive functions.
Children with NS (and all RASopathies for that matter) show common learning difficulties such as impaired reading/vocabulary, visuospatial function, planning and organisational skills. Almost half of all children with NS have special education needs. Interestingly, longitudinal studies have shown that IQ improves over the lifespan within NS as adult IQ scores were significantly higher than childhood scores (+11 points on average!).
People with NS have better immediate memory for verbal information than visual information. Interestingly, immediate recall for verbal memory and verbal recognition are the only domains in which NS individuals don’t differ from non-NS individuals. NS people perform better with recognition tasks than they do with free recall tasks and delayed recognition is also better than delayed recall. Many people with NS have difficulty with visual memory and working memory. Working memory deficits may result in functional deficits in everyday tasks such as forgetting steps in an activity or becoming distracted during occupational performance.
Individuals with NS tend to have poorer attention skills than non-NS people and approximately 30% of people with NS have received a diagnosis of ADHD (Attention-Deficit-Hyperactivity Disorder). NS appears to affect auditory attention, sustained attention and impulse control which explains the high rate of ADHD diagnosis. However not all attention deficits demonstrated within NS result in an ADHD diagnosis but there is considerable overlap of symptoms. Some researchers believe ADHD may actually be more prevalent in NS than 30%. Thankfully attention difficulties are not always accompanied by or responsible for intellectual deficits. In fact over 70% of NS children with an ADHD diagnosis demonstrate average IQ.
Verbal skills of children with NS develop slower than non-NS peers and many children with NS will have difficulties with articulation. The average age of the first word in NS individuals is 15 months with simple two word phrases emerging at 31 months which is slower than non-NS peers. Almost 70% of children with NS receive speech therapy.
Verbal IQ is the one IQ domain that is consistently affected across all NS mutation types and the domain that improves the least over the lifespan. Hearing loss is more common in children with speech delay and many children with NS have frequent ear infections which may indicate environmental and/or structural reasons responsible for speech delay as well as neurological ones.
Refractory errors occur in almost 66% of people with NS and over 80% have difficulty with visual acuity. Visual deficits in Noonan Syndrome was covered in our previous Blog Post available here: Eye Issues In Noonan Syndrome
Obviously visual deficits can create learning difficulties particularly when these issues have not been identified. Both classroom (seating arrangements, material type presented etc.), and personal interventions (glasses/contacts etc.) can be initiated to address these difficulties.
Social skills competence is consistently identified in many studies as an area of difficulty for people with NS. Areas of concern identified are social immaturity, reduced social interaction and diminished insight in social settings but these are generally of only a mild to moderate level of impairment. Characteristics of Autism may be relatively common in NS but the vast majority of children with NS do not meet the full diagnostic criteria for Autism.
Intellectual Difficulties Vary Across Mutation Type
There appears to be no difference between NS subtypes on overall memory ability.
In one study, individuals with SOS1 mutations perform significantly higher on verbal and non-verbal cognitive tests than people with PTNP11 and other NS related mutations. However another study showed PTNP11 individuals to have better memory, attention and concentration.
There is evidence that ‘upstream’ mutations (genes involved earlier in the RAS pathway) such as PTNP11, SOS1 and RAF1 are less associated with low IQ. In fact, some studies have shown people with SOS1 mutations to have little to no intellectual deficits at all. ‘Downstream’ mutations (genes involved later in the RAS pathway process) such as HRAS, KRAS, RAF1, BRAF and MEK1 are more often associated with low IQ scores.
30% of people who have been diagnosed as having Noonan Syndrome with Multiple Lentigines (formerly LEOPARD Syndrome) have learning diabilities; most evident of which being verbal recall memory.
Regardless of mutation type there appears to be a link between the severity of physical dysfunction and intellectual dysfunction. This may be due to severe physical pathologies such as hearing loss, vision dysfunction, poor muscle tone/co-ordination or heart defects resulting in delays in starting, accessing or attending lessons/educational institutions at the same frequency as non-NS peers. This link may also be due to the severity of the mutation; meaning certain gene mutations will severely affect all functional areas – intellectual, socio-emotional and physical.
There are no known differences in intellectual performance between males and females with NS and having a familial inheritance of NS rather than a novel mutation does not appear to create additional cognitive deficits. However parental education level has been demonstrated to have a significant positive impact on the child’s cognitive abilities.
It is recommended that Neuropsychological evaluations of cognitive, adaptive and psychological domains be performed on all individuals with NS. Early diagnosis leads to earlier treatment and better long term outcomes. Also by assessing strengths and weaknesses early in the education experience, classroom materials, assessments and teaching methods can be tailored to the individual to maximise their chances of success.
Whilst professional assessment is a must it should be remembered that speech, motor or attention deficits can prevent accurate diagnosis during assessments thus any other identified issues should be communicated to the attending physician. For a great resource on which relevant health professional to see and when to see them view our Clinical Management Guideline here: Clinical Guide for NS.
There have been promising studies with using Lovastatin as it increases RAS-ERK activations and thus improves brain function and learning outcomes. In animal studies Lovastatin has reversed deficits in learning and memory in cases of RAS pathway errors.
Implications for the Classroom
Individuals with NS may have greater knowledge than they are able to demonstrate on free form testing. This presents a challenge for educators wishing to assess their true ability. As people with NS have better recognition than recall multiple choice testing is the best method for assessment.
As there is evidence of better performance with immediate verbal memory than delayed free recall tasks assessments are best done sooner after learning content than later.
Children with NS perform significantly better on verbal memory tasks than on visual memory or working memory tasks so being allowed to give answers orally and having complex questions broken into smaller subsections would be beneficial. Children with NS may require more time to complete their assessments also particularly if attention issues are noted.
There are other considerations for education besides assessments. Information within lessons and classes are best presented in a meaningful or contextual format as this will be better retained than learning by rote or repetition. Asking the student to repeat content back to the teacher can be a useful strategy.
Due to attention difficulties children with NS will often learn better with multiple short lessons rather than long blocks of uninterrupted content. Prepare children for transitions and review schedules both visually and verbally. You can pair the child up with a well organised peer if an Educational Assistant is unavailable. Allowing a fidget toy may help with sensory seeking behaviours which impede attention.
Physical and Visual Considerations
Children with NS are smaller physically on average and may need modified seating and desk equipment to improve comfort as discomfort will impede attention. Visual deficits such as shortsightedness and astigmatism are higher in NS and must be assessed for and remembered when positioning NS children in the classroom (e.g. shortsighted children should be in the front of the class rather than in the back).
The RAS pathway is critical in the development and execution of numerous cognitive functions and thus NS is adversely affected in many intellectual domains. Very few people with NS suffer from intellectual disability and the majority of NS individuals have average to above-average IQ. Childhood IQ and intellectual deficits can and do improve over time and early assessment, diagnosis and intervention are critical in yielding positive long term outcomes. There are many ways to help people with the aforementioned difficulties so be sure to seek professional advice from educators, health professionals and remember we have many resources available at our website: http://www.noonansyndrome.com.au.
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