Developmental Disorders:
What they are; why test,
what to test for
Isabelle Rapin
Child Neurology, Sept. 11, 2013
No conflict of interest
AIM OF THE SEMINARS
 Prevalent reason for child neurology office
consult → deepen your knowledge beyond
pushing pills (boring !)
 Showcase their neural basis
 Help you interpret test & other reports
 Prepare you to inform/educate parents
and therapists
 Make the consult more effective
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What are developmental disorders ?
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Unexpected deficits in the acquisition of specific
learned skills
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Reflect atypical development of some but not all
circuitry in the immature brain  uneven skills
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Prevalent, with major impacts on children’s and
their families’ lives and society
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Examples of developmental
disorders
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Developmental language disorders
Dyslexia, problems with other academic skills
Attention deficit disorders with/without
hyperactivity
Autism spectrum disorders
Inept acquisition of motor skills
Tone deafness
Etc…
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Develomental disorders:
Conventional Clinical Diagnostic Criteria
Not due to
 *major brain malformation, disease, trauma,
epilepsy, identified genetic disorder, etc.
 lack of opportunity, e.g., environmental or
social deprivation, poor teaching
 global intellectual disability
 medication effect
 etc.
*Controversial view ! Stay tuned…
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Nature of DSM behavioral
“diagnoses”
• They are behavioral syndromes
 Defined by clusters of behaviors/symptoms
• Behavioral DSM “diagnoses” are pseudo-
dichotomous, but needed !
• Keep this in mind when speaking with biologic
investigators researching their causes and
pathophysiologies
• But the real world requires dichotomies for
resource allocation, school placement, etc. !!
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Genes to behavior
1. BEHAVIORAL DOMAIN/LEVEL ―
- descriptive, observational
 continuous range of severity, i.e.,
distance from a population norm
2. BIOLOGIC DOMAIN/LEVEL ―
 dichotomous, discrete, yes/no (despite
some gene mutations having dimensional
effects)
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Diagnosis: Fundamental
classification issues
2 distinct domains →
1. behavior, 2. biology
3 distinct levels →
A. Behavior = classification
B. Pathophysiology = mechanisms
C. Etiologies = classification
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Hierarchies: genes to behavior
A. BEHAVIOR – COMPLEX, MAINLY DESCRIPTIVE
Living, behaving whole person – many behaviors
B. PATHOPHYSIOLOGY, BIOLOGIC MECHANISMS
1. Brain – molecules, cells, networks
2. Cells – molecules, networks
3. Molecules - networks
C. ETIOLOGY, BIOLOGIC CAUSES
1. Genetics
2. Environment
3. Both (incl. epigenetics)
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Endophenotypes
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Specific components of complex behaviors/
observations
Examples: perfect pitch, atypical head growth,
hand stereotypies, shyness, etc.
May run in “unaffected” family members →
suggest an underlying gene(s)/CNV*
Correlated gene/CNV does not “cause” a
behavioral trait, much less clinical diagnosis !
*CNV=copy number variation, i.e., dup or del of numbers of bases
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Genes
Genes do not
program
behaviors !
Cellular metabolic
microcircuitry
Brain
Brain networks
program
behaviors
Anatomo-physiologic
networks
Behaviors
CAVEAT !
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Contentious issues
• Do specific etiologies, e.g., Down
syndrome, previous meningitis, Fra-X, etc.
exclude the diagnosis of autism, or
dyslexia ?
• Is it likely that “idiopathic” XYZ is “pure” ?
• What do we mean by co-morbidity ?
What do multiple “diagnoses” imply ?
Does ADHD exclude an ASD diagnosis ?
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Level A - Behavioral “Diagnoses”
(data on behaving persons)
 Clinical observations (written reports)
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- behavioral observations, scales, etc.
Standardized (quantitative) tests of function
- questionnaires (history, observations)
- psychologic/neuropsychologic tests
- language, standardized observations, etc.
Computerized tests (ADHD, faces, etc.)
Photos, videos, recordings
Etc.
