|Café au lait spots @ Wikipedia|
I'm not going to claim to be an expert on the RASopathies because I'm not. From what I gather from the accumulated literature on these developmental syndromes is that we are dealing with a group of conditions which are marked by "mutations in Ras/mitogen-activated protein kinase (Ras/MAPK) pathway genes" which is involved in cell signalling. Quite a good overview of the Ras/MAPK pathway can be found in this article by Jarell and colleagues*** (open-access) with melanoma in mind, hinting at the connection with cancer (see here).
Neurofibromatosis type 1 (NF1), one of the RASopathy family of conditions, is a genetic condition characterised by the presence of coffee coloured patches on the skin called café au lait spots. There are certain criteria for the minimum number of such spots to be present on the skin as part of the diagnosis of NF1. Neurofibromas (little bumps under the skin) are also generally noted in later development, alongside other potential symptoms such as scoliosis and tumours on the optic nerve (optic nerve glioma) among other things.
There is also a connection between NF1 and cognitive and behavioural functions. Although not a universal connection, NF1 is associated with some degree of learning disability for some; as per the paper by Lorenzo and colleagues**** "young children with NF1 have significantly poorer intellectual functioning, expressive language, and visual perception". Other research has detailed an overlap in cases of NF1 with the symptoms of conditions such as ADHD*****.
OK so after all that, what was found?
The paper by Garg et al reports a "high prevalence of ASD in NF1" based on a survey of an NF1 registry based on first a screen for possible autistic traits (using the SRS) and then further assessment of a random sample of the group screening positive for a potential ASD. Indeed: "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". These figures are pretty astounding in terms of the presentation of autism in cases of NF1.
This is not the first time that neurofibromatosis has been linked to autism. I note that Prof. Gillberg (he of the ESSENCE suggestion) discussed "the simultaneous occurrence of neurofibromatosis and childhood psychosis" back in the early 1980s******. For those slightly mystified as to why I'm referencing a paper on childhood psychosis, I might point you to some of the history of autism research and times perhaps less scientifically enlightened. The paper by Mbarek and colleagues******* carries an even more startling revelation in that "Neurofibromatosis type 1 (NF1) is increased about 150-fold in autistic patients" and their linking back to the severity of presentation in autism.
Right up to date, there is also another paper by Garg and colleagues******** from earlier this year (2013) including Prof. Jonathan Green on the authorship list, noting "a high prevalence of ASD symptoms associated with NF1 as well as substantial co-occurrence with ADHD symptoms". That also NF1 was "a potentially important single-gene cause for autism symptoms" brings us full circle as to the latest paper by Garg and colleagues. I should also tip my hat to the paper by Walsh and colleagues which very much supported the previous Garg findings (see here*********).
This is an interesting area of autism research, of that there is no doubt. I'm minded to suggest that the results pointing towards an association between NF1 and autism not only offer some potentially interesting insights into how genes and biochemical pathways might intersect across the conditions, but also provide further evidence that our use of the singular term 'autism' is becoming more and more outdated as time goes on, to eventually be replaced by the 'autisms'. As part of those autisms, the NF1 connection might eventually offer new targets for intervention for some (yes, even a potential role for things like mTOR inhibitors as per some connection**********) and given that skin connection, might even fit into that emerging skin-brain axis that I've talked about on a previous post (see here).
In short, some really quite interesting findings.
* Garg S. et al. Neurofibromatosis Type 1 and Autism Spectrum Disorder. Pediatrics. November 2013.
** Adviento B. et al. Autism traits in the RASopathies. J Med Genet. 2013 Oct 7. doi: 10.1136/jmedgenet-2013-101951.
*** Jarell AD. et al. The RAS/mitogen activated protein (MAP) kinase pathway in melanoma biology and therapeutics. Biologics. 2007 December; 1(4): 407–414.
**** Lorenzo J. et al. Cognitive Features that Distinguish Preschool-Age Children with Neurofibromatosis Type 1 from Their Peers: A Matched Case-Control Study. J Pediatr. 2013 Aug 1. pii: S0022-3476(13)00797-X.
***** Mautner VF. et al. Treatment of ADHD in neurofibromatosis type 1. Dev Med Child Neurol. 2002 Mar;44(3):164-70.
****** Gillberg C. & Forsell C. Childhood psychosis and neurofibromatosis--more than a coincidence? J Autism Dev Disord. 1984 Mar;14(1):1-8.
******* Mbarek O. et al. Association study of the NF1 gene and autistic disorder. Am J Med Genet. 1999 Dec 15;88(6):729-32.
******** Garg S. et al. Autism and other psychiatric comorbidity in neurofibromatosis type 1: evidence from a population-based study. Dev Med Child Neurol. 2013 Feb;55(2):139-45.
********* Walsh KS. et al. Symptomatology of autism spectrum disorder in a population with neurofibromatosis type 1. Dev Med Child Neurol. 2013 Feb;55(2):131-8.
********** Liu N. et al. Mammalian target of rapamycin inhibitor abrogates abnormal osteoclastogenesis in neurofibromatosis type 1. Chin Med J (Engl). 2013 Jan;126(1):101-7.
Shruti Garg, Jonathan Green, Kathy Leadbitter, Richard Emsley, Annukka Lehtonen, D. Gareth Evans, MD, Susan M. Huson, MD, FRCP (2013). Neurofibromatosis Type 1 and Autism Spectrum Disorder Pediatrics