Developmental Psychopathology

Chapter 12

Wide Range

• As high as 1 in 4 children with diagnosable disorder

• Pervasive developmental, attention deficit and disruptive behaviour, anxiety, tic, elimination

Developmental Disorders

• Recently, lots of focus on childhood, but technically, cover the whole lifespan

• A number of adult disorders manifest early– Median age onset for anxiety and impulse-

control disorders ~11 years, vs. 30 years for mood disorders

– About half of diagnosed disorders identifiable by age 14

Autism

• First formally documented 1943

• Neurodevelopmental disorder– Language, social-emotional, theory of mind

disfunction, restricted, repetitive interests and behaviours

• 1-2 in 1000 for strict diagnosis and 1 in 160 for broader diagnostic criteria (Austism Spectrum Disorder, ASD)

Etiology

• Early-mid 20th C. thought to be due to poor parenting (“refrigerator mothers”) and/or brain damage (no obvious neuronal damage)

• Folstein & Rutter (1977): landmark twin study showing genetic role

• Now recognized to be one of the most heritable mental disorders

Autism Spectrum Disorder• Autism• Asperger syndrome

– Social impairment, motor clumsiness, no delay in cognitive or language development, stereotyped and restricted patterns of activities and interests, intense preoccupation with a narrow subject

• Pervasive developmental disorder not otherwise specified (PDD-NOS)– Criteria not met for specific disorder– Usually milder than autism

Non-ASD Conditions of Interest

• Williams– Highly verbal and overly sociable, but lack

understanding of social cognitive situations, inhibited intelligence

– Series of deletions in 7q11.23

• Obsessive Compulsive Disorder– Role for genes involved in serotonin pathway

– Autistics also show repetitive, obsessive behaviours

– Serotonin pathway also implicated in some autism studies

Male Connection

• 4:1 male-to-female ratio• Fathers of autistics

– Better at piecemeal local processing tasks– Weak central coherence

• Physics, engineering, etc. in male relatives of autistics

• So-called “extreme male” brain• Consider, folk physics vs. folk psychology

Social Cognition

• “Theory of mind”

• Autistics fail false belief test– No IQ or specific cognitive deficits

• No joint attention, poor at deceit, no/limited pretend play, poor grasp of desire

• Similar ToM deficits in Williams and OCD as in ASD

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Neuro

• Medial frontal cortex– Mental state attributions, social behaviour, language

deficits, inappropriate affect– Very similar to autistics

• Mirror neurons– Autistic children show reduced mirror neuron activity

than normal children (Wicker, 2005)– Normal and autistic teens imitate and identify distinct

facial expressions, but autistics don’t show mirror neuron activity

– Autistic knows the expression cognitively, but doesn’t empathize

Autism

• Genetics complex• Can’t be traced to single-gene mutation or

chromosomal abnormalities• Unclear if ASD is explained more by polygenic

effects or rare mutations with major effects• ASD as quantitative extreme of a continuum of

normal variation– “Abnormal is normal”

Heritability

• MZ twins show 60% concordance (3-5% in DZ twins)

• Heritability estimate of 90%

• Relatives show traits phenotypically similar, but milder, to autism’s diagnostic criteria more frequently than controls

Identifying Genes: Inconsistent Results

• Select homogeneous groups of subjects for molecular genetic studies– Characteristics such as language delay– Clear history of developmental regression

• Unclear whether such characteristics are more influenced by genetics or environment

• More power if subgroups could be chosen based on behavioural genetic analyses identifying characteristics with strong genetic basis

Genome Screens

• Over a dozen genome-wide linkage analysis studies

• Suggestive linkage peaks, but relatively little congruence across them

• Most consistent evidence for linkage on 7q and 11p

Genome-wide Linkage Scans

• Red: LOD>3; dark grey: LOD>2; light grey: LOD>1.5• Source: Losh et al. (2008)

Inconsistent Findings

• Genome-wide linkage analysis useful for identifying highly penetrant single-gene disorders

• Poorly suited for polygenic disorders with multiple risk alleles of small effects

Candidate Gene Association

• 5-15% of ASD individuals have identifiable single gene or chromosome disorders (e.g., Jamain et al. 2003, Durand et al. 2007)

• Molecular genetic studies• Generally, inadequate sample sizes and

sparse genotyping• Over 100 possible genes identified so far• Only a few supported by replication

MET Gene

• 7q31 region

• Encodes a tyrosine kinase receptor involved in neuronal growth and organization

• Decreased MET protein levels in autopsied cortical tissue from autistic individuals

SLC6A4

• Role in serotonin (5HT) pathway

• Elevated levels of platelet 5HT in 25-30% of cases of autism

• Studies of SLC6A4 locus generally support its involvement in autism, but no convergence on specific allele or polymorphism to date

RELN• Reelin encodes a protein controlling

intercellular interactions in neuronal migration in brain development

• RELN maps to 7q22 region• A large polymorphic trinucleotide repeat in

RELN gene has been linked to autism in several studies

• RELN also implicated in schizophrenia and OCD

Tumor Suppressor Genes

• PTEN involved in preventing uncontrolled cell growth and division– Mutations linked to Cowden syndrome and

macrocephaly, both also correlated with autism

• TSC1 and TSC2 encode growth suppressor proteins– Mutations cause tuberous sclerosis complex;

autism in 15-60% of cases

Structural Variants

• New technologies have led to greater appreciation for frequency of de novo structural variation in human genome

