Co-morbidly of Autism and Co-morbidly of Autism and SLI: Kinds, Kin or SLI: Kinds, Kin or

Confounds?Confounds?Bruce Tomblin, Ph.D.Bruce Tomblin, Ph.D.

Department of Communication Department of Communication Sciences and DisordersSciences and Disorders

University of IowaUniversity of Iowa

Research Supported by Grant R01 NIH-DC-19-90 from the NIDCD

The Issue The Issue

Is there an excess of specific language Is there an excess of specific language impairment (SLI) among children with impairment (SLI) among children with autism?autism?

If so why?If so why?

Early Perspectives on Autism Early Perspectives on Autism and Language Impairment and Language Impairment

““central language deficits related to those found in central language deficits related to those found in children with developmental aphasia, but more severe, children with developmental aphasia, but more severe, may be the necessary and sufficient cause of behavior may be the necessary and sufficient cause of behavior which marks children as autistic” (Churchill, 1972).which marks children as autistic” (Churchill, 1972).

““It is concluded that the autistic child's language It is concluded that the autistic child's language deviance is deviance is not justnot just a reflection of language a reflection of language impairment” (Cantwell, Baker & Rutter, 1978)impairment” (Cantwell, Baker & Rutter, 1978)

The Relationship Re-stated and The Relationship Re-stated and RebuttedRebutted

– The Shot Heard Round the WorldThe Shot Heard Round the World SLI is co-morbid with Autism (Kjelgaard SLI is co-morbid with Autism (Kjelgaard

& Tager-Flusberg, 2001)& Tager-Flusberg, 2001) There is a subgroup of children with There is a subgroup of children with

Autism plus SLI (Tager-Flusberg)Autism plus SLI (Tager-Flusberg)

– The British RespondThe British Respond There is no excess of SLI in autism.There is no excess of SLI in autism. Language problems of children with Language problems of children with

autism do not represent cases of SLI autism do not represent cases of SLI (Whitehouse, Barry & Bishop, 2008; (Whitehouse, Barry & Bishop, 2008; Williams, Botting & Boucher, 2008)Williams, Botting & Boucher, 2008)

Goals of TalkGoals of Talk

Review autism and the place of Review autism and the place of communication problems within autism. communication problems within autism.

Summarize models on the relationship of Summarize models on the relationship of language impairment in autism with SLIlanguage impairment in autism with SLI

Examine key pieces evidence for and Examine key pieces evidence for and against there being a group of children against there being a group of children with both autism and SLI. with both autism and SLI.

Where does the solution lie?Where does the solution lie?– A re-conceptualization of SLI A re-conceptualization of SLI – An alignment of SLI with a model of autismAn alignment of SLI with a model of autism

Communication as MultidimensionalCommunication as Multidimensional Communication is accomplished by the use of Communication is accomplished by the use of

conventionalized conventionalized gesturesgestures to convey to convey messagesmessages that accomplish that accomplish social actssocial acts..– Gesture=Speech or sign (how communication Gesture=Speech or sign (how communication

is accomplished)is accomplished)– Messages= comprise symbols (words) and Messages= comprise symbols (words) and

symbol arrangements (grammar) to convey symbol arrangements (grammar) to convey and interpret meaning (Language)and interpret meaning (Language)

– Social Acts=Pragmatics (why the message is Social Acts=Pragmatics (why the message is expressed)expressed)

Gesture Pragmatics

Language

AutismAutism DSM-IV PerspectiveDSM-IV Perspective

– Triad of Qualitative Autism SymptomsTriad of Qualitative Autism Symptoms Impaired social interactionsImpaired social interactions restricted and repetitive interests and restricted and repetitive interests and

activitiesactivities Qualitative impairments in Qualitative impairments in

communicationcommunication– Abnormal use of language as a social Abnormal use of language as a social

tooltool

– Etiologic core comprised of a single Etiologic core comprised of a single etiology underlying all features.etiology underlying all features.

