Neurodevelopmental disorders from bench to bedside
Neurodevelopmental disorder according to DSM-5
- intellectual disability
- communication disorders
- specific learning disorders (e.g. dyslexia)
- motor disorders
- ADHD
- ASD
Defining characteristics (not universal/strict)
1. typical onset before puberty
2. clinical course steady in the long term, rather than remitting/relapsing (not like bipolar
where your mood changes very quickly)
3. early onset neurocognitive deficits
4. more prevalent in males
5. high heritability, aetiology multifactorial
6. high level of overlap (comorbidity/heterogeneity)
ADHD: hyperactivity, impulsivity, inattention, deviating empathy
ASD: social/communication problems, inattention, impulsivity, compulsivity, deviating
(cognitive) empathy
Oppositional defiant disorder (ODD) & conduct disorder (CD): aggression, antisocial
behavior, impulsivity, deviating (emotional) empathy
Heterogeneity
Clinical heterogeneity: different patients with the same disorder have different patterns and
clusters of symptoms
Etiological heterogeneity: different causes can be at play for different patients with the same
symptoms and/or disorder
- treatment response is also heterogeneous
Co-occurrence (co-morbidity)
co-occurrence: the same patient has multiple disorders → within neurodevelopmental and
with other disorders
- Co-occurrence itself is heterogeneous → Different patients with the same disorder
can have different co-occurring disorders
Dimensional traits vs categorical diagnoses
● dimensional
, - cut-off can be placed differently → now you only have ADHD if you score very high
- advantages of these dimensions: no artificial cut-off, better reflection of underlying
biology, statistically more powerful, similar prognostic, genetic & neuroimaging
correlates as diagnosis
● categorical
- you have the disorder yes or no
- advantages of categorical: aids clinical decision making, includes impairment,
access to treatment
Genes and behavior
- most behaviors (complex traits or phenotypes) are heritable (complex trait =
neurodevelopmental disorder)
- most are multifactorial, and highly polygenic due to multiple genes (of small effect
size)
- environment is also important
- genes provide a recipe but not a blueprint
Endophenotype
Definition: Measurable components “unseen by the unaided eye” along the pathway
between clinical phenotype and distal genotype. An endophenotype may be
neurophysiological, biochemical, endocrinological, neuroanatomical, cognitive in nature
● Heritable biomarker, dimensional trait
1. The endophenotype is associated with disorder in the population.
2. The endophenotype is heritable.
3. The endophenotype is primarily state-independent (manifests in an individual
whether or not disorder is active).
4. Within families, endophenotype and disorder co-segregate.
5. The endophenotype (found in affected family members) is found in non-affected
family members at a higher rate than in the general population.
- predictions:
, 1. closer to genetic effect than original diagnosis
2. Stronger effect of risk genes on endophenotype than on clinical phenotype,
and/or
3. Few genes involved, lower genetic complexity
- The endophenotype concept, in its original form (especially its underlying
predictions), is outdated. Complex interaction at different levels from genes to brain
to cognitive function to behavior
Autism Spectrum Disorder
- autism is a heterogeneous disorder with multiple causes and courses a great range
in the severity of symptoms and several associated comorbid disorders
- autism is better named as the autisms i.e. a collection of different conditions
- autism is a synaptic disorder
- autism is a disorder of brain development, brain connectivity, abnormal social
information processing, sensory-perceptual dysfunction
ASD in DSM-5
● social communication deficits:
- lack of social understanding
- non-verbal behaviors (eye contact, gestures)
- atypical intonation, rate, volume of speech
- idiosyncratic language
- echolalia (repetition of noises and phrases they hear)
- language delay
● fixated interests, repetitive behaviors, and abnormal sensory responses:
- unusual sensory interests
- hand/finger/complex mannerisms
- excessive interest in highly specific topics
- compulsions/rituals
- sensory aversions
→ autism is found in young children (around age 5), thus it is already present at birth and
does not develop later in life (like bipolar disorder, etc.)
, ASD diagnosis
● Autism diagnostic observation schedule (ADOS)
- structured and semi-structured tasks
- observation of social interaction
● Autism diagnostic interview (ADI)
- standardized, semi-structured clinical interview with parents
- 93 items
- three content areas: quality of social interaction, communication and
language, and repetitive, restricted and stereotyped interests and behavior
- autism is prevalent in males (male:female ratio is 4:1)
- WHY? - females are better at compensating/camouflaging?, male-biased diagnostic
criteria (boys are more often interested in certain objects and females are often more
social naturally)?, present phenotypically differently, female sex is a protective
factor?
Comorbidities: 70% of individuals with ASD diagnoses have at least one other diagnosis
(DSM-5) → ODD, ADHD, OCD, Tourettes, Anxiety, ADD, Depression, ...
