Download Development

NEURODEVELOPMENTAL
DISORDERS
RITE REVIEW
Cindy Wang
PGY-5
2-4-16
Outline
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Pervasive developmental disorders
 Autism/Asperger/PDD-NOS
 Childhood disintegrative disorder
 Rett Syndrome
Cognitive impairment
 Fragile X
 Down
 Angelman
 Prader-Willi
 Williams
ADHD
Tourette
# of RITE Q?
2001-2013
18
2
9
8
10
5
3
2
8
11
Diagnosis?
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2-year-old boy presents to
neurology clinic because he is not
talking yet
He does not make eye contact or
point to objects of interest
He lines up his toys in order of
size and groups them by color
He likes to spin in circles and rock
back and forth in place
He has a meltdown with any
change in activity
Autism DSM-IV criteria
At least two from 1 and at least one each from 2 and 3.
1. Impairment in social interaction
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Impairment in nonverbal behaviors
Failure to develop peer relationships
Lack of spontaneous sharing of enjoyment, interests, achievements
Lack of social or emotional reciprocity
2. Impairment in communication
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Delay in or lack of spoken language without compensation with gesture
In those with speech, inability to initiate or sustain conversation
Stereotyped, repetitive, or idiosyncratic language
Lack of make-believe or social imitative play
3. Restrictive repetitive and stereotypic behavior, interests, and activities
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Preoccupation with stereotyped and restricted interests, abnormal in focus or
intensity
Inflexible adherence to nonfunctional routines or rituals
Stereotyped/repetitive motor mannerisms
Persistent preoccupation with parts of objects
DSM-V Criteria
Diagnostic Criteria for 299.00 Autism Spectrum Disorder
Persistent deficits in social communication and social interaction across multiple contexts, as
manifested by the following, currently or by history (examples are illustrative, not exhaustive; see
text):
1. Deficits in social-emotional reciprocity, ranging, for example, from abnormal social
approach and failure of normal back-and-forth conversation; to reduced sharing of
interests, emotions, or affect; to failure to initiate or respond to social interactions.
2. Deficits in nonverbal communicative behaviors used for social interaction, ranging, for
example, from poorly integrated verbal and nonverbal communication; to abnormalities
in eye contact and body language or deficits in understanding and use of gestures; to a
total lack of facial expressions and nonverbal communication.
3. Deficits in developing, maintaining, and understand relationships, ranging, for
example, from difficulties adjusting behavior to suit various social contexts; to difficulties
in sharing imaginative play or in making friends; to absence of interest in peers.
Autism DSM-IV criteria
• Delays or abnormal functioning in at least one of
three areas, before 3 years old.
– 1. Social interaction
– 2. Language as used in social communication
– 3. Symbolic or imaginative play
• Not better accounted for by Rett Syndrome or
Childhood Disintegrative Disorder
– CDD: Between 2 and 10 yo, previously normal child has severe
regression in at least 2 but usually all of: language, social skills,
bowel/bladder, play, motor
Autism behaviors
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No eye contact, social reciprocity, repetitive play
Spinning wheels
Hand flapping
Autism-other features
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Semantic pragmatic syndrome is common in high
functioning autism
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Lifetime risk of epilepsy 20-35%
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accurate repetition of language elements, but with vapid content
and impaired prosody.
usually develops in later adolescence
MRI not typically recommended (low yield)
Younger sibs have 3-7% chance of having autism
Mental retardation in 75% (but tests are hard to interpret
because of language impairment)
Head size generally larger
Case
A 4-yo girl presents to your clinic with language
regression from having 200 words in her vocabulary to
having 50 words over a few months. An outside EEG
showed few focal epileptiform discharges during the
awake state. The most appropriate next step would be:
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A. Initiate intensive speech therapy
B. Evaluate for Rasmussen encephalitis
C. Evaluate for Landau-Kleffner syndrome
D. Treat with anti-convulsant medications
Case
A 4-yo girl presents to your clinic with language
regression from having 200 words in her vocabulary to
having 50 words over a few months. An outside EEG
showed few focal epileptiform discharges during the
awake state. The most appropriate next step would be:
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A. Initiate intensive speech therapy
B. Evaluate for Rasmussen encephalitis
C. Evaluate for Landau-Kleffner syndrome
D. Treat with anti-convulsant medications
Landau-Kleffner Syndrome
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Landau-Kleffner syndrome (acquired epileptic aphasia) needs to be
differentiated from cases of autism with minimal language regression,
especially when associated with isolated EEG abnormalities.
