Neurodevelopmental disorders:

Why do they co-occur?

Dorothy Bishop

Wellcome Principal Research Fellow

Department of Experimental Psychology

University of Oxford

2

Meanings of ‘neurodevelopmental

disorder’

Neurological disorders with known prenatal

cause (genetic or acquired)

• e.g. Williams syndrome, fetal alcohol syndrome

Disorders where abnormal neurodevelopment is

inferred: actual cause is complex or unknown

• e.g. developmental dyslexia, autistic disorder, specific

language impairment (SLI), developmental

coordination disorder (DCD), developmental

dyscalculia, ADHD

3

Common characteristics of

neurodevelopmental disorders

Defined in terms of behaviour

Often use medical terminology, drawing parallel

with acquired disorders

Tend to run in families

No single biological cause

Male preponderance in most

Distinct disorders?

Kaplan et al, 2001

Developmental co-ordination disorder, 17%

ADHD, 65%

Dyslexia, 70%

“Comorbidity is the rule, not the exception” (Gilger & Kaplan, 2001)

• Sample of 179 children

and families recruited from

clinics, special schools

• All had dyslexia and/or

ADHD

• Comprehensive

assessment for ADHD,

dyslexia, DCD, and

psychiatric disorders

Kaplan, B. J., et al (2001). The term comorbidity is of questionable value in reference to

developmental disorders: data and theory. Journal of Learning Disabilities, 34, 555-565.

Dyck, M. J., et al. (2011). The validity of psychiatric diagnoses: The case of 'specific'

developmental disorders. Research in Developmental Disabilities, 32(6), 2704-2713.

608 children aged 3 – 14 years 449 Typically-developing

30 Autism spectrum disorder (ASD)

24 Mental retardation (MR)

30 Receptive-expressive language disorder (SLI)

22 Developmental co-ordination disorder (DCD)

53 Attention deficit hyperactivity disorder (ADHD)

Assessments of IQ, language, motor, attention, social cognition, executive function

Western Australian study

Murray Dyck

Typical

Autism

MR

SLI

DCD

ADHD

Dyck et al: Discriminant function analysis

A non-causal explanation:

Ascertainment bias

Language

Moto

r Population

sample

needed to

test if

association

is true

Likelihood

of referral

Genuine association:

Needs causal explanation

Reading

Moto

r r = .25

e.g., Brookman, A., et al (2013). Fine motor deficits in reading disability and language

impairment: same or different? PeerJ. doi: 10.7717/peerj.217

Motor impairment

Reading impairment

Motor impairment

Reading impairment

Q1: Why are disorders associated?

• Generally, simple causal model doesn’t work

• Too many cases of dissociation

• Also, in this case, implausible

Motor impairment

Reading impairment

Motor impairment

Reading impairment

Factor X

Motor impairment

Reading impairment

Q1: Why are disorders associated?

12

Q2: At what level is the overlap?

Bishop, D., & Rutter, M. (2008). Neurodevelopmental disorders: conceptual issues. In M.

Rutter et al (Eds.), Rutter's Child and Adolescent Psychiatry (pp. 32-41).Blackwell.

How to distinguish causal accounts?

Better measures of phenotype – get at

common underlying cognitive processes

Use family data: can test whether disorders

“breed true”

Training study

Example: Autistic spectrum disorder and Specific

Language Impairment

Autism spectrum disorder (ASD)

Autistic disorder: impairments in:

Communication

Social interaction

Behavioural repertoire

14

14

Specific language impairment (SLI)

Diagnosed in children when language does not follow normal developmental course

Not due to hearing loss, physical abnormality, acquired brain damage

Normal development in other areas

Problems with language structure (phonology and syntax) common

15

Good ‘markers’ of SLI

16

Measures which are sensitive to SLI, and heritable

• Nonword repetition

Child listens to spoken nonwords and repeats, e.g.

