Developmental and Learning Disabilities in Tuberous Sclerosis

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					Autism and Epilepsy in
 Tuberous Sclerosis

         Dr. Ayla Humphrey
    Consultant Clinical Psychologist
       Autism Research Centre
  Cambridge Tuberous Sclerosis Clinic
      Developmental Psychiatry
       University of Cambridge
Tuberous Sclerosis (Complex)

1 in 10,000
40% inherited autosomal dominant genetic
disorder
60% spontaneous mutation
TSC1 gene (9q34) 20% -hamartin       Proteins
                                     control cell
TSC2 gene (16p13) 80% -tuberin       growth
characterised by hamartomas affecting many
organs (90% cerebral involvement)
Epilepsy in 80%
  Psychiatric/Developmental
      Impairments in TS
Variable phenotypic expression
global learning disability in 40-60%
(IQ<70)
specific learning disorders
ADHD (2-55% associated with IQ, PDD,
and epilepsy)
Aggression
Memory impairment
Sleep disorders
 Autism Spectrum Disorders
& Tuberous Sclerosis Complex
 Prevalence of TS in population of those
 with an autism spectrum disorder is 1-
 4%
 – TS strongest association of known medical
   conditions with ASD (Rutter et al., 1994)


 25% Autistic, 25% Autism Spectrum
 Disorder
  Causes of Autism Spectrum
        Disorder in TS
Location of tubers and extent of measured abnormality is
NOT sufficient to explain TS/ASD association (Curatolo et
al., 1993; Bolton & Griffiths, 1997)

Type of seizure NOT sufficient to explain TS/ASD
association

Mental retardation NOT sufficient to explain TS/ASD
association

Genetic linkage, autism susceptibility in 16p13 and 9q34
region NOT sufficient to explain TS/ASD association
         Obstetric History
          Normal Pregnancy
          Caesarian Section at 37
          weeks (1 twin breech
          presentation)

Twin 1                 Twin 2
–5 lbs                  –5 lbs
–No Neonatal Problems –No Neonatal Problems
–Home at 5 days         –Home at 5 days
Intellectual Ability from 18
to 36 Months for Twin Pair
                            100                              Twin A
   Developmental Quotient



                                                             Twin B
                             90
                             80       81       83
                             70       69                71
                             60                64
                             50
                             40
                                                        45
                             30
                             20
                             10
                                   18       24       36
                                  months   months   months
                                                Age
 Scores on Autism Diagnostic
Observation Schedule (Autism
  Spectrum>7; Autism>12)

         20
                                      Twin A
         18        18
                                      Twin B
         16
         14
 Score




         12
         10
          8        8           8
                                           7
          6
          4                                4
          2                    2
          0
              18 months   24 months   36 months
                            Age
     Tubers and Epilepsy for Twins
                     Twin A                                     Twin B

TUBERS               Left            Right          Total       Left         Right   Total
Temporal             2               2              4           1            3       4
-Sup gyri            0               1              1           0            0       0
-Middle gyri         0               0              0           0            0       0
-Inferior gyri       2               1              3           1            2       3
-Fusiform gyri       0               0              0           0            1       1
Occipital            2               3              5           3            4       7
Cerebellar           0               0              0           0            1       1
Frontal              7               6              13          8            5       13
 Parietal            0               3              3           4            2       6
TOTAL                11              14             25          16           15      31
EPILEPSY             Partial                                    Infantile spasms
Seizure type         •3 mnths                                   •7 mnths
-Age at onset        •1-6/day                                   •3-8/day
-Seizure frequency   •33 mnths (ongoing)                        •5 mnths
-Seizure duration    •Multifocal bilateral temporal /parietal   •Multifocal
-Seizure foci                                                   Partial
                                                                •31 mnths
                                                                •6/day
                                                                •5mnths (ongoing
MRI Scans Illustrating Number of
  Tubers and Extent of Brain
         Abnormality
      Summary of Findings
Many between-twin differences inconsistent with
theoretical predictions of mechanism underlying autism
spectrum disorder
  –non-autistic twin had tubers in right temporal lobe,
  cerebellum, fusiform gyrus (face processing)
  –non-autistic twin, not autistic twin had infantile
  spasms
Twin A had less well-controlled seizures, bilateral
temporal lobe discharges (fits pattern in previous
reported MZ twins), not infantile spasms, early onset
More intellectually impaired twin had fewer tubers than
co-twin but more extensive brain involvement.
            Autistic Regression
              The Case of P.
5 months
 – Diagnosis TSC
 – Parental report brief weekly jerks rt side
6 months
 – EEG: spike and polyspike waves, hypsarrthymia
 – Vigabatrin – high seizure risk
7 months
 – EEG normal
13 months
 – Vigabatrin discontinued, risk of visual field defects
 – P. seizure free
                                        Humphrey et al.,2006
           Autistic Regression
             The Case of P.
21 months
 – Partial seizures secondary generalisation
 – Infantile spasms 8x/day, secondarily generalised partial
   6x/day
 – Frequent multi-focal sharp and slow wave discharges,
   bilateral
24 months
 – Social & cognitive regression, Autism diagnosis
 – Vigabatrin and Steroids, seizures stop
28 months
 – EEG normal
 – Persistent cognitive impairment and Autism
Regression of Intellectual
        Function
                                                   Com pos ite     Social     Com m unication

