To determine the prevalence of autism spectrum disorder (ASD) in Neurofibromatosis Type 1 (NF1).
Second-phase population-based epidemiologic study using an allcase NF1 registry in a defined UK 4.1 million population area. A total of 109 (52.7%) of 207 responders from the initial screening phase were grouped by using the parent-rated Social Responsiveness Scale (SRS) as significant ASD (SRS≥76; n = 32), moderate ASD (SRS ≥ 60<76; n = 29), or non-ASD (SRS <60, n = 48). Twenty-three cases from the significant ASD group, 16 from moderate ASD, and 8 from non-ASD (total n = 47), invited proportionately by random selection, were seen for detailed confirmatory ascertainment. Assessments on Autism Diagnostic Interview-Revised, Autism Diagnostic Observation Scale-Generic, and verbal IQ were combined by using standard Collaborative Program for Excellence in Autism criteria into an ASD categorization for each case (ASD, broad ASD with partial features, non-ASD). A preplanned weighted analysis was used to derive prevalence estimates for the whole population.
Fourteen (29.5%) of 47 showed ASD, 13 (27.7%) broad ASD, and 20 (42.5%) non-ASD. The ASD/broad ASD group showed male predominance (1.7:1.0), but did not differ significantly from the non-ASD group on IQ, age, socioeconomic status, inheritance, physical severity, or education. The population prevalence estimate is 24.9% ASD (95% confidence interval 13.1%–42.1%) and 20.8% broad ASD (95% confidence interval 10.0%–38.1%); a total of 45.7% showing some ASD spectrum phenotype.
Findings indicate high prevalence of ASD in NF1, with implications for clinical practice and further research into NF1 as a single-gene model for autism.
We thank Walsh and Payne for their interest in our paper. They raise several important points deserving of response.
Firstly they suggest that our detailed phase 2 phenotyping of ASD is not related back to the phase 1 data. On the contrary, we describe in the paper how the phase 2 phenotyping systematically sampled from each of three bands of parent-rated phase 1 SRS screening data, including screen negative cases. This methodology allowed a two-stage weighting procedure to calculate the population prevalence, which specifically adjusted for response biases at both phases of the epidemiological study.
We discuss in our phase 1 paper (1) the discrepancy between parent and teacher screening ratings; this kind of discrepancy is common in psychopathology research - hence the key value of the in-person phase two phenotyping that we undertook. ADI-R and ADOS-G are known to give excellent sensitivity and specificity for ASD, particularly when their data is combined (2) and have been used internationally in numerous ASD phenotyping studies without evidence of high false positive rates. We are therefore confident in our population prevalence estimates for ASD.
Walsh and Payne further raise issues of comorbidity and diagnostic overshadowing. We agree that children with severe ADHD can show social difficulties, however the nature and extent of such social problems are very different from those in full ASD. It was to illustrate this that we described the ASD phenomenology in our cases in detail across social communicative and repetitive and stereotyped behaviour domains (Table 1 in the paper), a profile quite different to that which could be accounted for by ADHD. We also demonstrate equivalent levels of rated ADHD symptoms across each of our ASD, Broad ASD and non-ASD groups, strongly suggesting the independent comorbidity of ASD and ADHD disorders in NF1. This is not unusual; comorbidity is generally common in psychopathology and research has specifically found comorbidity with ADHD in 28.2% cases of familial idiopathic ASD (3).
We used the term 'diagnostic overshadowing' to refer to the clinical attribution of behaviours to one disorder without considering additional diagnosis and treatment of comorbid conditions. We agree that this is unlikely in relation to cognitive impairment, which was rare in the sample; instead we argue that previous under-recognition of ASD may well be due to presenting symptoms being attributed either to ADHD or to the NF1 disorder itself. For instance, children on our NF1 register who do not have major physical NF1 problems are generally followed in non- specialist paediatric clinics and our clinical information suggests that most behavioural problems in this context are assumed to be due to the NF1 itself rather than any specific co-morbidity; only 6 out of the 47 children (12.7%) in our phase 2 cohort for example had an independent prior diagnosis of ADHD.