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Level A “diagnoses”
= behavioral syndromes
 Dimensional, not yes/no binary
 Bell-shaped distribution of scores
 Fuzzy overlapping margins
• Between syndromes
• Between syndromes and “normality”
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Overlapping behaviorally defined syndromes
One brain !
Etc.
OCD
Autism
Tourette
MR
ADHD
Learning
disability,
dysphasia,
dyslexia, etc.
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Level B – Pathophysiology
= hierarchy of mechanisms
1.
2.
3.
Brain networks, connectivity between
many participant cortical/subcortical
neuronal nodes
Cellular networks, e.g., glial/neuronal,
excitatory/inhibitory, etc
Molecular networks, gene products
within/between cells
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Differentially methylated RORA & other genes (blue) affecting
processes/disorders differentially expressed by DNA micro-arrays (yellow)
(Courtesy V.W. Hu, 2011)
RORA = retinoic acid-related orphan receptor-alpha
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Overlaps of genes in pathways controlling CNS development or function and
other signaling pathways
(Courtesy V.W. Hu 2010)
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Level B clinical tests – Goal:
document pathophysiology
(not etiology) of behavioral diagnosis
1.
2.
3.
4.
5.
Brain imaging (morphometry, fMRI, PET, etc.)
EEG, other electrophysiologic tests
Blood and urine tests
Neurotransmitter, metabolite levels;
other cellular gene products/correlates
Etc.
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Level C - ETIOLOGIES
 GENETICS (nuclear, mitochondrial
–
inherited, de novo* )
 ENVIRONMENT (e.g., infection, intoxication…)
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GENETICS + ENVIRONMENT (epigenetic)
 UNKNOWN
– true of most cases today
*parents not arriers, but affected proband transmits
if reproduces !
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Epigenetics
 Heritable changes in gene activation
without alteration of its DNA sequence
 Modification of histone shape
 Cytosine methylation (CpG sites)
 Role in development & life-long (MZ twins)
 Environmentally influenced, e.g.,
 Toxins, cancer…
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Level C - GENETIC TESTS
(discrete etiologies !)
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Genetic loci (identified in family trees)
Chromosomal anomalies – number, cytogenetics:
deletions, duplications, translocations, copy
number variations (CNVs), etc.
Single gene mutations, deletions, trinucleotide
repeats, etc. with major/minor effects – GWAS
(genome-wide association studies)
Gene sequencing – identify specific mutation
Epigenetic effects (± environmental)
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Level C - GENETIC ETIOLOGIES
Clinical tests
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Genetic tests (including microarrays [GWAS*,
chips]  CNVs, genes)
Molecular gene products (~ proteins, enzymes,
receptors, etc.)
Etc.
Indications: see Michelson et al report –
Neurology 2011; 77:1629.
*GWAS=genome-wide association study=micro-array
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Goals of neurologic evaluation Role of the child neurologist
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Neurologist’s responsibility
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Determine whether an actual disorder is likely
What kind?
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What probable cause?
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What to do about it
• Systemic, overtly neurologic? Needs medical Rx?
• Behavioral/developmental/psychiatric?
• What tests may be needed? Referrals needed?
• Problem not significant. Advise how to handle
• Likely to be biologically treatable?
• Requires behavioral/educational intervention?
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Office visit
 Watch child play with appropriate toys
while… (advantage: warm up)
 History/family history/review records
 Screening mental status
 Screening neurologic exam
 Undressed screening general physical
 Preliminary impression
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Decide on need for tests
 Hard core disease/lesion likely? Epilepsy?
 work-up accordingly
 Learning disability? Need further
evaluation/management?
 Behavioral issues? Need further
evaluation/management, medication?
 Need to determine biologic etiology?
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Goals of tests in the clinic - 1
Targeted: no algorithm applies to all !
1.
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Clinical & behavioral (neuropsychologic)
tests
For clinical diagnosis of the disorder
To plan specific educational remediation
To guesstimate prognosis
For formal funded research
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Goals of tests in the clinic - 2
Targeted: no algorithm applies to all !
2. Biologic tests (genetic, imaging, EEG, etc.)
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Not for “diagnosis” of the clinical disorder,
e.g., ADHD, ASD
To discover the biologic etiology and
pathophysiology
Perhaps provide genetic counseling, etc.