• Copy Number Variations (CNVs)– Deletions and duplications of chunks of DNA– Sort of the other end of spectrum from SNPs

• CNVs could cause subsets of cases in complex diseases, like autism

CNVs in Autism Studies

• 24% of autistics had de novo CNVs (Jacquemont et al., 2006)

• 593-kb deletions found in three autism study samples in the 16p11.2 region (Weiss et al., 2008)

• Multiple rare genic CNVs (both genome-wide and at specific loci) involved in ASD (Pinto et al. 2010)

Mouse Models

• Recently, mouse models developed that reflect genetic alterations associated with autism

• Some mutant lines based on monogenic aberrations

• Others relevant to loci for autism susceptibility identified by human linkage or association studies

• Prenatal or neonatal environmental challenges

Social Deficits

• Social disfunction and repetitive behaviour central phenotypic classifiers in human autism

• Can identify social deficits and behavioural repetitiveness in mice

• E.g., mice from C57BL/6J and FVB/NJ, but not A/J, BALB/cByJ or BTBR T+tf/J inbred strains show significant preferences to be with other mice than alone

e.g., RELN

• RELN associated with human autism

• Loss of Reln function in mice leads to motor impairment, increased anxiety, learning deficits, abnormal neuroanatomy

• Reeler mouse pups show markedly lower rates of ultrasonic vocalizations (used by mothers)

e.g. 5HT

• Genes for 5HT signaling identified in human autism (e.g., SLC6A4)

• Mouse models often involve targeted disruptions of 5HT pathway

• Some mutant mouse lines for 5HT pathway• Behavioural changes related to anxiety,

depression, aggression, spatial memory, response to reward

e.g. PTEN

• Neuron-specific ablation of Pten in embryonic mice– As adults, show low social approach and

increased activity in novel environments

• Pten-null mice show progressive macrocephaly, dendritic hypertrophy, ectopic dendrites, increased spine density

Attention-Deficit and Disruptive Behaviour Disorders

• Attention deficit hyperactivity disorder (ADHD)– Substantially heritable– Restless, poor attention span, impulsive– ~4% of 6-12 year olds– Boys outnumber girls

• Conduct disorder– Only modest heritability, when occurring in absence of

overactivity/inattention– Aggression to people and animals, destruction of

property, deceitfulness, violation of rules– May be reclassified as antisocial personality disorder

once child passes age 18

ADHD

• 5% risk for first-degree relatives– Risk higher if ADHD in proband continues into

adulthood

• Heritability of about 76%; shared environment negligible

• Substantial genetic overlap between the AD and HD components in this disorder

Conduct Disorder

• 5-10% of children and adolescents meet diagnostic criteria

• Boys greatly outnumber girls• MZ concordance, 87%; DZ concordance, 72%

– Only modest heritability, but high shared environment component

– Should ADHD and CD really be grouped together in DSM-IV?

Overlap

• Latent class analysis technique• Without a hyperactivity component, N.Sig. genetic

contribution to conduct disorder– But shared environment effect very significant

• What ADHD and conduct problems share is largely due to genetics; what conduct problems don’t share with ADHD due to environment

• Antisocial behaviour also a factor complicating interpretation– Aggressive antisocial behaviour more heritable than

nonaggressive antisocial behaviour

Genes

• Dopamine pathway likely involved

• Dopamine transport gene DAT1 was investigated early on, but …poor replication

• Two other dopamine receptor genes, DRD4 and DRD5 are now considered quite likely

• But, another 30 candidate genes also proposed, with mixed results

Autism Spectrum Disorder and ADHD

• Core diagnostic symptoms do not explicitly overlap

• However, high levels of comorbidity between ASD and ADHD reported

Ronald et al. (2008)

• Used Twins Early Development Study, a UK sample of twins born 1994-96 as sample

• Phenotypic overlap– Behavioural criterial, parental and teacher

assessment– 41% of unrelated ASD children also had

suspected ADHD– 22% of unrelated ADHD children met criteria

for ASD

• Genetic overlap– Assessed as quantitative traits, extremes

analysis, and categorical cases– Genetic correlations estimated at 0.5 or higher– Moderate degree of overlap between genetic

influences on autistic and ADHD traits; remainder of genetic influences specific to each

– Over 72% of phenotypic correlation explained by genetic influences; co-occurrence of autistic and ADHD bethaviours mostly due to genetic factors affecting both behaviour types

Childhood Anxiety Disorders

• Three components comparable to adult anxiety disorders– Generalized anxiety– Fears– Obsessive-compulsive behaviours

• Two specific to childhood– Separation anxiety– Shyness/inhibition

Heritability Shared Environment?Shyness/inhibition 75% no Obsessive-compulsive 65% noGeneralized anxiety 40% noFears 40% 10%Separation anxiety 40% 35%

Heritability

• Five components only moderately correlated genetically

• Obsessive-compulsive behaviours least related to the others genetically