ASD outcomes
- good outcome: moderate to high levels of independence (living, job, friends,
acquaintances)
- fair outcome: need support at work/home but some autonomy
- bad outcome: living in situation with close supervision in most activities
- 80% poor - 20% good
- subjects that do poor early (at age 2) will do poor later, and subjects that do good
early will do good later
Neurodevelopmental disorder according to DSM-5
- intellectual disability
- communication disorders
- specific learning disorders (e.g. dyslexia)
- motor disorders
- ADHD
- ASD
Defining characteristics (not universal/strict)
1. typical onset before puberty
2. clinical course steady in the long term, rather than remitting/relapsing (not like bipolar
where your mood changes very quickly)
3. early onset neurocognitive deficits
4. more prevalent in males
5. high heritability, aetiology multifactorial
6. high level of overlap (comorbidity/heterogeneity)
ADHD: hyperactivity, impulsivity, inattention, deviating empathy
ASD: social/communication problems, inattention, impulsivity, compulsivity, deviating
(cognitive) empathy
Oppositional defiant disorder (ODD) & conduct disorder (CD): aggression, antisocial
behavior, impulsivity, deviating (emotional) empathy
Heterogeneity
Clinical heterogeneity: different patients with the same disorder have different patterns and
clusters of symptoms
Etiological heterogeneity: different causes can be at play for different patients with the same
symptoms and/or disorder
- treatment response is also heterogeneous
Co-occurrence (co-morbidity)
co-occurrence: the same patient has multiple disorders → within neurodevelopmental and
with other disorders
- Co-occurrence itself is heterogeneous → Different patients with the same disorder
can have different co-occurring disorders
Dimensional traits vs categorical diagnoses
● dimensional
, - cut-off can be placed differently → now you only have ADHD if you score very high
- advantages of these dimensions: no artificial cut-off, better reflection of underlying
biology, statistically more powerful, similar prognostic, genetic & neuroimaging
correlates as diagnosis
● categorical
- you have the disorder yes or no
- advantages of categorical: aids clinical decision making, includes impairment,
access to treatment
Genes and behavior
- most behaviors (complex traits or phenotypes) are heritable (complex trait =
neurodevelopmental disorder)
- most are multifactorial, and highly polygenic due to multiple genes (of small effect
size)
- environment is also important
- genes provide a recipe but not a blueprint
Endophenotype
Definition: Measurable components “unseen by the unaided eye” along the pathway
between clinical phenotype and distal genotype. An endophenotype may be
neurophysiological, biochemical, endocrinological, neuroanatomical, cognitive in nature
● Heritable biomarker, dimensional trait
1. The endophenotype is associated with disorder in the population.
2. The endophenotype is heritable.
3. The endophenotype is primarily state-independent (manifests in an individual
whether or not disorder is active).
4. Within families, endophenotype and disorder co-segregate.
5. The endophenotype (found in affected family members) is found in non-affected
family members at a higher rate than in the general population.
- predictions:
, 1. closer to genetic effect than original diagnosis
2. Stronger effect of risk genes on endophenotype than on clinical phenotype,
and/or
3. Few genes involved, lower genetic complexity
- The endophenotype concept, in its original form (especially its underlying
predictions), is outdated. Complex interaction at different levels from genes to brain
to cognitive function to behavior
Autism Spectrum Disorder
- autism is a heterogeneous disorder with multiple causes and courses a great range
in the severity of symptoms and several associated comorbid disorders
- autism is better named as the autisms i.e. a collection of different conditions
- autism is a synaptic disorder
- autism is a disorder of brain development, brain connectivity, abnormal social
information processing, sensory-perceptual dysfunction
ASD in DSM-5
● social communication deficits:
- lack of social understanding
- non-verbal behaviors (eye contact, gestures)
- atypical intonation, rate, volume of speech
- idiosyncratic language
- echolalia (repetition of noises and phrases they hear)
- language delay
● fixated interests, repetitive behaviors, and abnormal sensory responses:
- unusual sensory interests
- hand/finger/complex mannerisms
- excessive interest in highly specific topics
- compulsions/rituals
- sensory aversions
→ autism is found in young children (around age 5), thus it is already present at birth and
does not develop later in life (like bipolar disorder, etc.)
, ASD diagnosis
● Autism diagnostic observation schedule (ADOS)
- structured and semi-structured tasks
- observation of social interaction
● Autism diagnostic interview (ADI)
- standardized, semi-structured clinical interview with parents
- 93 items
- three content areas: quality of social interaction, communication and
language, and repetitive, restricted and stereotyped interests and behavior
- autism is prevalent in males (male:female ratio is 4:1)
- WHY? - females are better at compensating/camouflaging?, male-biased diagnostic
criteria (boys are more often interested in certain objects and females are often more
social naturally)?, present phenotypically differently, female sex is a protective
factor?
Comorbidities: 70% of individuals with ASD diagnoses have at least one other diagnosis
(DSM-5) → ODD, ADHD, OCD, Tourettes, Anxiety, ADD, Depression, ...
ASD outcomes
- good outcome: moderate to high levels of independence (living, job, friends,
acquaintances)
- fair outcome: need support at work/home but some autonomy
- bad outcome: living in situation with close supervision in most activities
- 80% poor - 20% good
- subjects that do poor early (at age 2) will do poor later, and subjects that do good
early will do good later