Autism represents a “natural kind” Autism represents a “natural kind” of developmental disorder.of developmental disorder.– ““Natural kind” “entities possessing Natural kind” “entities possessing

properties bound by natural law” properties bound by natural law” (Quine, 1969)(Quine, 1969)

Social Deficits

Rig

idity

Com

munication

Function

Spared and Impaired Spared and Impaired Communication in AutismCommunication in Autism

Communication Communication function (pragmatics) function (pragmatics) is universally impairedis universally impaired

Speech sound Speech sound production is spared production is spared in many children in many children

Language is highly Language is highly variablevariable

20+% normal or above language

40+% poor language 40+% or more have no usable

language

Gesture Pragmatics

Language

Autism normal language (A0)

Autism + LI (ALI)

ALI = Autism plus SLIALI = Autism plus SLI

““The language phenotype of the ALI The language phenotype of the ALI subtype is the same as the phenotype subtype is the same as the phenotype for SLI.” (Tager-Flusberg, 2006)for SLI.” (Tager-Flusberg, 2006)

SLI ConceptualizedSLI Conceptualized SLI constitutes a “natural kind” of language SLI constitutes a “natural kind” of language

learnerlearner– It posses features that are shared uniquely by all It posses features that are shared uniquely by all

other children with SLI. other children with SLI. – These children present with distinctive language These children present with distinctive language

and cognitive markers that differentiate them and cognitive markers that differentiate them from other poor language learnersfrom other poor language learners

High rates of co-morbidity with SSDHigh rates of co-morbidity with SSD Predominance of expressive problemsPredominance of expressive problems Extraordinary difficulties with grammar (omission of Extraordinary difficulties with grammar (omission of

INFL)INFL) Poor Non-word Repetition (Phonological Poor Non-word Repetition (Phonological

Processing/Memory)Processing/Memory) Heritability suggests a genetic aetiologyHeritability suggests a genetic aetiology

Models of Overlap between SLI Models of Overlap between SLI and Autismand Autism

ALI represents the co-ALI represents the co-morbidity of SLI and Autismmorbidity of SLI and Autism– Separate causal systems that Separate causal systems that

are themselves correlated.are themselves correlated. The ALI overlap is due to causal The ALI overlap is due to causal

factors for SLI being associated factors for SLI being associated with those causing Autism.with those causing Autism.

– The same causal factor yielding The same causal factor yielding different diseases (Pleiotropy)different diseases (Pleiotropy)

Autism and SLI are phenotypic Autism and SLI are phenotypic variants of the same set of genes variants of the same set of genes (Bishop, 2003)(Bishop, 2003)

Should expect overlap in both Should expect overlap in both directionsdirections

SLI AutismALI

A B

SLI ALI

A B C

Autism

ALI is a Phenocopy of SLIALI is a Phenocopy of SLI– ALI mimics many of the ALI mimics many of the

surface features of SLI but surface features of SLI but does not represent the same does not represent the same condition.condition.

– Those factors the cause ALI Those factors the cause ALI are distinct from those that are distinct from those that cause SLI.cause SLI.

– Many of these features may Many of these features may arise from the core features arise from the core features of autism.of autism.

ALI

SLI

A B C X Y Z

Autism

Models of Overlap between SLI Models of Overlap between SLI and Autismand Autism

Domains of Evidence for Overlap Domains of Evidence for Overlap between SLI and Autismbetween SLI and Autism

Language Profiles and MarkersLanguage Profiles and Markers Cognitive EndophenotypesCognitive Endophenotypes Brain StructureBrain Structure Familial AggregationFamilial Aggregation GeneticsGenetics

The SLI Language Features in ALIThe SLI Language Features in ALI ALI ALI

– Language profile on Language profile on standardized tests reveal standardized tests reveal depressed grammar scores depressed grammar scores relative to vocabulary.relative to vocabulary.

– Sentence repetition similar to SLI Sentence repetition similar to SLI group group

– Particular difficulties with tense Particular difficulties with tense and number agreement in and number agreement in elicited sentence tasks marked elicited sentence tasks marked by bare stems. (He walk_)by bare stems. (He walk_)

The language phenotype of The language phenotype of the ALI subtype is the same the ALI subtype is the same as the phenotype for SLI.” as the phenotype for SLI.” (Tager-Flusberg, 2006)(Tager-Flusberg, 2006)

Kjelgaard & Tager-Flusberg, 2001Joseph & Tager-Flusberg, 2003Roberts, Rice & Tager-Flusberg, 2004Rapin & Dunn, 2003Botting & Conti-Ramsden, 2003Whitehouse, Barry & Bishop, 2008

Grammar

Vocabulary

Non-SLI Features in ALINon-SLI Features in ALI– But unlike SLIBut unlike SLI

Few expressive only children.Few expressive only children.Preserved speech productionPreserved speech productionAgreement bare stem errors were not Agreement bare stem errors were not

different between groups (Adifferent between groups (A0,0, ALI) and there ALI) and there was a high rate of non-morphological errors. was a high rate of non-morphological errors. (Williams, Botting & Boucher, 2009)(Williams, Botting & Boucher, 2009)

Better sentence repetition in ALI than SLI Better sentence repetition in ALI than SLI ((Whitehouse, Barry & Bishop, 2008)Whitehouse, Barry & Bishop, 2008)

– Presence of differences and the possibility that Presence of differences and the possibility that similarities are phenocopies suggest that ALI is similarities are phenocopies suggest that ALI is not the same as SLI.not the same as SLI.