We acknowledge in our paper the importance of ADHD in NF1. Our findings show, however, additional independent high rates of ASD. The marked co-morbidity of these two neurodevelopmental disorders in NF1 does indeed deserve further study.
1. Garg S, Lehtonen A, Huson SM, et al. Autism and other psychiatric comorbidity in neurofibromatosis type 1: evidence from a population-based study. Dev Med Child Neurol. 2013;55(2):139-145
2. Lord C, Petkova E, Hus V, et al. A multisite study of the clinical diagnosis of different autism spectrum disorders. Arch Gen Psychiatry. 2012;69(3):306-313
3. Simonoff E, Pickles A, Charman T, Chandler S, Loucas T, Baird G. Psychiatric disorders in children with autism spectrum disorders: Prevalence, comorbidity, and associated factors in a population derived sample. Journal of American Academy of Child & Adolescent Psychiatry. 2008;47(8):921-929.
Conflict of Interest:
Prof Evans and Dr Huson receive small amounts in royalties from a book entitled Handbook on Neurofibromatosis. The other authors have indicated they have no potential conflicts of interest to disclose.
We are pleased to see the authors continue research into this previously neglected area of the NF1 phenotype. Strengths of this study lie in the population-based sampling of participants and the application of gold standard clinical and research techniques in the assessment of autism spectrum disorder (ADI-R and ADOS-G).
This follow-up to the initial symptom screening study presents mean scores for ADI-R and ADOS-G outcomes. Unfortunately, they are not related back to the phase 1 data, making the sensitivity and specificity of the screening tool (SRS) compared to the diagnostic gold standard undeterminable. In phase 1, parents reported a 28.7% prevalence of "severe" symptoms of autism, while teachers only rated 5.7% as severe (Garg et al., 2013). Therefore, the 25% Autism Spectrum Disorder (ASD) prevalence documented in this study either indicates significant underreporting by teachers, or unacceptably high false positive rates of the ADI-R and ADOS-G in this cohort.
We find it striking that 86% of the children who met criteria for ASD in this sample were never previously identified as such, even though the mean age of the sample is nearly 12 years. The argument for "diagnostic overshadowing" as conceptualized by the authors is unlikely, as the referenced research on overshadowing was conducted on intellectually disabled individuals. In those cases, the presence of such pervasive cognitive impairment is very likely to overshadow other diagnoses, including ASD. However, intellectual disability is rare in NF1, and given the significant functional limitations of ASD, it is unlikely that simply having NF1 is overshadowing the presence of ASD.
An alternative explanation is that autistic symptoms in this cohort may be confounded with other psychiatric conditions prevalent in children with NF1. There is a lack of full consideration of comorbid ADHD and the possibility of these symptoms masquerading as ASD-like symptoms. Research has shown high rates of "autism traits" in children with ADHD (Kotte et al 2013; Grzadzinski et al, 2011). While the authors state "parents and teachers rate ADHD symptoms uniformly across groups (i.e., ASD, broad ASD, no ASD) with no increase in the ASD groups compared with non-ASD groups," 81% (26/32) of the participants identified as "severe ASD" in the phase 1 study also had "ADHD." As such, the presence of ADHD and ASD symptoms were very likely comorbid, possibly confounding these results. The broad range of symptoms associated with ADHD can be expected to impair social functioning and development. Studies examining ASD symptoms in idiopathic ADHD have identified high levels of impaired social interaction (e.g., empathy, peer relationships) and communication (imagination, maintaining conversation; Clark et al., 1999), with up to 22% of ADHD children being socially disabled (Greene et al., 1996). It will be critical for future research to carefully consider differential diagnoses in order to develop and implement appropriate therapies targeting social functioning in children with NF1.
