The diagnosis and management of medical disorders in autism

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The diagnosis and management ofmedical
disorders in autism

• Dr Jeremy Parr

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Overview

• Investigations guided by history and examination
• Two main areas of investigation in paediatrics
• Genetics
• Aetiology medical disorders and genetics
  genetic tests
• Broader Autism Phenotypes in parents and
  siblings implications for relatives genetic
  counselling
• Regression
• when to investigate

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A neurodevelopmental / neurological perspective

• History
• Family
• Developmental
• Examination
• Facial and other physical characteristics skin
  exam
• Neurological examination (inc. head
  circumference)
• Are there clues to a possible medical cause of
  autism
• (cause vs. other medical problems)

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Aetiology

• Idiopathic vs. secondary
• 10-15 of children with autism have identified
  cause secondary
• Remainder related to genetic and other factors
  
• idiopathic or of presumed genetic origin
• Genes for autism not a useful description
  susceptibility
• genes
• Children with idiopathic autism are generally
  healthy

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Aetiology secondary autism

• The ASD phenotype is seen in children with a
  variety of neurodevelopmental disorders
• Fragile X
• Chromosomal abnormalities
• Tuberose sclerosis
• Perinatal factors not cause prematurity
• Lead?

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Aetiology secondary autism

• Down syndrome
• 15q11-13 duplication
• 22q13 deletion
• Septo optic dysplasia optic nerve hypoplasia
• Smith-Lemli-Opitz
• Smith-Magenis
• (Epileptic encephalopathy)

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Two diagnoses / labels?

• If the clinical features fit criteria, why not
  say that children have an ASD?
• Helps with
• Label aids understanding by professionals,
  families, friends
• Access support
• Education intervention, assistance, environment
• Family strategies
• Medication?

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Investigations

• History and examination guide investigations
• Genetic
• Blood and urine metabolic
• Neurophysiological
• Neuroimaging

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When to do genetic tests?Genetic autism An
historical perspective

• Case reports of MZ twins
• Twin studies
• Realisation that increased rate in siblings
  compared with population
• Family studies mild phenotypes in relatives
• Affected relative pair studies

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Genetics

• Genes are made of DNA
• Genes inherited from both parents (50 50
  siblings)
• Genes make up chromosomes which are present in
  all cells
• Genes make proteins proteins are building blocks
  of body
• Proteins involved in nerve cells and chemicals
  used to communicate (neurotransmitters)
• Neurotransmitters involved in brain cell signals
• Attention Deficit Hyperactivity Disorder

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Twin studies

• Twin studies increased concordance for autism
  in
• co twins
• Evidence for a Broader Autism Phenotype

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Genetic mechanisms

• multiple genes involved (3-4? As many as 10? Even
  more?)
• similar genetic mechanisms to heart disease,
  hypertension, dyslexia, schizophrenia
• non-deterministic have gene, dont necessarily
  have autism
• genetic and phenotypic variability
  (heterogeneity)

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Molecular Genetic Studies of Autism

• Many groups IMGSAC - researchers from UK, EU, US
• Affected relative pair study (ARPs) siblings
  with ASD
• Searching for autism susceptibility genes
• No obvious functional or positional candidate
  genes, linkage studies required increased
  sharing of genes in ARPs
• Test likely candidate genes at areas of linkage

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Candidate genes
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Autism Genome Project

• Further collaboration data sharing between
  IMGSAC and other groups
• Previous study sizes 300 ARPs
• AGP study 1496 ARPs from 4 individual
  collaborations
• Further identification of loci using linkage
  studies

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AGP findings and future direction

• Evidence of linkage to chromosome 11p12-p13
• CNVs (submicroscopic abnormalities)
• Modest linkage to 2q and 7p from European
  families
• Analysis implicates neurexins and neuroligins
  related to
• synaptic differentiation of glutamatergic
  neurons glutamate
• strongly linked to ASD
• FRAX, TS both associated with abnormal glutamate
  signalling
• Fine mapping of 11p12-13 particularly glutamate
  genes

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Investigations

• History and examination guide investigations
• Genetic
• Chromosomes
• Fragile X
• Tuberose sclerosis testing
• In the future, testing of specific areas of
  chromosomes
• 16p?
• CNVs?