2 syllables: hampent

3 syllables: dopelate

4 syllables: confrantually

5 syllables: pristoractional

• Verb inflectional morphology

“Here’s a farmer. Tell me what a

farmer does”

Measures of language form, rather than content/use

Evidence that aetiology is complex and

multifactorial in autism and SLI

i.e. Combined effect of many genes and environmental risks

Disorders aggregate but do not segregate in

families

Unaffected relatives of affected individuals may

show mild or partial symptoms

High heritability in twin studies, yet genome

scans have revealed few single gene causes

Relatively common disorders affecting

reproductive success, yet persist in population

17

Traditional view: two separate disorders

risk

factors

Y

ASD SLI

-liability X

risk

factors

X

-liability Y

18

19

Predictions: independent disorders model

• Children with ASD and SLI together

should be vanishingly rare:

• SLI prevalence 7%

• ASD prevalence 1%

• Predicts comorbid 7 per 10,000

19

ASD

SLI

• Many children with ASD have language problems similar to SLI:

Kjelgaard & Tager-Flusberg (2003): poor nonword repetition and use of verb inflections;

76% ASD with LI

Loucas et al (2008): epidemiological sample, cases with ASD and normal nonverbal IQ & impaired performance on a language battery:

57% (41 of 72) ASD with LI

20

High comorbidity between ASD and

language impairment (LI)

20

Kjelgaard, M. M., & Tager-Flusberg, H. (2001). An investigation of language impairment in autism:

Implications for genetic subgroups. Language and Cognitive Processes, 16, 287-308.

Loucas, T. et al. (2008). Autistic symptomatology and language ability in autism spectrum disorder

and specific language impairment. [Article]. Journal of Child Psychology and Psychiatry, 49(11),

1184-1192. doi: 10.1111/j.1469-7610.2008.01951.x

21

Key question

ASD and LI can be dissociated

Yet they co-occur far more often than by chance

Conventional wisdom of independent disorders

seems wrong

How to explain?

21 ?

Correlated risk factors

Some possible reasons for correlation:

• Same gene influences both liabilities (pleiotropy)

• Genes close together on same chromosome (linkage)

• Correlated environmental factors (e.g. poverty)

• Non-random (assortative) mating

risk

factors

Y

ASD SLI

-liability X

risk

factors

X

-liability Y

r

22

23

But nonword repetition shows

different pattern in relatives

• In SLI, nonword repetition deficit is

clearly familial (e.g. Barry et al, 2007)

• In autism, where child is poor at nonword repetition, parents and sibs are not

23

Barry, J. G., Yasin, I., & Bishop, D. V. M. (2007). Heritable risk factors associated with language

impairments. Genes, Brain and Behavior, 6, 66-76.

Bishop, D. V. M., et al (2004). Are phonological processing deficits part of the broad autism

phenotype? American Journal of Medical Genetics: Neuropsychiatric Genetics, 128B(54-60).

Whitehouse, A. J. O., et al (2008). Further defining the language impairment of autism: Is there a

specific language impairment subtype? Journal of Communication Disorders, 41, 319-336.

Lindgren, K. A.,et al (2009). Language and reading abilities of children with autism spectrum

disorders and specific language impairment and their first-degree relatives. Autism Research, 2(1),

22-38.

24

Shared genetic risk? CNTNAP2

CNTNAP2 gene; polymorphic gene, neurexin, regulated by FOXP2.

Common variant associated with risk of neurodevelopmental problems

• Alarcon et al, 2008; assoc with late language in ASD

• Vernes et al, 2008: assoc with nonword repetition in children with SLI

• Li et al, 2010: autism association in Chinese Han

• Steer et al, 2010; assoc with late lang acquisition

• Whitehouse et al, 2011; assoc with delayed language milestones in gen pop. sample

but NB very small effect sizes!

24 Graham, S. A., & Fisher, S. E. (2013). Decoding the genetics of speech and language.

Current Opinion in Neurobiology(0). doi: http://dx.doi.org/10.1016/j.conb.2012.11.006

Alternative genetic

explanation

G x G interaction (epistasis)

25 25

Bishop, D. V. M. (2010). Overlaps between autism and language impairment:

phenomimicry or shared etiology. Behavior Genetics, 40, 618-629.

