The document summarizes research on autism spectrum disorder (ASD) in individuals with tuberous sclerosis complex (TSC). It finds that ASD is common in TSC, with a prevalence of around 40-50%. It also finds that having more cortical tubers, as seen on MRI scans, is related to more severe ASD. However, cognitive functioning also plays an important explanatory role. While ASD remains significant even for those with higher IQ, it is important to provide regular psychiatric/behavioral follow-up and management for ASD adapted to developmental level in individuals with TSC.
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Utrecht/Kenniscongres2016/14.2./ S. Mous/Hersenpathologie en autisme spectrum kenmerken bij Tubereuze Sclerose Complex
1. Hersenpathologie en autisme spectrum kenmerken bij
Tubereuze Sclerose Complex
Kenniscongres van Wijk tot Wetenschap
24 november 2016
S.E. (Sabine) Mous, PhD
s.mous@erasmusmc.nl
Afdeling Kinder- en Jeugdpsychiatrie/Psychologie
Expertise centrum ENCORE
Erasmus Medisch Centrum-Sophia Kinderziekenhuis, Rotterdam
2. Expertise center ENCORE
Multidisciplinary pooling of knowledge, care and scientific research for children
with rare genetic neurodevelopmental disorders
Outpatient clinics for:
• Neurofibromatosis type I
• Tuberous Sclerosis Complex
• Angelman syndrome
• Fragile X syndrome
• Sturge-Weber syndrome
• Cardiofaciocutaneous syndrome
• Costello syndrome
3. Gain knowledge about ASD in genetic neurodevelopmental disorders
• Enhance diagnostic assessment in these populations
o Study suitability of instruments
o Development of disorder/ID specific norms
• Improve patient care
Gain knowledge about the wider ASD population
• Genetic NDD’s have a known genetic background, monogenic
• Identification of biological pathways involved in non-syndromic ASD
Why study ASD in genetic NDD’s?
4. Tuberous Sclerosis Complex (TSC)
Prevalence 1:6,000
Autosomal dominant disorder
Mutation TSC1 or TSC2 gene
Decrease in hamartin/tuberin protein
Hyperactivation of the mTOR pathway
Abnormal/uncontrolled cell growth
Multi-systemic disorder
Skin, heart, kidneys, teeth, bones, eyes
Brain (tubers, epilepsy, psychiatric and
cognitive problems)
5. IQ
Large individual differences
Intellectual disability: ~50% (IQ<70)
van Eeghen et al, 2012Dark grey = TSC1
Shaded grey = TSC2
Light Grey = no mutation identified
7. ASD severity and cortical tubers
Number of tubers (specifically in the temporal lobe) predictor of ASD
diagnosis (Bolton et al, 1997; Huang et al, 2014)
Gaps:
No studies investigating ASD severity on a continuum
No studies separately investigating
relation with deficits in social
communication/interaction and
restricted/repetitive behaviors
Role of IQ/DQ in association
insufficiently studied
O’Callaghan et al, 2004
8. ASD severity and cortical tubers
N=52, 2-17 years, 46.2% boys
Cortical tuber count MRI
• Total
• Per lobe
ASD severity ADOS (calibrated severity scores)
• Total
• Social Affect
• Restricted and Repetitive Behaviors
IQ/DQ Wechsler scales/BSID
9. B 95% CI β p pcorr
a
B 95% CI β p pcorr
a
Total number of tubers 0.06 0.03;0.09 0.46 <0.001 - 0.02 -0.01;0.06 0.18 0.188 -
Frontal lobes 0.09 0.03;0.15 0.41 0.002 0.007 0.03 -0.04;0.09 0.11 0.414 1
Parietal lobes 0.24 0.10;0.39 0.43 0.002 0.005 0.11 -0.04;0.25 0.19 0.150 0.447
Temporal lobes 0.31 0.10;0.52 0.38 0.005 0.016 0.11 -0.09;0.31 0.14 0.278 0.829
Occipital lobes 0.40 0.13;0.67 0.39 0.004 0.012 0.24 -0.00;0.47 0.23 0.054 0.160
Model I + IQ/DQ
Note: n=52. ADOS=Autism Diagnostic Observation Scale, IQ=intelligence quotient, DQ=developmental quotient. a
Multiple testing
correction (2.98 effective tests) applied.
