Co-morbidly of Autism and SLI: Kinds, Kin or Confounds?Bruce Tomblin, Ph.D.Department of Communication Sciences and DisordersUniversity of IowaResearch Supported by Grant R01 NIH-DC-19-90 from the NIDCD

The Issue Is there an excess of specific language impairment (SLI) among children with autism?If so why?

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

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

Broader Autism PhenotypeThe BAP is found in near relatives of persons with autism. Subclinical dysfunction in communication, social, or stereotyped behaviors A lesser variant of autism that will be expressed in one or more of these domains.LI (reported or observed) in family members Elevated rates of communication language-learning problems (Bolton et al., 1994; Le Couteur et al., 1996; Landa et al., 1992 ) Normal communication skills in family members (Szatmari et al., 1993; Fombonne & Du, 1992; Gillberg, Gillberg, & Steffenburg, 1992)

The Relationship Re-stated and RebuttedThe Shot Heard Round the WorldSLI is co-morbid with Autism (Kjelgaard & Tager-Flusberg, 2001)There is a subgroup of children with Autism plus SLI (Tager-Flusberg)

The British RespondThere is no excess of SLI in autism.Language problems of children with autism do not represent cases of SLI (Whitehouse, Barry & Bishop, 2008; Williams, Botting & Boucher, 2008)

Goals of TalkReview autism and the place of communication problems within autism. Summarize models on the relationship of language impairment in autism with SLIExamine key pieces evidence for and against there being a group of children with both autism and SLI. Where does the solution lie?A re-conceptualization of SLI An alignment of SLI with a model of autism

Communication as MultidimensionalCommunication is accomplished by the use of conventionalized gestures to convey messages that accomplish social acts.Gesture=Speech or sign (how communication is accomplished)Messages= comprise symbols (words) and symbol arrangements (grammar) to convey and interpret meaning (Language)Social Acts=Pragmatics (why the message is expressed)

AutismDSM-IV PerspectiveTriad of Qualitative Autism SymptomsImpaired social interactionsrestricted and repetitive interests and activitiesQualitative impairments in communicationAbnormal use of language as a social toolEtiologic core comprised of a single etiology underlying all features.Autism represents a natural kind of developmental disorder.Natural kind entities possessing properties bound by natural law (Quine, 1969)

Social DeficitsRigidityCommunicationFunction

Spared and Impaired Communication in AutismCommunication function (pragmatics) is universally impairedSpeech sound production is spared in many children Language is highly variable20+% normal or above language40+% poor language40+% or more have no usable language

GesturePragmaticsLanguage

ALI = Autism plus SLI

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

SLI ConceptualizedSLI constitutes a natural kind of language learnerIt posses features that are shared uniquely by all other children with SLI. These children present with distinctive language and cognitive markers that differentiate them from other poor language learnersHigh rates of co-morbidity with SSDPredominance of expressive problemsExtraordinary difficulties with grammar (omission of INFL)Poor Non-word Repetition (Phonological Processing/Memory)Heritability suggests a genetic aetiology

Models of Overlap between SLI and AutismALI represents the co-morbidity of SLI and AutismSeparate causal systems that are themselves correlated.The ALI overlap is due to causal factors for SLI being associated with those causing Autism.The same causal factor yielding different diseases (Pleiotropy)Autism and SLI are phenotypic variants of the same set of genes (Bishop, 2003)Should expect overlap in both directions

SLIAutismALIA B SLIALIA B C Autism

ALI is a Phenocopy of SLIALI mimics many of the surface features of SLI but does not represent the same condition.Those factors the cause ALI are distinct from those that cause SLI.Many of these features may arise from the core features of autism.