Typically develops in healthy children who acutely or progressively
lose receptive and expressive language ability coincident with the
appearance of paroxysmal EEG changes usually in sleep.
Speculation is that the neurological deficits in Landau-Kleffner syndrome
are mediated by inappropriate reinforcement of synaptogenesis, which
in turn is mediated by epileptiform discharges during a critical period
of synaptic reinforcement/pruning.
Case
A 2 year old boy is being evaluated in your clinic for poor
communication, and social skills. What finding on skin exam is
most likely associated with autism?
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A. Xanthomas
B. Café au lait spots
C. Port-wine stain
D. Telangectasia
E. Ash leaf spots
F. Swirling hyperpigmented lesions
Case
A 2 year old boy is being evaluated in your clinic for poor
communication, and social skills. What finding on skin exam is
most likely associated with autism?
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A. Xanthomas
B. Café au lait spots
C. Port-wine stain
D. Telangectasia
E. Ash leaf spots
F. Swirling hyperpigmented lesions
Tuberous Sclerosis
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Tuberous sclerosis is a genetic disorder
associated with numerous skin and systemic
manifestations as well as intracranial tubers,
mental retardation, and seizures.
Although numerous neuropsychiatric symptoms
have been reported to be associated with
tuberous sclerosis, autism spectrum disorder is
the most common.
About 25-60% of patients with tuberous
sclerosis have autism
DSM-IV: Asperger Syndrome
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Impairment in social interaction, at least 2 of:
 1. impairment in the use of nonverbal behaviors (eye contact, facial expression,
body posture, social gestures)
 2. failure to develop peer relationships
 3. lack of spontaneous seeking to share enjoyment, interests, achievements
 4. Lack of social or emotional reciprocity
Restricted repetitive and stereotyped behavior interests, activities, at least 1 of:
 1. encompassing preoccupation with one or more stereotyped/restricted interests
abnormal in intensity or focus
 2. inflexible adherence to specific, nonfunctional routines/rituals
 3. stereotyped and repetitive motor mannerisms
 4. Persistent preoccupation with parts of objects
The disturbance significantly impairs social, occupational, other areas of function
No significant delay in language
No significant delay in cognitive development, self-help skills, adaptive behavior,
curiosity about environment
Doesn’t meet criteria for other PDD or schizophrenia
Autism
Asperger
Childhood
disintegrative
disorder
•Cognition often (but not
always) impaired
•No cognitive delay
•Stereotyped, repetitive
use of language
•No language acquisition
problem
•Severe disorder marked
by regression in multiple
domains (usually including
language and cognition),
usually in preschool years
– Can have unusual
speech patterns,
dyslexia
•Onset after age 2
•No problems with selfhelp, adaptive behaviors
All display impairment in social functioning skills and show repetitive behavior and
restricted interests.
What’s the diagnosis?
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A girl appears mostly normal to her parents for
most of the first year of life.
Sometime between 1 and 2 years, she experiences
a regression of these skills. She stops playing with
toys, has poor eye contact.
She loses communication skills, stops responding
to the spoken word and stops using the few single
words she has learned. She becomes withdrawn
and loses interest in social interaction. She stops
walking.
Purposeful hand use is replaced by stereotypic
hand movements.
Her pediatrician also notes that she had a
deceleration in head growth.
