Hersenpathologie en autisme spectrum kenmerken bij Tubereuze Sclerose Complex

Kenniscongres van Wijk tot Wetenschap24 november 2016

S.E. (Sabine) Mous, PhD s.mous@erasmusmc.nl

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Preliminary work, unpublished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 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/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