Overview of G x G model

• Common variant of gene such as CNTNAP2

creates mild risk for poor nonword repetition

• Other genes have risk variants that contribute

to autism

• If CNTNAP risk variant occurs together with

certain ASD risk genes, effect on language

much more severe

26

Evaluation of G x G model

• Predicts high frequency of comorbid ASD + LI

• Predicts lower rate of LI symptoms in relatives of ASD+LI than relatives of SLI

• Fits with current move to look at gene networks rather than individual genes

• Predicts molecular genetic overlaps

27

risk

factors

Y

-liability Y

ASD SLI

-liability X

risk

factors

X

Phenomimicry model

• Primary form of disorder, each with own cause, but also secondary

form that mimics the other disorder.

• Crucially, does NOT predict SLI in relatives of those with ASD+LI 28

LI

Evidence for phenomimicry

Different error patterns for ASD+LI cf. SLI on tests

of nonword repetition and verb inflection

29

Williams, D., Botting, N., & Boucher, J. (2008). Language in autism and

specific language impairment: Where are the links? Psychological Bulletin,

134(6), 944-963. doi: 10.1037/a0013743

From Whitehouse

et al (2008)

Remaining puzzle:

Why do only a subset of ASD have LI?

30

Not down to severity

Lindgren et al found language in ASD cases was not correlated

with ASD symptoms measured by ADI-R

communication social repetitive

normal language

language impaired

Lindgren, K. A., et al

(2009). Language and

reading abilities of

children with autism

spectrum disorders and

specific language

impairment and their first-

degree relatives. Autism

Research, 2(1), 22-38.

The terminological jungle

Overlap in neurodevelopmental disorders

Clinical implications

ASD

SLI

Dyslexia

DCD ADHD

Same child, different diagnosis

Educational psychologist: Dyslexia

Speech and language therapist: SLI

Psychiatrist: Autism spectrum

disorder (ASD)

Neurologist: Developmental

co-ordination disorder (DCD)

Paediatrician: ADHD

Implications of terminological confusion

• Children’s needs may go unmet

• Arbitrary and unfair decisions about access to services

• Lack of recognition of some conditions

34

35

Amount of research (1985-2009) and

prevalence of neurodevelopmental disorders

Condition

papers

/year

freq.

%

Tourette syndrome 83 0.5

Autistic spectrum disorder 643 0.7

Developmental dyscalculia 9 3.0

Attention deficit hyperactivity disorder 505 5.0

Developmental dyslexia 152 6.0

Developmental coordination disorder 16 6.5

Specific language impairment 46 7.4

Data from: Bishop, D. V. M. (2010). Which neurodevelopmental

disorders get researched and why? PLOS One, 5(11), e15112. doi:

10.1371/journal.pone.0015112

36

NIH funding over time for

neurodevelopmental disorders

$K

0

100000

200000

300000

400000

500000

600000

700000

800000

900000

2000-

2001

2002-

2003

2004-

2005

2006-

2007

2008-

2009

Attention deficit

hyperactivity

disorder

Autistic spectrum

disorder

Dyslexia/SLI/speech

/dyscalc/DCD

Data from: Bishop, D. V. M. (2010). Which neurodevelopmental

disorders get researched and why? PLOS One, 5(11), e15112. doi:

10.1371/journal.pone.0015112

One alternative

Broad category of ‘neurodevelopmental disability’ to

establish need for services

‘Disability’ emphasises impact on individual

‘Neurodevelopmental’ emphasises biological basis: not

just poor teaching

Supplemented with assessment to establish profile of

difficulties/strengths on different dimensions, and

determine which services to prioritise

http://deevybee.blogspot.com.au/2010/12/whats-in-name.html

Raising Awareness of Language Learning Impairments

http://www.youtube.com/RALLIcampaign

Dorothy Bishop

Oxford Study of Children’s

Communication Impairments,

Department of Experimental

Psychology,

South Parks Road,

Oxford,

OX1 3UD,

England.

dorothy.bishop@psy.ox.ac.uk

@deevybee