Rett Syndrome: Main Criteria
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Developmental regression followed by stabilization
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Loss of purposeful hand movements
Replaced by stereotyped/repetitive midline hand mannerisms
(wringing, knitting)
Gait apraxia, truncal ataxia
Severe impairment of expressive and receptive language + intellect
Excluded:
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birth injury, metabolic abnormalities, infections
Grossly abnormal development in first 6 months of life
Rett Syndrome: Supportive Features
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Abnormal breathing while awake (apnea, intermittent
hyperventilation, breath holding, forced exhalation)
Bruxism while awake
Impaired sleep pattern
Abnormal muscle tone (Spasticity/dystonia, late)
Peripheral vasomotor disturbances
Small cold hands/feet
Growth retardation
Scoliosis/kyphosis
Diminished pain response
Inappropriate laughing/screaming spells
Intense eye communication: “eye pointing”
Rett Syndrome: Other features
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Deceleration in head growth between 5 and 18
months
Irritability
QTc prolongation
Seizures in 70% of patients
 Onset
often in early childhood, but prevalence with
age
 most commonly in sleep, sometimes intractable
Rett Syndrome behaviors
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Hand wringing
Ataxic/apraxic gait
Stages of Rett Syndrome
Stage
Onset
Duration
Symptoms
I
6-18 mo
Several months
Developmental arrest
II
1-4 yrs
Weeks to months
Developmental regression
III
2-10 yrs
Several years
Pseudostationary (behavioral
improvement, hand use,
communication)
IV
>10 years
Years (mean survival Late motor deterioration (rigidity,
45 years)
reduced mobility, dystonia,
hypomimia, and bradykinesia).
Can be come non-ambulatory
Rett Syndrome-Genetics
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Almost exclusively occurs in girls
X-linked disorder caused by mutation in methyl-CpGbinding protein 2 (MECP2) gene. Sporadic de novo
mutation from father.
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In 80-85% of classic Rett and 50% of atypical Rett
Other genes:
CDLK5
 FOXG1
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Case
In patients with autism, testing for which of
the following conditions would most likely
yield a positive result?
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A. MECP2 mutation
B. Inborn errors of metabolisms
C. Fragile X
D. Epilepsy syndromes
E. Cortical migrational defects
Case
In patients with autism, testing for which of
the following conditions would most likely
yield a positive result?
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A. MECP2 mutation
B. Inborn errors of metabolisms
C. Fragile X
D. Epilepsy syndromes
E. Cortical migrational defects
Fragile X
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Fragile X syndrome is the most commonly detected
genetic etiology for autistic spectrum disorder, and
often has milder presentations.
MECP2 abnormalities, inborn errors, epilepsy
syndromes and cortical migrational defects can
have autistic symptomology, but routine screening is
not advised unless other symptoms point to these
disorders.
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5 yo boy presents with history of autism presents
with cognitive impairment, ADHD.
Physical exam reveals long thin face, prominent
forehead and jaw, protuberant ears
Fragile X: Cognitive aspects
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Most common cause of inherited mental retardation in boys is fragile
X syndrome.
Most frequent neurocognitive symptoms are difficulty with abstract
reasoning, complex problem solving, and expressive language.
Many will also show manifestations of autism, with 33% meeting criteria
for autism.
Often have mood and behavioral abnormalities, ADHD, hyperarousal to
sensory stimuli leading to periods of anxiety, aggressiveness and
sometimes psychosis
Female carriers can have a milder form of the disease with learning
disabilities, ADHD, anxiety, and about 50% will manifest disorder.
Epilepsy in 20%
Fragile X: Physical aspects
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Characteristic physical features include a long thin
face, prominent forehead and jaw, large testicles,
protuberant ears, hip dislocation, and club feet.
Cardiac abnormalities including mitral valve
prolapse and a dilated aortic arch can be
common.
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Can have delayed puberty
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Premature ovarian failure in premutation carriers
Fragile X: genetics
Transmission pattern: X-linked inheritance with no
male to male transmission.
 Both males and females can be affected.
 Unlike most X-linked recessive disorders, males
carrying the mutant gene do not always have
manifestations of the disorder but can pass the
gene on to their daughters.
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Fragile X: genetics
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Trinucleotide CGG repeat in FMR1 (fragile X mental retardation)
gene.
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Normal 5-55 repeats, Premutation 55-200, FXS >200.
With full mutation, RNA is not translated to protein (FMRP), which may be
involved in synaptic plasticity via mRNA regulation.
Full mutation 1:4000 male and 1:6000 female.
Premutation 1:800 male and 1:260 female.