A B CX Y ZAutismModels of Overlap between SLI and Autism

Domains of Evidence for Overlap between SLI and AutismLanguage Profiles and MarkersCognitive EndophenotypesBrain StructureFamilial AggregationGenetics

The SLI Language Features in ALIALI Language profile on standardized tests reveal depressed grammar scores relative to vocabulary.Sentence repetition similar to SLI group Particular difficulties with tense and number agreement in elicited sentence tasks marked by bare stems. (He walk_)The language phenotype of the ALI subtype is the same as the phenotype for SLI. (Tager-Flusberg, 2006)Kjelgaard & Tager-Flusberg, 2001Joseph & Tager-Flusberg, 2003Roberts, Rice & Tager-Flusberg, 2004Rapin & Dunn, 2003Botting & Conti-Ramsden, 2003Whitehouse, Barry & Bishop, 2008

Non-SLI Features in ALIBut unlike SLIFew expressive only children.Preserved speech productionAgreement bare stem errors were not different between groups (A0, ALI) and there was a high rate of non-morphological errors. (Williams, Botting & Boucher, 2009)Better sentence repetition in ALI than SLI (Whitehouse, Barry & Bishop, 2008)Presence of differences and the possibility that similarities are phenocopies suggest that ALI is not the same as SLI.

Why Might ALI not Look Like SLI?Children with SLI are typically sampled from clinical service units for children with communication impairments.Children with autism are sampled from service units for children with autism.Does the referral pattern influence the phenotype?

Is SSD Prominent in SLI?Rates of SSD and SLI in Clinically Served ChildrenPrevalence of SSD

Rates of Expressive Receptive Subtypes in SLI 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. NeitherBothExpressiveOnlyReceptive Only0204060801002.3180.610.656.48

Endophenotypes of SLINon-Word RepetitionCo-morbidity in ALI ALI children were less able to repeat nonwords accurately than A0 children. ALI children were similar to SLI children on overall accuracy of non-word repetition. Kjelgaard & Tager-Flusberg, 2001Botting & Conti-Ramsden, 2003Whitehouse, Barry & Bishop, 2008

Phonological Memory Endophenotype of SLIPhenocopy (Whitehouse, Barry & Bishop, 2008)The effect of word length (# of syllables) was different in SLI than ALI.ALI children with poor NWR were also more likely to have more severe autism symptoms.Many of the LI symptoms of ALI children are caused by the autism symptoms.

Brain Structure SimilaritiesOverall brain size larger Language areas (inferior frontal, superior temporal gyrus)Greater rates of reduced or reversed hemispheric asymmetry in Brocas areaRight=>leftMixed finding regarding greater than normal asymmetry (L>R) for SLI and ALI in posterior regions.

Brain Imaging of Language Areas in Children with Autism and SLIHerbert et al., 2001; 2002; 2005DeFosse et al., 2004Joseph & Tager-Flusberg, 2003Inferior FrontalSuperiorTemporal G.

Language Status of SLI and Autism Family Members ofBishop et al. (2006) observed that in the BAP studies language and communication were not distinguished.A parent questionnaire (CCC-2) distinguishing between language and communication was with siblings of children with ASD.The siblings showed elevated rates of BOTH language and communication deficits. Whitehouse et al. (2007) tested parents of probands with ASD or SLI or TD childrenASD parents were similar to TD parents on language measures, but SLI parents were poorer.ASD parents were poorer than TD and SLI parents on pragmatics.

Ruser et al. (2007) compared parents of ASD, SLI or Down Syndrome on communication and language from spontaneous language samples.ASD & SLI parents were poorer than DS parents in both communication and language.Language features in parents were more associated with SLI in children Communication features were associated with ASD in children.Lindgren et al. (2008) compared language, phonological processing and reading test performance in sibs and parents of SLI, ALI and A0Relatives of SLI children were generally poorer than the relatives of the ALI or A0. the hypothesis that ALI and SLI families share similar genetic loading for language is not strongly supported

Language Status of SLI and Autism Family Members of

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

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

Association of LI to 7q31 region outside of FOXP2 (OBrien et al. 2003)

