Hersenpathologie en autisme spectrum kenmerken bij Tubereuze Sclerose Complex
Kenniscongres van Wijk tot Wetenschap24 november 2016
S.E. (Sabine) Mous, PhD [email protected]
Afdeling Kinder- en Jeugdpsychiatrie/PsychologieExpertise centrum ENCORE
Erasmus Medisch Centrum-Sophia Kinderziekenhuis, Rotterdam
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
Gain knowledge about ASD in genetic neurodevelopmental disorders• Enhance diagnostic assessment in these populations
o Study suitability of instrumentso 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?
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)
IQ
Large individual differences Intellectual disability: ~50% (IQ<70)
van Eeghen et al, 2012Dark grey = TSC1Shaded grey = TSC2Light Grey = no mutation identified
Autism Diagnostic Observation Scale (ADOS)
none58%
ASD16%
autism26%
ADOS classification
none69%
ASD13%
autism19%
TSC 1
none58%
ASD15%
autism27%
TSC 2
N=16
N=33
N=57
Preliminary work, unpublished
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
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
B 95% CI β p p corra B 95% CI β p p corr
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 1Parietal lobes 0.24 0.10;0.39 0.43 0.002 0.005 0.11 -0.04;0.25 0.19 0.150 0.447Temporal lobes 0.31 0.10;0.52 0.38 0.005 0.016 0.11 -0.09;0.31 0.14 0.278 0.829Occipital 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. aMultiple testing correction (2.98 effective tests) applied.
Table 2. Association ADOS total calibrated severity score and tuber count
ASD severity and cortical tubers
B 95% CI β p p corra B 95% CI β p p corr
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 1Parietal lobes 0.24 0.10;0.39 0.43 0.002 0.005 0.11 -0.04;0.25 0.19 0.150 0.447Temporal lobes 0.31 0.10;0.52 0.38 0.005 0.016 0.11 -0.09;0.31 0.14 0.278 0.829Occipital lobes 0.40 0.13;0.67 0.39 0.004 0.012 0.24 -0.00;0.47 0.23 0.054 0.160Note: n=52. ADOS=Autism Diagnostic Observation Scale, IQ=intelligence quotient, DQ=developmental quotient. aMultiple testing correction (2.98 effective tests) applied.
Table 2. Association ADOS total calibrated severity score and tuber countModel I
Manuscript in preparation, unpublished
ASD severity and cortical tubers
B 95% CI β p p corra B 95% CI β p p corr
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 1RRB domain CSS 0.12 0.06;0.17 0.49 <0.001 0.001 0.07 0.00;0.14 0.30 0.042 0.124SA domain CSS 0.22 0.08;0.36 0.40 0.003 0.010 0.10 -0.05;0.25 0.19 0.169 0.503RRB domain CSS 0.22 0.06;0.38 0.36 0.008 0.025 0.09 -0.08;0.26 0.15 0.275 0.821SA domain CSS 0.20 -0.01;0.41 0.26 0.064 0.192 0.02 -0.19;0.23 0.02 0.876 1RRB domain CSS 0.37 0.15;0.58 0.43 0.001 0.004 0.21 -0.02;0.43 0.25 0.071 0.211SA domain CSS 0.34 0.08;0.61 0.35 0.012 0.036 0.20 -0.05;0.45 0.20 0.111 0.330RRB 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. aMultiple testing correction (2.98 effective tests) applied.
Table 3. Association ADOS subdomain calibrated severity scores and tuber countModel I Model I + IQ/DQ
Total number of tubers
Frontal lobes
Parietal lobes
Temporal lobes
Occipital lobes
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
Contact [email protected] | 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/PsychologyGwen 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 bySophia 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