Case
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55 y.o. male presents with tremor and difficulty walking
He also has a history of anxiety, autonomic dysfunction, and mild
cognitive impairment
On examination, you find decreased reflexes, action and postural
tremor, and ataxia.
On family history, the patient’s daughter’s son has mental retardation
A. Charcot Marie-Tooth
B. Friedreich Ataxia
C. Dentatorubral-pallidoluysian atrophy (DRPLA)
D. Fragile X-associated tremor ataxia syndrome (FXTAS)
E. Spino-cerebellar ataxia type 3
Fragile X-associated tremor ataxia
syndrome
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Male (and occasionally) premutation carriers (grandpa)
develop progressive intention tremor and/or ataxia after 50yo
May also have peripheral neuropathy, parkinsonism,
anxiety/irritability, autonomic dysfunction, dementia
Can resemble multiple system atrophy
A. Charcot Marie-Tooth
B. Friedreich Ataxia
C. Dentatorubral-pallidoluysian atrophy (DRPLA)
D. Fragile X-associated tremor ataxia syndrome (FXTAS)
E. Spino-cerebellar ataxia type 3
What’s the diagnosis?
Down Syndrome (Trisomy 21)
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1:650-1000 live births
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most common genetic cause of
mental retardation
Characteristic physical features:
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Almond shaped eyes (epicanthal
fold),
Upslanted palpebral fissures
Microgenia (small chin)
Macroglossia
Round face
Short limbs
Hypotonia
Single transverse palmar crease
Widened space between 1st and
2nd toes
Down Syndrome Risks
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Congenital heart defects (especially endocardial cushion
defects)
Leukemia
Hypothyroidism
Celiac disease
Juvenile Onset Diabetes
Juvenile idiopathic arthritis
Infantile Spasms (0.6-13% vs <0.4% general population)
Epilepsy (1-13% overall, 15-50% in older groups)
Autism
Moyamoya, but low risk for atherosclerosis and HTN
Depression
Down Syndrome and dementia
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Early Alzheimer-like dementia (70% by 60 yo).
Amyloid Precursor Protein (APP) is on chromosome 21.
 Plaques and neurofibrillary tangles develop in late
30s/early 40s
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Epilepsy
By age 50, about 50% will have had seizures
 About 80% of Down syndrome patients with dementia have
seizures
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Down Syndrome: Atlantoaxial instability
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15-40% of children with Down syndrome have
atlantoaxial instability
Other heritable conditions with similar predisposition are
Klippel-Feil, Morquio (MPS IV), and Larsen syndromes,
achondroplasia and previous cervical spinal surgery.
If these individuals plan to participate in athletic
competition, they should have imaging of the cervical spine.
Special precautions must be taken prior to any
intubation in order to prevent neurologic damage.
What’s the diagnosis?
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5 year old presents with:
microcephaly
 gait ataxia (jerky movements)
 severe MR
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Little or no spoken language (sign
language may amplify language)
Seemingly happy demeanor,
inappropriate laughter and excitability.
 Sleep disturbance (frequent waking,
altered sleep cycle)
 Epilepsy
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high voltage slow-wave interictal activity
Angelman syndrome
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Most common cause is a de novo deletion of the
15q11-13 region, from the maternally derived
chromosome 15
paternal uniparental disomy of chromosome 15 is
occasionally responsible for the same syndrome.
 Mutations in UBE3A gene
 Defects in methylation/imprinting
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Diagnosis?
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4 yo presents with global developmental
delay
Low birth weight
Severe hypotonia, FTT in infancy
Short stature, small hands/feet, narrow
forehead, almond shaped eyes, triangular
mouth, hypogonadism
Temper tantrums, obsessive/compulsive,
hyperphagia, obesity
Prader-Willi Syndrome
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4 yo presents with global developmental
delay
Low birth weight
Severe hypotonia, FTT in infancy
Short stature, small hands/feet, narrow
forehead, almond shaped eyes, triangular
mouth, hypogonadism
Temper tantrums, obsessive/compulsive,
hyperphagia, obesity
loss of the paternal copy of 15q11.2-13
What’s the diagnosis?