Why Might ALI not Look Like SLI?Why Might ALI not Look Like SLI?

Children with SLI are typically Children with SLI are typically sampled from clinical service units sampled from clinical service units for children with communication for children with communication impairments.impairments.

Children with autism are sampled Children with autism are sampled from service units for children with from service units for children with autism.autism.

Does the referral pattern influence Does the referral pattern influence the phenotype?the phenotype?

Is SSD Prominent in SLI?Is SSD Prominent in SLI?

0

10

20

30

40

50

60

70

80

90

100

Normal SLI

SSD/SLI52%

SSD26%

SLI16%

Neither6%

Rates of SSD and SLI in Clinically Served Children

0

10

20

30

40

50

60

70

80

90

100

No Clinical Clinical

Pre

vale

nce

of

SSD

Rates of Expressive Receptive Rates of Expressive Receptive Subtypes in SLI Subtypes in SLI

ExpressiveOnly

ReceptiveOnly

Both Neither0

10

20

30

4033

28

35

4

Percent of Children

Within a Population Sample

•Expressive only problems are not the predominant subtype of SLI.•The rate of subtypes is dependent on how they are computed.

Neither Both ExpressiveOnly

Receptive Only

0

20

40

60

80

100

2.31

80.6

10.65 6.48

Endophenotypes of SLIEndophenotypes of SLINon-Word RepetitionNon-Word Repetition

Co-morbidity in ALI Co-morbidity in ALI – ALI children were less ALI children were less

able to repeat nonwords able to repeat nonwords accurately than Aaccurately than A0 0

children. children. – ALI children were similar ALI children were similar

to SLI children on overall to SLI children on overall accuracy of non-word accuracy of non-word repetition. repetition.

Kjelgaard & Tager-Flusberg, 2001Botting & Conti-Ramsden, 2003Whitehouse, Barry & Bishop, 2008

Phonological Memory Phonological Memory Endophenotype of SLIEndophenotype of SLI

Phenocopy Phenocopy (Whitehouse, Barry & Bishop, 2008)(Whitehouse, Barry & Bishop, 2008)

– The effect of word length (# of syllables) The effect of word length (# of syllables) was different in SLI than ALI.was different in SLI than ALI.

– ALI children with poor NWR were also ALI children with poor NWR were also more likely to have more severe autism more likely to have more severe autism symptoms.symptoms.

– Many of the LI symptoms of ALI children Many of the LI symptoms of ALI children are caused by the autism symptoms. are caused by the autism symptoms.

Brain Structure SimilaritiesBrain Structure Similarities– Overall brain size larger Overall brain size larger – Language areas (inferior frontal, superior Language areas (inferior frontal, superior

temporal gyrus)temporal gyrus)– Greater rates of reduced or reversed Greater rates of reduced or reversed

hemispheric asymmetry in Broca’s areahemispheric asymmetry in Broca’s area Right=>leftRight=>left

– Mixed finding regarding greater than normal Mixed finding regarding greater than normal asymmetry (L>R) for SLI and ALI in posterior asymmetry (L>R) for SLI and ALI in posterior regions. regions.

Brain Imaging of Language Areas Brain Imaging of Language Areas in Children with Autism and SLIin Children with Autism and SLI

Herbert et al., 2001; 2002; 2005DeFosse et al., 2004Joseph & Tager-Flusberg, 2003

Inferior Frontal

SuperiorTemporal G.

Language Status of SLI and Language Status of SLI and Autism Family Members ofAutism Family Members of

Bishop et al. (2006) observed that in the BAP studies Bishop et al. (2006) observed that in the BAP studies language and communication were not distinguished.language and communication were not distinguished.– A parent questionnaire (CCC-2) distinguishing between A parent questionnaire (CCC-2) distinguishing between

language and communication was with siblings of children language and communication was with siblings of children with ASD.with ASD.

– The siblings showed elevated rates of BOTH language and The siblings showed elevated rates of BOTH language and communication deficits. communication deficits.

Whitehouse et al. (2007) tested parents of probands Whitehouse et al. (2007) tested parents of probands with ASD or SLI or TD childrenwith ASD or SLI or TD children– ASD parents were similar to TD parents on language ASD parents were similar to TD parents on language

measures, but SLI parents were poorer.measures, but SLI parents were poorer.– ASD parents were poorer than TD and SLI parents on ASD parents were poorer than TD and SLI parents on

pragmatics.pragmatics.