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Might family history help us decide about
genetic tests? Studies of relatives of
individuals with ASD

• Broader autism phenotype (BAP)
• relatively mild autistic like behavioural
  traits
• improve understanding of whole dimensional autism
  spectrum phenotype
• Part of Family History

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Definition of Broader Autism Phenotype

• BAP not only expressed behaviourally specific
  cognitive impairments face processing deficits
  imaging findings
• Sometimes parents of individuals with autism see
  similarities between their own behaviour and
  their child
• Personality traits vs. transient behaviours

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BAP research populations and findings

• BAP assessed in relatives of individuals with
  autism / ASD
• Rates of impairment higher in relatives of
  sibling pairs with ASD than singletons
• Males gt females siblings gt parents 1st degree
  relatives gt more distant
• Social domain impairment gt communication gt
  repetitive
• Are data from studies of sibling pairs with ASD
  applicable to singleton
• samples?
• Are singleton families genetically similar to
  multiplex? Stoppage effects

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EMOTIONAL CUES AND RESPONSIVENESS IN CHILDHOOD
Focus on age 5.0-15.11. This item focuses on
the subject's sensitivity to the expressed
emotions of others and their response. As a
child how were you at picking up on how other
people were feeling? For instance if someone was
upset could you tell? Did you ever have
difficulty recognising whether people were happy,
sad or angry? Did you ever have difficulty
responding to whether people were happy, sad or
angry? How did you usually react when someone
was obviously sad? Did you usually try to comfort
them? If difficulties mentioned, probe Did you
ever get into trouble for not noticing or
responding to how someone was feeling? 0
no difficulties in recognising and responding to
emotional cues 1 some difficulties
recognising and responding to emotional cues may
have been remarked upon by others, but not
associated with significant social
difficulties 2 persistent and significant
difficulties recognising and responding to
emotional cues code here if subjects behaviour
led to distress, conflicts or avoidance of
emotionally charged situations, or was
associated with teasing/bullying
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Distribution of adult FHI-I scores (n 320, mean
7.4)
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Communication impairments (n 52 males vs. 60
female sibs stat signif diff between rates)

• Language delay rates relatively low 10
• Conversational impairment
• Lack of interest 18 males, 5 females
• Reciprocal quality 16 (MF)
• Pedantic speech 16 (MgtF)

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Social impairment rates (n 52 males vs. 60
female sibs stat signif diff between rates)

• Social play 25 males, 5 females
• Aloofness 26 males, 7 females
• Friendships 26 males, 16 females
• Affection 22 males, 9 females
• Emotional cues 26 males, 12 females

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Psychiatric co morbidity

• Consistent finding is for liability to depression
• 20 IMGSAC female siblings
• 12 IMGSAC mothers during childhood (n153)
• Other studies have shown high rates depression
  prior to the
• birth of children with ASD
• Bipolar disorder previously considered linked
  lt1 in IMGSAC study

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Why identify the BAP? clinical reasons

• Childhood
• Diagnosis explains strengths and weaknesses
  social skills
• Adulthood
• Traits seen as negative may afford advantage
  (employment)
• Target provision in the workplace, explain
  difficulties with relationships
• Genetic counselling
• Generic risk for another child with ASD
• Might lead to more quantifiable risk for
  individual families

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Regression
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Neurodevelopmental regression in autism

• Loss of acquired skills (loss vs. plateau, or
  variability in
• performance)
• Prevalence
• Subtypes
• Key findings
• When to be concerned about medical disorders
• Investigations

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Prevalence

• (To some extent dictated by methodology)
• Most studies find 25 35 regression
• Majority of regression is loss of speech
• Equal in males and females
• Most common before age 3 years late regression
  does
• occur, more likely to be social or motor than
  language

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Subtypes

• Early or late loss (i.e. pre and post 3 years)
• Language
• Speech words or phrases (Definite loss)
• Less complex speech (Lower level language loss)
• Social
• Motor
• Functional

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Key findings

• Second year of life may be a presenting feature
• Regression children use first words and phrases
  earlier
• Most children regain skills those who dont may
  have more severe autism and lower attainments
• Some evidence that children with language loss
  may have more severe autism, lower verbal IQ,
  lower attainments
• Investigations are negative
• Part of autism phenotypic heterogeneity? Or
  genetics? Or something else?