4 year old girl presents with:
Insensitivity to loud noises
 Very social, cheerful demeanor
 Low tone in infancy, followed by
increased tone
 History of failure to thrive
 Relatively preserved verbal skills
 Likes to play with musical toys
 Elfin facies
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Williams Syndrome
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1:7,500-20,000.
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Hemizygous deletion of ~26 genes on
long arm of chromosome 7 (7q11.23)
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Mild to moderate MR
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Relatively preserved language and facial
processing.
Hypersocial
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“Cocktail party” type personality
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Musically “talented”
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Profoundly deficient visual processing
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Ventral (what) and dorsal (where) streams
Williams Syndrome
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Infantile hypercalcemia
Supravalvular aortic stenosis and other vascular stenoses
(elastin)
Decreased tone in children, increased with contractures in
adults
Hyperacusis
Elfin facies, broad brow, flat nasal bridge, short upturned
nose, wide mouth with full lips, irregular dentition.
Diagnosis?
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8-year-old boy presents for difficulties
at school.
His teachers report he constantly is out
of his seat, fidgets with things, and does
not pay attention in class.
He does poorly on tests but his mother
thinks he is very smart.
He frequently forgets to turn in his
homework
He is very active and can only watch TV
and listen to books for a few minutes
before getting up.
Attention deficit hyperactivity disorder
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A: At least 6 symptoms of inattention for at least 6 months,
disruptive and inappropriate for developmental level
B: At least 6 symptoms of hyperactivity-impulsivity for at least
6 months, disruptive and inappropriate for developmental level
Can’t be due to oppositional-defiant disorder or failure to
understand directions
3 types of ADHD
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Combined Type: A and B
Predominantly Inattentive Type: A, not B
Predominantly Hyperactive-Impulsive Type: B, not A
ADHD: Etiology
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Highly heritable
Etiology and pathogenesis is poorly understood
There have been relatively few genome-wide linkage studies, and
no chromosomal region has yet been unequivocally implicated.
Evidence from pharmacological, neuroimaging, and animal studies
has suggested the involvement of specific neurotransmitter systems,
notably dopaminergic pathways.
Meta-analyses or pooled data analyses have supported
association between ADHD and polymorphisms in DRD4, DRD5,
and SLC6A3, which encode dopamine D4 and D5 receptors and
the dopamine transporter, respectively.
A weaker, but nevertheless replicated, body of evidence also
supports associations with SNAP-25 (synaptosomal-associated
protein, 25 kDa) and SLC6A4 (serotonin transporter).
You are evaluating a 5 year old boy with tics
and ADHD. Which medication treats ADHD
symptoms and is not believed to worsen tics?
A.
B.
C.
D.
E.
dextroamphetamine
methylphenidate
haloperidol
atomoxetine
pimozide
You are evaluating a 5 year old boy with tics
and ADHD. Which medication treats ADHD
symptoms and is not believed to worsen tics?
A.
B.
C.
D.
E.
dextroamphetamine
methylphenidate
haloperidol
atomoxetine
pimozide
BUT a 2002 large study of ADHD+tic patients showed no big difference in tic
worsening between methylphenidate vs. clonidine vs. placebo…
ADHD: Medications
Immediate
Stimulants
Methylphenidate
Amphetamines
Ritalin
Adderall
Atomoxetine
(SNRI)
Ritalin-SR
Adderall XR
Metadate ER
Vyvanse
Metadate CD
Concerta
Daytrana (patch)
Focalin XR
Alpha-2 adrenergic
agonists
Tenex (guanfacine)
Focalin
Ritalin LA
Long-acting
Non-Stimulants
Strattera
Intuniv (guanfacine)
Kapvay (clonidine)
Diagnosis?
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6-year-old boy presents for disruptive
behavior at school
He makes barking noises while the
teacher is trying to talk
His parents took him to an allergist
because he is constantly sniffing,
clearing his throat, and blinking his eyes
He is very particular about the way his
room is arranged
He stands up and walks around during
storytime
Tourette Syndrome
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Diagnostic criteria
 onset before 18 years
 motor and vocal tics occurring many times daily for at least 12 months
 sufficient to cause psychologic distress or compromise social functioning.
