Cognitive and Behavioral Issues, Educational Strategies and New Paths to Treatment in Fragile X Syndrome

1
Cognitive and Behavioral Issues, Educational
Strategies and New Paths to Treatment in Fragile
X Syndrome

• Elizabeth Berry-Kravis MD PhD
• Rush University Medical Center, Chicago

2
Fragile X Syndrome

• Form of X-linked MR/ID discovered by Martin and
  Bell 1943
• Lubs fragile site 1969
• 1991 Caused by mutations that inactivate FMR1
  gene
• Prevalence 14000 males and females
• Carriers 1250 females, 1800 males
• All ethnic groups worldwide

MOST COMMON KNOWN INHERITED FORM OF COGNITIVE
DISABILITY
3
Features of Fragile X Syndrome

• Physical large prominent ears, long face, large
  head, prominent jaw and forehead, midfacial
  hypoplasia, hyperflexible joints, large testis
• Intellectual Disability/LD
• Behavior problems
• Seizures
• Strabismus
• Medical otitis, sinus, mitral valve prolapse,
  reflux, sleep apnea, loose stools, allergies

4
Fragile X is hard to diagnose in babies
physical features not obvious
5
Growth in Fragile X Syndrome

• Rate of growth increased early
• head
• ears
• height
• dental maturity
• Height growth increased in pre-adolescence
• Pubertal height gain reduced
• On average, FXS adults shorter than controls
• Testis overgrowth late - during puberty

6
Fragile X SyndromeEye Problems

• Hyperopia (59)
• Strabismus (30)
• Myopia (17) - like general population
• Congenital nystagmus - increased but occasional
• No ocular health problems

7
Epilepsy in Fragile X

• Rush Fragile X Clinic (Chicago) largest cohort
  studied
• 229 FXS (181 M, 48 F) seizures in 15.4 M, 6.2
  F
• 61 partial seizures, 35 generalized, 4 unknown
• Most easily controlled, gt80 resolve in childhood
• Epileptiform EEG in 51 with seizures, 20
  without treat only when clinical seizures
• Centrotemporal spikes (CTS) most common epileptic
  EEG abnormality
• 45 with CTS did not have clinical seizures
• All with CTS pattern seizures gone by age 15
  good prognostic sign

Berry-Kravis, 2002 Berry-Kravis, 2004
8
Fragile X SyndromeIntellectual Disability

• Males - average adult IQ about 40 and mental age
  5-6y, range severe ID to normal (mosaics)
• IQ scores higher when young, decline with age
• Specific cognitive profile
• Achievement and Adaptive skills higher

9
Fragile X Syndrome Characteristic cognitive
pattern with prominent executive function deficits

• Weaknesses
• Auditory processing
• Sequencing
• Abstraction
• Short-term memory
• Topic maintenance/ "connectedness"
• Mathematics
• Working memory
• Coordination/praxis

• Strengths
• Receptive vocabulary
• Syntax
• Imitation
• Grammaticalstructure
• Visual memory
• Simultaneous processing
• Experiential learning

10
Fragile X Syndrome Developmental Problems

• Motor delays in some
• Hypotonia - orofacial when young
• Fine motor problems - poor writing ability
• Gross motor clumsiness
• Speech/language delays
• Delayed imitative and symbolic play

11
Developmental Problems

• Parents most frequently become concerned first
  about speech delay
• Other concerns that may lead to childs initial
  evaluation
• Motor delay
• Extreme hypersenstivity/defensiveness
• Hyperactivity or anxiety
• Cognitive delays or LD at school age
• Therapists for child with delay may first
  encourage testing if parents dont recognize
  problem or are in denial

12
Developmental Screening in FXS

• Developmental delays can be detected in boys with
  FXS by most standard screens at 9-18 months
• Denver II 91 at 9 months, 100 at 12 and 18
  months
• Early Language Milestone Scale 2 100 at 12 and
  18 months
• Batelle 75 at 12 and 18 months
• More comprehensive tests Mullen,
  Receptive-Expressive Emergent Language Scale 2
  agree 76 of cases

13
Fragile X Syndrome - Pattern of Speech/Language
Deficits

• Most abnormal
• Jargon/tangential language
• Jocular litanic phraseology
• Perseverative speech
• Lack of use of gestures
• Talking to self
• Cluttering