CNTNAP2CNTNAP2 is telomeric to FOXP2 on ch 7 and is regulated by FOXP2CNTNAP2 has been found to be associated with autism and especially those with language impairment (Alercon et al. 2008).CNTNAP2 is associated with Phonological Memory (non-word rep.) in children with SLI (Vernes, et al. 2009)

FOXP2CNTNAP2

Iowa Replication in 484 Children (Mueller, in prep)

Phonological Memory (NWR)Phonological AwarenessLanguageMarkerSNPp-valuep-valuep-valueExon 13Rs17236239 (Vernes et al.)A/G0.000050.0080.015QTDT (Mueller/Iowa )0.00038570.003487 0.1699 Exon 14Rs2710117 (Vernes et al.)A/T0.00040.0330.019QTDT (Mueller/Iowa) 0.3173 0.7681 0.9042

Summary of ALI/SLI Co-MorbidityLanguage PhenotypeSimilarities in profiles and grammatical morpheme markers, but some features are missing Perhaps due to phenocopyPerhaps due to ascertainment.Phonological Memory Deficits in both groups, but some differencesPerhaps due phenocopyBrain StructureSimilarities in general size and anterior L-R (a)symmetries.Co-FamilialityIncreased liability of language/communication deficits, but language deficits are less likely to be found in relatives of ASD children but more so in SLI families.GeneticsAssociation of ASD and SLI at CNTNAP2.

Current Status of IssueThe data are not completely in favor of one or the other position. Overlap is most robust when we look at the children (phenotype, brains, genes) Less overlap in family members.Is there a way forward?

Toward a Resolution: Reconceptulizing SLI (and Autism)

SLI is not a natural kind of language learner Language emerges out of multiple interactive neuro-cognitive systems that are highly responsive to the biological and experiential environment.These multiple systems are influenced by many factors including genes The same systems that give rise to normal variation contribute to abnormal.This results in traits that are continuous from exceptionally high to exceptionally low (Multifactorial trait)

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SLI represents a region of low language ability that shares the same etiologic factors as those that contribute to normal variation. There is no unique causation for SLI, but rather it is a constellation (conspiracy) of common factors.Poor language arises out of the number of risk factors and nature of their interactions.Some children with very good language may carry the CNTNAP2 risk allele, but this allele is more likely in children with poor language.SLI as Region of Individual DifferencesLanguage

Autism as a set of multiple quantitative traitsAutism as a set of multiple quantitative traits (Happe, Ronald & Plomin,2006; Mandy & Skuse, 2008)Each primary feature (social, communication, restricted interests) is the tail of a continuous trait distribution.In a population these traits are not strongly correlated.Autism as a clinical syndrome is formed by the coincidence of these three traits.Is language a part of this convergence?

Where does the convergence come from?Standard Model (co-morbidity)Liability factors are themselves correlated if not shared (plieotropy).Convergence as an outgrowth of help seekingIllness represents the complaints of patients (Englehardt)When children present with troubling development, parents seek help. Certain combinations of developmental difficulty are more troubling than others.This results in convergence of symptoms in the clinic. (Skuse, 2007)Language impairment is likely to follow this pattern.

A Possible ResolutionThe triad of symptoms of autism and to a lesser degree the poor language skills (SLI) arise from somewhat different causes.Phenotypic interaction remains likely.Among children with ASD, there is likely to an excess of children with poor language abilities (SLI) as an outgrowth of the added burden of worry.

ConclusionWe need to avoid thinking of children with disabilities as natural kinds distinct from normalIndividual differences among children across domains of ability are usually multifactorial.We need to acknowledge that clinical populations are formed by help seeking and that the causes for this are not the same as those that generate individual differences in the population. Population based research is needed to ensure that we identify artificial co-morbidity.

Complex Variation Emerges via Multilevel PathwaysLanguage emerges from complex interactions within and between levels of brain and cognitive systems. Genetic processes contribute to this emergence. The nonlinear interactions within one level give rise to emergent properties at another level.Language emerges out of multiple layers of causal systems. Causal relationships are not deterministic across levels.

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