Ruser et al. (2007) compared parents of ASD, SLI or Down Ruser et al. (2007) compared parents of ASD, SLI or Down Syndrome on communication and language from Syndrome on communication and language from spontaneous language samples.spontaneous language samples.– ASD & SLI parents were poorer than DS parents in both ASD & SLI parents were poorer than DS parents in both

communication and language.communication and language. Language features in parents were more associated with SLI in children Language features in parents were more associated with SLI in children Communication features were associated with ASD in children.Communication features were associated with ASD in children.

Lindgren et al. (2008) compared language, phonological Lindgren et al. (2008) compared language, phonological processing and reading test performance in sibs and processing and reading test performance in sibs and parents of SLI, ALI and Aparents of SLI, ALI and A00

– Relatives of SLI children were generally poorer than the relatives of Relatives of SLI children were generally poorer than the relatives of the ALI or Athe ALI or A00..

– “ “the hypothesis that ALI and SLI families share similar genetic the hypothesis that ALI and SLI families share similar genetic loading for language is not strongly supported” loading for language is not strongly supported”

Language Status of SLI and Language Status of SLI and Autism Family Members ofAutism Family Members of

Is There a Genetic Link?Is There a Genetic Link?

Autism linked to regions on 7q Autism linked to regions on 7q (Alarcon et (Alarcon et al., 2002: 2005; Wassink et al. , 2001) with al., 2002: 2005; Wassink et al. , 2001) with linkage improved when language is linkage improved when language is incorporated into phenotype.incorporated into phenotype.

FOXP2 FOXP2 (7q31) associated with speech and (7q31) associated with speech and language (language (Lai et al., 2001) in isolated Lai et al., 2001) in isolated families, but mutations in families, but mutations in FOXP2FOXP2 are not are not often associated with autism or SLI. often associated with autism or SLI.

Association of LI to 7q31 region outside of Association of LI to 7q31 region outside of FOXP2 FOXP2 (O’Brien et al. 2003)(O’Brien et al. 2003)

CNTNAP2 CNTNAP2 CNTNAP2 is telomeric to is telomeric to FOXP2FOXP2 on ch 7 and is on ch 7 and is

regulated by regulated by FOXP2FOXP2 CNTNAP2 CNTNAP2 has been found to be associated has been found to be associated

with autism and especially those with with autism and especially those with language impairment (Alercon et al. 2008)language impairment (Alercon et al. 2008)..

CNTNAP2CNTNAP2 is associated with Phonological is associated with Phonological Memory (non-word rep.) in children with SLI Memory (non-word rep.) in children with SLI (Vernes, et al. 2009)(Vernes, et al. 2009)

FOXP2 CNTNAP2

  

Phonological Memory (NWR)

Phonological Awareness Language

Marker SNP p-value p-value p-value

Exon 13

Rs17236239 (Vernes et al.) A/G 0.00005 0.008 0.015

QTDT (Mueller/Iowa ) 0.0003857 0.003487 0.1699

Exon 14 

Rs2710117 (Vernes et al.) A/T 0.0004 0.033 0.019

QTDT (Mueller/Iowa) 0.3173 0.7681 0.9042

rs17236239

rs2710117

Iowa Replication in 484 Children (Mueller, in prep)

Summary of ALI/SLI Co-Summary of ALI/SLI Co-MorbidityMorbidity

Language PhenotypeLanguage Phenotype– Similarities in profiles and grammatical morpheme markers, but Similarities in profiles and grammatical morpheme markers, but

some features are missing some features are missing Perhaps due to phenocopyPerhaps due to phenocopy Perhaps due to ascertainment.Perhaps due to ascertainment.

Phonological Memory Phonological Memory – Deficits in both groups, but some differencesDeficits in both groups, but some differences

Perhaps due phenocopyPerhaps due phenocopy

Brain StructureBrain Structure– Similarities in general size and anterior L-R (a)symmetries.Similarities in general size and anterior L-R (a)symmetries.

Co-FamilialityCo-Familiality– Increased liability of language/communication deficits, but Increased liability of language/communication deficits, but

language deficits are less likely to be found in relatives of ASD language deficits are less likely to be found in relatives of ASD children but more so in SLI families.children but more so in SLI families.

GeneticsGenetics– Association of ASD and SLI at Association of ASD and SLI at CNTNAP2CNTNAP2..

