Neurobehavioral Phenotype of Autism Spectrum Disorder Associated with Germline Heterozygous Mutations in PTEN

Background: Mutations in PTEN, the gene that encodes phosphatase and tensin homolog, have been identified in up to 20% of children with autism spectrum disorder (ASD) and macrocephaly and are associated with marked abnormalities in the white matter of the brain.

Objectives: This study sought to comprehensively characterize the neurobehavioral phenotype of PTEN-ASD.

Methods: Comprehensive neurobehavioral evaluations were conducted in 28 children/adolescents (ages 3 to 21 years) with PTEN-ASD and compared to two groups of controls: non-syndromic ASD with macrocephaly (Macro-ASD, n=20) and PTEN mutations without ASD (PTEN-no ASD, n=19). ANOVA, ANCOVA, or Kruskal Wallis tests were used to examine group differences on neurobehavioral measures (cognitive, behavioral, sensory, and adaptive functioning) and, for select measures, t-tests were used to compare group performance to healthy control norms.

Results: There is a distinct neuropsychological profile associated with mutations in PTEN suggesting primary disruption of frontal lobe systems (i.e., processing speed, motor coordination, attention/working memory, executive functioning). Cognitive deficits in PTEN-ASD are more severe than those in PTEN-no ASD and extend to other areas of neurobehavioral function (i.e., adaptive behavior and sensory deficits). Interestingly, group differences in IQ were no longer apparent after controlling for processing speed. While core ASD symptoms are similar in PTEN-ASD and Macro-ASD, PTEN-ASD had lower clinical ratings of autism severity and showed more sensory abnormalities.

Conclusions: PTEN-ASD has a distinct neurobehavioral phenotype compared to idiopathic ASD that is likely to warrant special consideration for overall assessment and treatment.