Autism Spectrum Disorder Profile in Neurofibromatosis Type 1

Background:   Neurofibromatosis Type 1 (NF1) is a common autosomal dominant single-gene disorder, in which the co-occurrence of Autism Spectrum Disorder (ASD) has attracted considerable research interest recently with prevalence estimates of 21-40 %. However, detailed characterization of the ASD behavioral phenotype in NF1 is still lacking. NF1 has a well described neurobiology and a number of putative interventions have shown to reverse the cognitive phenotype in NF1 rodent models

Objectives:   The aim of this study is two-fold: characterize the ASD profile in NF1 and to compare it to idiopathic ASD. 

Methods: Participant data were gathered from existing databases with the following inclusion criteria (i) Diagnosis of NF1 AND (ii) Meeting the ASD cut-off on the Social Responsiveness Scale (T scores ≥ 60) AND on ADOS-2 Module 3 (overall total of social affect and restricted and repetitive behaviors ≥ 7). The NF1+ASD phenotypic profile was compared to the two reference groups in the original ADOS validation sample- autism and autism spectrum disorder groups. 

Results:   The mean SRS T-score of the NF1 sample was 78.58(SD 11.37). Based on selection criteria, all children met ASD cut-off scores on ADOS-2. In terms of severity using the ADOS-2 comparison scores, 11% (n = 4) had a low level of autism spectrum symptoms, 66% (n = 24) had moderate symptoms and 23% (n = 8) had a high level of symptoms. On the Social Affect (SA) algorithm items, there were no significant differences between the NF1+ASD group and the autism group apart from unusual eye contact, which was worse in the autism group. On all of the RRB items, NF1+ASD children had significantly lower scores compared to autism group. The NF1+ASD group in comparison to the reference ASD group was more impaired on the SA algorithm items for language and communication items including conversation and use of gestures and reciprocal social interaction items including facial expressions directed to examiner, shared enjoyment in interaction, quality of social overtures, quality of social responses, amount of reciprocal social communication and overall quality of report. In contrast, the ASD group was significantly more likely to have poorer eye contact in comparison to NF1+ASD group. 

Conclusions: Behavioural phenotyping in genetic syndromes is a promising approach to illuminating the pathogenesis for ASD. NF1 is an important single gene disorder model for studying ASD with well-described neurobiology and the exciting possibility of interventions capable of reversing the phenotype. Within this context, our study sheds light in the profile of ASD in NF1 thus continuing the pursuit of a biological underpinning of the disorder.  Using two standardized and well-validated ASD instruments, the findings support previous suggestions of subtle but significant overall differences in ASD symptomatology between NF1 and polygenic autism. Differences include, comparatively in NF1, overall improved eye contact, less repetitive behaviors and better language skills.Results highlight that the use of clinical cut-off scores and total scores alone may mask more subtle, but potentially significant, differences in the precise nature of ASD symptomatology in different genetic syndromes.