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Is there a genetic influence on regression?
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When one sibling regresses, is there an increased
likelihood of regression in the second sibling
(increased concordance)?

• IMGSAC
• 133 / 486 individuals regress (27)
• 89 pairs discordant, 22 pairs concordant

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When to be concerned about medical causes

• Outside autism, regression is rare
• Presenting feature which doesnt fit
  developmental history
• or
• After age 3 years
• definite language regression
• social or motor regression

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Investigations

• History and examination guide investigations
  only when
• history or exam unusual
• Genetic MECP2, CDLK5 (chromosomes etc)
• Metabolic (blood and urine) long list
• Neurophysiological EEG (wake and sleep)
• Neuroimaging (MRI brain with and without IV
  contrast)
• May find nothing late regression is poorly
  researched as rare

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History and examination guide investigations

• Genetic
• Blood and urine metabolic
• Neurophysiological
• Neuroimaging

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History and examination guide investigations

• Genetic
• Blood and urine metabolic no evidence
• Neurophysiological no evidence
• Neuroimaging no evidence

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Future understanding of medical issues in
autism High risk sibling studies

• Siblings of individuals with autism inc. risk of
  autism (5-10?)
• Allows prospective assessment of phenotype and
  other factors
• Pregnancy and perinatal factors
• Macrocephaly (increased head circumference)
• Language and social development regression
• Epilepsy

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High risk sib research methodological factors

• Challenges
• Sample size
• Enrolment age freq of assessments
• Measurement of behaviours
• Generalisability are multiplex different to
  singletons?
• Clinical issues and ethics diagnosis and
  intervention

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Thank you

• Questions?

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Diagnosis and management
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Intervention and medication

• Evidence is that early intervention is effective
  data sparse few
• RCTs
• Studies with varying methodological weaknesses
• autism or ASD?
• characterisation clinical or research criteria?
• adequate randomisation?
• duration of intervention? Maintained?
• clinical benefit or improved outcome scores?
• long term outcome?
• No gold standard intervention no comparative
  studies
• No medication lessens core features of ASD (side
  effects)

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Considerations for families

• Clinicians should help parents consider the
  evidence families
• are searching for an approach that works
  cures?
• Home or school based intervention by teachers or
  parents?
• Balance likely improvement against costs
• Negative effects to child
• Financial direct costs, lost earnings
• Impact on siblings
• Impact on parental relationship

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Questions that you should ask (yourselves and us)

• What is the evidence regarding the efficacy of
  ____ in autism?
• For whom does it work? At what age should it
  start?
• What are the costs? Financial? Emotional? Family?
• What are the negative effects?
• How much improvement is expected? In what
  proportion of
• individuals?
• Is improvement maintained?

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Intervention

• Evidence is that early intervention is effective
  data sparse
• EIBI (Lovaas / ABA) RCTs modest evidence
• TEACCH Quasi RCT, 22 children
• Childs Talk RCT, 28 children
• More Than Words Quasi RCT, 29 children
• PECS Good evidence!
• No data on APP, social skills, social stories,
  floor time, SonRise

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Medication / diet / treatment

• Useful
• Risperidone RUPP RCT, 101 children
• Methylphenidate RCT, 47 children 30 response
• Selective Serotonin Reuptake Inhibitors (e.g.
  fluoxetine) data weak, clinical consensus
• Not useful Secretin
• Insufficient data Diets, AIT, SIT, chelation,
  immunoglobulin,
• fish oils, probiotics, B6-Mg etc
• Pharmacogenetics?

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Resources
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Thank you

• Questions?