Developmental Disorders:

What they are; why test, what to test for

Isabelle Rapin

Child Neurology, Sept. 11, 2013

No conflict of interest

11 22

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

11 33

What are developmental disorders ?

Unexpected deficits in the acquisition of specific learned skills

Reflect atypical development of some but not all circuitry in the immature brain uneven skills

Prevalent, with major impacts on children’s and their families’ lives and society

11 44

Examples of developmental disorders

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…

11 55

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…

11 66

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. !!

11 77

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)

11 88

Diagnosis: Fundamental classification issues

2 distinct domains →1. behavior, 2. biology

3 distinct levels → A. Behavior = classification B. Pathophysiology =

mechanisms C. Etiologies = classification

11 99

Hierarchies: genes to behavior

A. BEHAVIOR – COMPLEX, MAINLY DESCRIPTIVELiving, behaving whole person – many behaviors

B. PATHOPHYSIOLOGY, BIOLOGIC MECHANISMS1. Brain – molecules, cells, networks2. Cells – molecules, networks3. Molecules - networks

C. ETIOLOGY, BIOLOGIC CAUSES1. Genetics2. Environment3. Both (incl. epigenetics)

11 1010

Endophenotypes

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

11 1111

Genes

Brain

Behaviors

Genes do not program behaviors !

Brain networks program behaviors

Cellular metabolic microcircuitry

Anatomo-physiologic networks

CAVEAT !

11 1212

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 ?

11 1313

Level A - Behavioral “Diagnoses”

(data on behaving persons) Clinical observations (written reports)

- 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.

11 1414

Level A “diagnoses”= behavioral syndromes

Dimensional, not yes/no binary Bell-shaped distribution of scores Fuzzy overlapping margins

• Between syndromes• Between syndromes and “normality”

11 1515

Overlapping behaviorally defined syndromes

One brain !

Autism

OCDOCD

MRMR

Learning Learning disabilitydisability, , dysphasia, dysphasia, dyslexia, etc.dyslexia, etc.

TouretteTourette

ADHDADHD

Etc.

11 1616

Level B – Pathophysiology= hierarchy of mechanisms

1. Brain networks, connectivity between many participant cortical/subcortical neuronal nodes

2. Cellular networks, e.g., glial/neuronal, excitatory/inhibitory, etc

3. Molecular networks, gene products within/between cells

11 1717

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

11 1818

Overlaps of genes in pathways controlling CNS development or function and other signaling pathways

(Courtesy V.W. Hu 2010)

11 1919

Level B clinical tests – Goal:document pathophysiology(not etiology) of behavioral

diagnosis 1. Brain imaging (morphometry, fMRI, PET, etc.)

2. EEG, other electrophysiologic tests3. Blood and urine tests4. Neurotransmitter, metabolite levels;

other cellular gene products/correlates 5. Etc.

11 2020

Level C - ETIOLOGIES

GENETICS (nuclear, mitochondrial – inherited, de novo* )

ENVIRONMENT (e.g., infection, intoxication…)

GENETICS + ENVIRONMENT (epigenetic)

UNKNOWN – true of most cases today

*parents not arriers, but affected proband transmits if reproduces !

11 2121

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…

11 2222

Level C - GENETIC TESTS(discrete etiologies !)

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)

11 2323

Level C - GENETIC ETIOLOGIESClinical tests

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

11 2424

Goals of neurologic evaluation -

Role of the child neurologist

11 2525

Neurologist’s responsibility

Determine whether an actual disorder is likely

What kind?• Systemic, overtly neurologic? Needs medical Rx? • Behavioral/developmental/psychiatric?

What probable cause?• What tests may be needed? Referrals needed?

What to do about it• Problem not significant. Advise how to handle• Likely to be biologically treatable?• Requires behavioral/educational intervention?

11 2626

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

11 2727

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?

11 2828

Goals of tests in the clinic - 1

Targeted: no algorithm applies to all !

1. Clinical & behavioral (neuropsychologic) tests For clinical diagnosis of the disorder To plan specific educational remediation To guesstimate prognosis For formal funded research

11 2929

Goals of tests in the clinic - 2

Targeted: no algorithm applies to all !

2. Biologic tests (genetic, imaging, EEG, etc.) 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

11 3030

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

11 3131

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?

11 3232

Benefits for researchBE 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

11 3333

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?

11 3434

Targeted mental status screen:

Goal: need for referral ? After warm-up, how does child respond to

parent, to you? Able to talk on a topic? What does he/she do? need for age-

appropriate 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?

11 3535

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

11 3636

Referral for behavior/psychologic testing

Omnibus IQ needed, but not predictive < age 10 yrs; surrogate for overall severity of brain dysfunction

Test hearing & language when speech unclear/absent/bizarre, or comprehension poor

Neuropsychologic testing: very useful for planning remediation in complex cases, but expensive and not universally needed

Consider autism spectrum disorder when atypical behaviors, language, repetitive behaviors, etc.

11 3737

Management -Child neurologist’s

responsibility

11 3838

Summarize consult

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

11 3939

Goals of management

Accomodation, not cure Acceptance by self, family, peers Adequate function within limitations Avoidance of detrimental secondary

consequences for child “ of parental guilt “ of shopping for ineffective Rx

11 4040

Focused psychotropic medications

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

11 4141

Summary

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

11 4242

Flies in the ointment

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.