Table 2. Association ADOS total calibrated severity score and tuber count
Model I
ASD severity and cortical tubers
B 95% CI β p pcorr
a
B 95% CI β p pcorr
a
Total number of tubers 0.06 0.03;0.09 0.46 <0.001 - 0.02 -0.01;0.06 0.18 0.188 -
Frontal lobes 0.09 0.03;0.15 0.41 0.002 0.007 0.03 -0.04;0.09 0.11 0.414 1
Parietal lobes 0.24 0.10;0.39 0.43 0.002 0.005 0.11 -0.04;0.25 0.19 0.150 0.447
Temporal lobes 0.31 0.10;0.52 0.38 0.005 0.016 0.11 -0.09;0.31 0.14 0.278 0.829
Occipital lobes 0.40 0.13;0.67 0.39 0.004 0.012 0.24 -0.00;0.47 0.23 0.054 0.160
Model I + IQ/DQ
Note: n=52. ADOS=Autism Diagnostic Observation Scale, IQ=intelligence quotient, DQ=developmental quotient. a
Multiple testing
correction (2.98 effective tests) applied.
Table 2. Association ADOS total calibrated severity score and tuber count
Model I
Manuscript in preparation, unpublished
10. ASD severity and cortical tubers
B 95% CI β p pcorr
a
B 95% CI β p pcorr
a
SA domain CSS 0.05 0.01;0.08 0.37 0.008 - 0.01 -0.02;0.05 0.10 0.497 -
RRB domain CSS 0.07 0.03;0.10 0.49 <0.001 - 0.04 0.00;0.08 0.29 0.046 -
SA domain CSS 0.07 0.01;0.12 0.32 0.023 0.069 0.00 -0.06;0.07 0.02 0.882 1
RRB domain CSS 0.12 0.06;0.17 0.49 <0.001 0.001 0.07 0.00;0.14 0.30 0.042 0.124
SA domain CSS 0.22 0.08;0.36 0.40 0.003 0.010 0.10 -0.05;0.25 0.19 0.169 0.503
RRB domain CSS 0.22 0.06;0.38 0.36 0.008 0.025 0.09 -0.08;0.26 0.15 0.275 0.821
SA domain CSS 0.20 -0.01;0.41 0.26 0.064 0.192 0.02 -0.19;0.23 0.02 0.876 1
RRB domain CSS 0.37 0.15;0.58 0.43 0.001 0.004 0.21 -0.02;0.43 0.25 0.071 0.211
SA domain CSS 0.34 0.08;0.61 0.35 0.012 0.036 0.20 -0.05;0.45 0.20 0.111 0.330
RRB domain CSS 0.34 0.04;0.63 0.31 0.026 0.079 0.18 -0.10;0.46 0.16 0.201 0.598
Note: n=52. ADOS=Autism Diagnostic Observation Scale, CSS=calibrated severity score, SA=Social Affect, RRB=Restricted and Repetitive
Behaviors, IQ=intelligence quotient, DQ=developmental quotient. a
Multiple testing correction (2.98 effective tests) applied.
Table 3. Association ADOS subdomain calibrated severity scores and tuber count
Model I Model I + IQ/DQ
Total number of tubers
Frontal lobes
Parietal lobes
Temporal lobes
Occipital lobes
11. Take home message
ASD is common in TSC (prevalence ~40-50%)
Having more cortical tubers is related to more severe ASD
Cognitive functioning is an important explanatory factor, but
• ASD remains a significant problem in ASD,
• is also present in TSC patients with a higher IQ,
• and should be treated accordingly.
For clinical practice:
• Regular psychiatric/behavioral follow-up in children/adolescents with TSC
is important
• Be aware of ASD in children with TSC, also when IQ is higher
• Management/treatment of ASD should be adapted to developmental level
12. Contact
s.mous@erasmusmc.nl | http://www.erasmusmc.nl/encore/ | http://www.sabinemous.com
Expertise center ENCORE, Erasmus Medical Center –
Sophia Children’s Hospital, Rotterdam, the Netherlands
Dep. of Child and Adolescent Psychiatry/Psychology
Gwen Dieleman, MD
Bram Dierckx, MD, PhD
Leontine ten Hoopen, MD
Jeroen Legerstee, PhD
Pieter de Nijs, MD, PhD
Andre Rietman, MSc
Prof. Frank Verhulst, MD, PhD
Financial support provided by
Sophia Foundation (Stichting Vrienden van Sophia),
Rotterdam, the Netherlands
Other departments
Coriene Catsman-Berrevoets, MD, PhD
Rene de Coo, MD, PhD
Agnies van Eeghen, MD, PhD
Prof. Ype Elgersma, MD, PhD
Laura de Graaff, MD, PhD
Karen Bindels-de Heus, MD
Maartje ten Hoven-Radstaake, PhD
Anneke Kievit, MD, PhD
Carsten Linke, MD, PhD
Grazia Mancini, MD, PhD
Prof. Henriette Moll, MD, PhD
Rick van Minkelen, MD, PhD
Rianne Oostenbrink, MD, PhD
Myrthe Ottenhof, MSc
Iris Overwater, MSc
Barbara Sibbles, MD
Joke Tulen, MD, PhD
Prof. Rob Willemsen, MD, PhD
Marie-Claire de Wit, MD, PhD
Shimriet Zeidler, MD
Acknowledgments