Current Status of IssueCurrent Status of Issue

The data are not The data are not completely in favor of completely in favor of one or the other position. one or the other position. – Overlap is most robust Overlap is most robust

when we look at the when we look at the children (phenotype, children (phenotype, brains, genes) brains, genes)

– Less overlap in family Less overlap in family members.members.

Is there a way forward?Is there a way forward?

Toward a Resolution: Toward a Resolution: Reconceptulizing SLI Reconceptulizing SLI

(and Autism)(and Autism)

SLI is not a natural kind of SLI is not a natural kind of language learner language learner

Language emerges out of multiple Language emerges out of multiple interactive neuro-cognitive systems that interactive neuro-cognitive systems that are highly responsive to the biological are highly responsive to the biological and experiential environment.and experiential environment.

These multiple systems are influenced These multiple systems are influenced by many factors including genes by many factors including genes

The same systems that give rise to The same systems that give rise to “normal” variation contribute to “normal” variation contribute to “abnormal.”“abnormal.”

This results in traits that are continuous This results in traits that are continuous from exceptionally high to exceptionally from exceptionally high to exceptionally low (Multifactorial trait)low (Multifactorial trait)

abcdea b c d e

SLI represents a region of low language SLI represents a region of low language

ability that shares the same etiologic factors ability that shares the same etiologic factors as those that contribute to normal variation. as those that contribute to normal variation. – There is no unique causation for SLI, but rather There is no unique causation for SLI, but rather

it is a constellation (conspiracy) of common it is a constellation (conspiracy) of common factors.factors.

– Poor language arises out of the number of risk Poor language arises out of the number of risk factors and nature of their interactions.factors and nature of their interactions.

– Some children with very good language may Some children with very good language may carry the carry the CNTNAP2 CNTNAP2 risk allele, but this allele is risk allele, but this allele is more likely in children with poor language.more likely in children with poor language.

SLI as Region of Individual SLI as Region of Individual DifferencesDifferences

Language

Where does the convergence Where does the convergence come from?come from?

Standard Model (co-morbidity)Standard Model (co-morbidity)– Liability factors are themselves correlated if not Liability factors are themselves correlated if not

shared (plieotropy).shared (plieotropy). Convergence as an outgrowth of help seekingConvergence as an outgrowth of help seeking

– Illness represents the complaints of patients Illness represents the complaints of patients (Englehardt)(Englehardt)

– When children present with troubling development, When children present with troubling development, parents seek help. parents seek help.

– Certain combinations of developmental difficulty Certain combinations of developmental difficulty are more troubling than others.are more troubling than others.

– This results in convergence of symptoms in the This results in convergence of symptoms in the clinic. (Skuse, 2007)clinic. (Skuse, 2007)

– Language impairment is likely to follow this pattern.Language impairment is likely to follow this pattern.

A Possible ResolutionA Possible Resolution

The triad of symptoms of autism and to The triad of symptoms of autism and to a lesser degree the poor language skills a lesser degree the poor language skills (SLI) arise from somewhat different (SLI) arise from somewhat different causes.causes.

Phenotypic interaction remains likely.Phenotypic interaction remains likely. Among children with ASD, there is Among children with ASD, there is

likely to an excess of children with poor likely to an excess of children with poor language abilities (SLI) as an outgrowth language abilities (SLI) as an outgrowth of the added burden of worry.of the added burden of worry.

ConclusionConclusion We need to avoid thinking of children We need to avoid thinking of children

with disabilities as natural kinds with disabilities as natural kinds distinct from “normal”distinct from “normal”

Individual differences among children Individual differences among children across domains of ability are usually across domains of ability are usually multifactorial.multifactorial.

We need to acknowledge that clinical We need to acknowledge that clinical populations are formed by help seeking populations are formed by help seeking and that the causes for this are not the and that the causes for this are not the same as those that generate individual same as those that generate individual differences in the population. differences in the population.

Population based research is needed to Population based research is needed to ensure that we identify artificial co-ensure that we identify artificial co-morbidity.morbidity.

Complex Variation Emerges via Complex Variation Emerges via Multilevel PathwaysMultilevel Pathways

Language emerges from Language emerges from complex interactions within and complex interactions within and between levels of brain and between levels of brain and cognitive systems.cognitive systems.

Genetic processes Genetic processes contribute to contribute to this emergence. this emergence.

The nonlinear interactions The nonlinear interactions within one level give rise to within one level give rise to emergent properties at another emergent properties at another level.level.

Language emerges out of Language emerges out of multiple layers of causal multiple layers of causal systems. Causal relationships systems. Causal relationships are not deterministic across are not deterministic across levels.levels.

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