Early Development and ASD Risk in Neurofibromatosis Type 1

Background: Neurofibromatosis Type 1 (NF1) is a monogenic disorder which affects 1 in every 2700 births (Evans et al.,2010), with up to 25% incidence of Autism Spectrum Disorder (ASD;Garg et al.,2013) and up to 45% presenting with ASD symptomatology (Garg et al.,2015). Levels of social impairment remain the main challenge for parents and children with NF1, although very little is understood about their early development. Our initial case series analysis of 10 infants revealed early motor and language delays at 10 months of age (Kolesnik et al.,2017).

Objectives: This project is designed to help identify early behavioural and neurophysiological markers of ASD in NF1, as well as gain a broader understanding of developmental trajectories. It further explores possible common pathways of ASD in children with NF1 and those without genetic disorders to inform construction of individualised intervention protocols.

Methods: We present data from a prospective study of infants with NF1 at 10 (n=10) and 14 (n=10) months. Data collection is ongoing and the final presentation will include data from 30 infants with NF1 recruited into the study. Results from a series of standardised assessments (Mullen,1995; McKinlay et al.,2011) were compared to a cohort of infants with familial risk of ASD including infants with a three-year diagnosis of ASD (HR-ASD:n=34), atypical (HR-Atyp:n=44) and typical development (HR-TD:n=89), as well as low risk controls (LR:n=89), co-varied by age (in days).

Results: Follow-up assessments at 14 months mirrored our initial findings (Fig1), showing reduced motor abilities in NF1 than non-ASD (HR-TD, HR-Atyp, LR) groups [Mullen Gross Motor(GM): ps=.03-.007], but not HR-ASD [p=n.s.]. Fine Motor(FM) and Vineland Adaptive Motor(VAM) scores were significantly lower in NF1 than all other groups [ps<.001]. Additionally, the NF1 group showed significant impairment in language ability, including lower Expressive (EL) [p=.033, η²=.07], Receptive Language(RL) [p=.022, η²=.044] and Adaptive Communication(VAC) scores [p<.001,η²=.11], with significant differences between NF1 and LR groups only. Age comparisons (10 vs.14m) revealed age x outcome interaction for EL [p=.03, η²=.023], RL [p=.02, η²=.024], and VAC[p=.008, η²=.01] scores, with comparable low scores in NF1 and HR-ASD groups, and lowest overall EL scores in NF1 group [ps ≤.001].

Conclusions: There are notable developmental difficulties in infants with NF1 in motor and language domains, which are similar to infants with later ASD diagnosis. Social skills are reported to be less affected at both time-points, which is unexpected relative to difficulties reported in later life. Based on our findings of pervasive language impairment in NF1 cohort, we will further discuss EEG data from an auditory habituation task (analysis ongoing), which was reported to show sensitivity to early variation in language growth (Kolesnik et al.,in review; Benasich et al.,2002). We hope to explore the relationship between neural markers of auditory processing and language difficulties observed in infants with NF1 and those with a later diagnosis of ASD. Using a prospective design will further help identify the time-window where these early impairments may be addressed.