                      18
                      16
                      14
ADOS Scores


                      12
                                         autism cut-off
                      10
                                   8
                                   6

                                                          seizures
                                   4
                                   2
                                   0
                                             18 m onths    24 m onths       30 m onths   36 m onths




                                        60
                                             Vigabatrin
              Mullen Subtest T Scores




                                        50                                                      visual reception
                                        40
                                                                                                fine motor
                                        30
                                        20                                                      receptive language
                                        10
                                                             seizures
                                         0                                                      expressive
                                                                                                language
                                                12     18         24     30        36
                                               mnth   mnth       mnth   mnth      mnth



                                                                                                      Humphrey et al., 2006
      Causes of Autism Spectrum
            Disorder in TS
Temporal lobe epileptiform focus on EEG by 15 months (Bolton et al.,
2002)

Functional imbalance in subcortical circuits = triad of impairments
(Asano et al., 2001) , Pet Scan

Tuberin modulates mTor and p44/42-MAPK cascades regulating
synaptic efficiency (Morozov et al, 2003; Sweat, 2004; Yoon et al.,
2004)

TSC2 heterozygous rats – reduced synaptic plasticity (von der Brelie et
al., 2006)

Mossy fiber sprouting following seizures in immature rats (Holmes et
al., 1999)
Increased head circumference in TS (Fidler et al., 2000)
Autism Spectrum Disorder in TS

                  TSC1/TSC2


         Subcortical synaptic abnormality
          axon and dentritic overgrowth


ASD I       Lower seizure threshold

                    Epilepsy           Temporal lobe tubers


             Mossy fiber growth               disruption to
                                            social com areas
ASD II
                                ASD III          Humphrey, 2006
       Ongoing Research
Early Infancy Pre-Epilepsy TS Study: Infants
diagnosed with TS before onset of seizures
assessed regularly pre and post seizure
onset

TS Cohort Study: All cases of TS identified in
UK since 2001 recruited. Longitudinal
developmental assessments and medical
investigations (MRI, EEG)
      Implications for Practice
Early detection of epilepsy with swift treatment,
 - treat abnormal EEG findings without clinical seizures?
 - lessening of autism symptomology with Vigabatrin
   (Deonna, ;Jambaque, )

Serial developmental assessments
 - Consensus Clinical Guidelines for the Assessment of
   Cognitive and Behavioural Problems in Tuberous
   Sclerosis (de Vries et al, 2005)

Evidence-based interventions for autism spectrum
disorders
 - National Autism Plan for Children [NAPC] (Le Couteur et
   al., 2003)
   Collaborators:
 Professor Patrick Bolton, Child and Adolescent Department,
  Institute of Psychiatry

 Professor John Yates, Department of Clinical Genetics,
  University of Cambridge

 Yael Granader, Developmental Psychiatry, University of
  Cambridge

 George Ploubidis, Department of Psychiatry, University of
  Cambridge

 Cathy McClean, Department of Clinical Genetics, University
  of Cambridge
Special thanks to the Tuberous Sclerosis Association