REFERENCES
Clark T, Feehan C, Tinline C, Vostanis P (1999). Autistic symptoms in children with attention deficit-hyperactivity disorder. European Child & Adolescent Psychiatry, 8:50-5.
Garg S, Lehtonen A, Huson SM, Emsley R, Trump D, Evans DG, Green J (2013). Autism and other psychiatric comorbidity in neurofibromatosis type 1: evidence from a population-based study. Developmental Medicine and Child Neurology, 55:139-45.
Greene RW, Biederman J, Faraone SV, Ouellette CA, Penn C, Griffin SM (1996). Toward a new psychometric definition of social disability in children with attention-deficit hyperactivity disorder. Journal of the American Academy of Child and Adolescent Psychiatry, 35:571-8.
Grzadzinski R, DiMartino A, Brady E, Mairena MA, O'Neale M, Petkova E, Lord C, Castellanos FX (2011). Examining autistic traits in children with ADHD: Does the autism spectrum extent to ADHD? Journal of Autism & Developmental Disorders, 41:1178-91.
Kotte A, Joshi G, Fried R, Uchida M, Spencer A, Woodworth KY, Kenworthy T, Faraone SV, Biederman J (2013). Autistic traits in children with and without ADHD. Pediatrics, 132:e612-22.
Conflict of Interest:
None declared
We read the article entitled "Neurofibromatosis Type 1 and Autism Spectrum Disorder" with great interest and attention. Unfortunately, we are concerned that the authors of this paper did not address mammalian Target Of Rapamycin (mTOR) as a cornerstone pathway for Neurofibromatosis type 1 (NF-1).
Although ASD is a myriad of heterogeneous and multi-factorial conditions, different single-gene related disorders converge on altered control of mTOR signaling , and recent studies of several autistic neurological disorders focus on this pathway: NF-1 and other ASD-related neurogenetic disorders (Tuberous Sclerosis Complex (TSC), Fragile X syndrome, and Phosphatase and Tensin homolog (PTEN) associated conditions) being associated with aberrant CNS activation of mTOR. (1)
In fact, protein synthesis regulation via the mTOR pathway is crucial for synaptic organization during brain development and for synaptic plasticity in the mature CNS. (2)
Also, ASD is associated with mutations leading to decreased PTEN and TSC proteins. These proteins are upstream inhibitors of the mTOR, which leads to microglia and mast cell proliferation; providing another argument to tie this pathway with brain inflammation (3)
Thus, in such disorders, ASD features - and other neurological symptoms - seem clearly linked (at least partially) to abnormal mTOR hyperactivation. It may narrow down therapeutic targets for autism, since targeting mTOR signaling reverses ASD. (4)
This is of a peculiar interest for NF-1 patients, for whom similar pharmacological strategies have proven efficacy in other mTOR-related symptoms (5)
References:
1. Veenstra-VanderWeele, Jeremy, and Randy D. Blakely. "Networking in autism: leveraging genetic, biomarker and model system findings in the search for new treatments." Neuropsychopharmacology 37.1 (2011): 196-212.
2. Hampson, D. R., S. Gholizadeh, and L. K. K. Pacey. "Pathways to drug development for autism spectrum disorders." Clinical Pharmacology & Therapeutics 91.2 (2011): 189-200.
3. Theoharides, Theoharis C., Shahrzad Asadi, and Arti B. Patel. "Focal brain inflammation and autism." Journal of Neuroinflammation 10.1 (2013): 46.
4. Wang, Hansen, and Laurie C. Doering. "Reversing autism by targeting downstream mTOR signaling." Frontiers in cellular neuroscience 7 (2013).
5. Endo, Makoto, et al. "Prognostic significance of AKT/mTOR and MAPK pathways and antitumor effect of mTOR inhibitor in NF1-related and sporadic malignant peripheral nerve sheath tumors." Clinical Cancer Research 19.2 (2013): 450-461.
Conflict of Interest:
None declared