For formal funded research
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Neurologic tests
 Imaging and electrophysiology: not
indicated if no suspicion of a hard core
neurologic condition/lesion, e.g., epilepsy
 Uninformative in isolated developmental
disorders
 Not diagnostic of developmental disorders
 Expensive, stressful
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Referral for etiologic/biologic/
genetic testing
 Indicated if + FH or exam or severe case
 What is the goal of the test if not?
• Direct benefit to child – very rarely
• Benefit to family – genetic counseling ??
psychologic, financial?
To physician/geneticist – curiosity, career
advancement, etc.
• Research?
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Benefits for research
BE CLEAR ABOUT GOAL AND WHO PAYS !
• If more testing than clinically indicated, must be paid
for by research funds
• Not fair to charge to family, clinical insurance,
Medicaid, etc.
• Engage family as collaborators in research
• Special IRB permission required for research. Discuss
goals, that specimens, videos (special permission
needed for teaching, publishing), that biologic
specimens and test results, etc. will be anonymized
and retained for later research
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Problems with micro-arrays (gwas)
Widely desired & recommended, but…
 Data ~ not interpretable  more testing
 False positives/negatives
 Child not consulted, e.g., Huntington
 May discover non-paternity, adoption etc.
 Relatives not consulted, e.g. re cancer risk
 Who pays?
 Money better spent otherwise?
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Targeted mental status screen:
Goal: need for referral ?
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After warm-up, how does child respond to
parent, to you? Able to talk on a topic?
What does he/she do?  need for ageappropriate toys, books, etc. in the office !
Level of activity, anxiety, compliance
At preschool: 1 inch blocks, drawing, counting,
naming colors, etc.
At schoolage: reading, writing, simple math
Mood, inappropriate behaviors or speech?
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Goals of Behavioral Testing
 Provide a clinical diagnosis  services
 Assess overall competence (IQ as
surrogate for severity of the brain
dysfunction)
 Identify specific deficit(s) to be addressed
educationally
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Referral for behavior/psychologic testing
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Omnibus IQ needed, but not predictive < age 10 yrs;
surrogate for overall severity of brain dysfunction
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Test hearing & language when speech
unclear/absent/bizarre, or comprehension poor
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Neuropsychologic testing: very useful for planning
remediation in complex cases, but expensive and not
universally needed
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Consider autism spectrum disorder when atypical
behaviors, language, repetitive behaviors, etc.
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Management Child neurologist’s responsibility
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Summarize consult
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Severity/type of problem
Findings, test results
Lack of evidence for “disease”
Developmental, likely genetic cause
Probable outcome
What to do/not to do, guidance on child rearing
Consider whether medication needed
Schedule follow-up visit to review
Send written report to parents
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Goals of management
 Accomodation, not cure
 Acceptance by self, family, peers
 Adequate function within limitations
 Avoidance of detrimental secondary
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“
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consequences for child
of parental guilt
of shopping for ineffective Rx
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Focused psychotropic medications
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Symptomatic, not curative
Focus on most troublesome behavior/symptom,
e.g, sleep, epilepsy, self-injury, aggressiveness,
etc.
First: adequate trial of behavioral treatments
Stimulants (methylphenidate) may be very
helpful in ADHD, even when cause known
Risperidone: approved for ASD to mitigate
aggressiveness and irritability. Potential
permanent side-effects
Too many psychotropic drugs prescribed
Avoid medication cocktails
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Summary
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Main etiology: genetics (+ environment)
Diagnosis: behavioral, not biologic
No direct jump from genetics to behavior
No routine biologic testing, including micro-arrays
Be honest about purpose of tests (clinical vs.
research vs. looking good on rounds, etc.)
Most effective intervention is targeted education,
not pills
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Flies in the ointment
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Too much to do in one hour !
Many insurances don’t pay child neurologists
(but do developmental pediatricians…)
Don’t know as much about interventions as
developmental pediatricians
Yet can often wrap up the most comprehensive
consult, including genetics, need/no need for
tests, brain basis, etc.
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