 Coprolalia is uncommon (30%), but socially disruptive. Can develop in
adulthood.
High comorbidity with ADHD and OCD (50%).
 Stimulant medications may aggravate tics but are not contraindicated
 Behavioral issues may develop secondarily due to social stigma, isolation
or family responses to the condition.
Likely Autosomal Dominant, with complex genetics
Tourette Syndrome
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Most children don’t need medications, and tics
improve in adolesence
Pharmacologic treatment of tics can be with:
 Alpha-2 adrenergic agonists (clonidine, guanfacine)
 Neuroleptics (fluphenazine, pimozide, risperidone,
haloperidol)
 MAO depleting agent (tetrabenazine)
 Dopaminergic agonists (e.g. ropinirole)
Habit reversal training may be helpful (but
weak evidence)
Match the disease
Moderate mental retardation, attention
deficits, and a long face with prominent
ears
Associated with developmental
regression
Shares the features of autistic disorder
except that language is spared. Children
with this syndrome are often referred to
as "little professors" owing to their
extensive knowledge of very restricted
fields of interest.
Associated with language regression and
very frequent electrographic seizures
during sleep
Asperger Syndrome
Childhood disintegrative
disorder
Landau-Kleffner syndrome
Fragile X
Match the disease
Moderate mental retardation,
attention deficits, and a long face
with prominent ears
Asperger Syndrome
Associated with developmental
regression
Childhood disintegrative
disorder
Shares the features of autistic
disorder except that language is
spared. Children with this syndrome
are often referred to as "little
professors" owing to their extensive
knowledge of very restricted fields of
interest.
Associated with language regression
and very frequent electrographic
seizures during sleep
Landau-Kleffner syndrome
Fragile X
Match the ocular findings
Kayser-Fleisher
rings
Ataxia telangectasia
Conjunctival
telangectasias
Hurler disesase (MPS 1)
Brushfield spots
Down Syndrome
Lisch nodules
Wilson disease
Corneal clouding
NF-1
Match the ocular findings
Kayser-Fleisher
rings
Ataxia telangectasia
Conjunctival
telangectasias
Hurler disesase (MPS 1)
Brushfield spots
Down Syndrome
Lisch nodules
Wilson disease
Corneal clouding
NF-1
Match the condition
Klüver-Bucy
Kleine-Levin
Prader-Willi
Gastaut-Geschwind
Personality disorder found in some patients with temporal
lobe epilepsy. Clinical manifestations include
hypergraphia, hyposexuality, hyperreligiosity, and
interpersonal viscosity.
Predominantly affects adolescent males with varying
duration. Symptoms include hyperphagia,
hypersomnolence, cognitive changes, and mood
disorders. The majority of cases follow infection.
Pathology typically is localized to the hypothalamic
region.
Inherited developmental disorder characterized by
hypotonia in infancy, short stature, developmental
delay, and increased appetite. There is hypothalamic
dysfunction in this disorder, as well.
A temporal lobe syndrome characterized by
hypersexuality, hyperorality, visual agnosia, and a
diminishment of emotional reactions. Lesion localization is
typically in the bilateral medial temporal lobes with
extension into the amygdala.
Match the condition
Klüver-Bucy
Kleine-Levin
Prader-Willi
Gastaut-Geschwind
Personality disorder found in some patients with temporal
lobe epilepsy. Clinical manifestations include
hypergraphia, hyposexuality, hyperreligiosity, and
interpersonal viscosity.
Predominantly affects adolescent males with varying
duration. Symptoms include hyperphagia,
hypersomnolence, cognitive changes, and mood
disorders. The majority of cases follow infection.
Pathology typically is localized to the hypothalamic
region.
Inherited developmental disorder characterized by
hypotonia in infancy, short stature, developmental
delay, and increased appetite. There is hypothalamic
dysfunction in this disorder, as well.
A temporal lobe syndrome characterized by
hypersexuality, hyperorality, visual agnosia, and a
diminishment of emotional reactions. Lesion localization is
typically in the bilateral medial temporal lobes with
extension into the amygdala.
And now for…
Neurollywood Round 2!
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