• Less abnormal
• Fluency
• Prosody
• Strengths
• Grammar
• Vocabulary

14
Language Characteristics in FXS Relative to
Normal Mental-Age Matched Controls and
Developmentally Delayed Subjects

• Decreased intelligibility
• Vowels sounds more variable than normal
  developmentally matched controls
• Poor oromotor control
• Faster rate of speech
• Decreased length of utterances
• Increased self-repetitious and perseverative
  language
• Single word vocabulary a strength

15
Language in FXS vs Autism

• More impaired in non-verbal communication than
  autistic group
• More impaired in expressive language
• Less impaired in receptive language which is a
  strength
• Tangential language more prevalent than in autism
  or general developmental delay (possibly due to
  anxiety, inhibitory control deficits)

16
FXS Socialization Deficits

• Friendly but social anxiety
• Good understanding of facial expression
  different from typical autism
• Deficits in peer entry
• Defcits in interpreting social cues correlate
  with anxiety, attention problems, social problems
• Discrimination deficit - body language, hidden
  curriculum

17
Behavior Problems in FXS

• Hyperactivity/fidgety (90)
• Short attention span (100)
• Anxiety (100)
• Tactile defensiveness (80)
• Eye (gaze) aversion (gt90)
• Perseverative speech and thinking (gt80)
• Hand flapping (60)
• Hand biting (50)-self regulatory
• Mood swings
• Outbursts/aggression

THE BIGGEST PROBLEM FOR MANY FAMILIES
Behavior in fragile X often out-of-proportion to
cognitive level
18
Fragile X Syndrome Distinguishing Behaviors

• delayed echolalia
• repetitive speech
• hand flapping
• gaze aversion
• good understanding of facial expression
• friendly and sociable but may be shy

19
FXS - Female Affecteds

• More mildly involved
• Average IQ 80
• NVLD, VIQgtPIQ, poor math, very impaired executive
  function, distractibiity
• Same cognitive pattern as males
• Physical features/medical problems variably
  present
• Social/psychiatric disability common
  anxiety/shyness, oddness
• Decreased education, job stability, socioeconomic
  status

20
Supportive Fragile X SyndromeTreatment/Therapy
in Clinic

• Early intervention
• Intensive speech therapy
• OT with sensory integration
• Inclusion in school as much as possible
• Educational curriculum, environment, teaching
  style matched to FXS cognitive profile
• Behavioral medications for ADD/anxiety/aggression
• Structured behavioral program
• Socialization therapy

• Yearly eye exams
• Aggressive treatment of otitis tubes/audiology
• Control seizures
• Orthopedics if needed - SMOs
• SBE prophylaxis if MVP
• Genetic counseling for family

Rush FXS Clinic since 1992 Now about 400 patients
21
Medical Treatments (behavior or learning may be
a problem if medical issues are not managed)
22
Eye Problems

• Strabismus lazy eye
• Ophthalmology/Optometry follow up
• Patching, glasses or surgery depending on type
  and severity
• Need to watch for far sightedness
• Farsightedness increased in FXS even when no
  strabismus
• Glasses if correction gets too big

23
Ear Infections

• If spaced far apart and fluid in ears clears
  between infections routine antibiotics
• If more frequent but fluid still clearing between
  may want preventative antibiotics especially
  for risk seasons
• If fluid not clearing in middle ear, infections
  extremely frequent, need tubes, especially if
  hearing loss, may need TA
• If fluid and hearing loss without overt
  infections need tubes
• Need to be aggressive hearing loss will add to
  speech problems

24
Sleep Apnea

• Increased in FXS due to floppy airway connective
  tissue, co-ordination problems with secretion
  clearance, large tongue or tonsils
• Aggravated if overweight
• Snoring, gasping for air, respiratory pauses
• Do sleep study if possible
• T A initially if sleep apnea, repeat sleep
  study after procedure
• May need additional surgery or CPAP
• Important to manage because can affect behavioral
  and cognitive performance

25
Flat Pronated Feet

• SMOs when young if severe enough
• Can help gait pattern, when learning to walk
• Can improve patterns of show wear
• SMOs usually not needed in older individuals with
  FXS, although may need shoe inserts to manage
  flat feet

26
Seizures Basic Principles of Seizure
Management in FXS

• 1. start medicines after 2 or more clinical
  seizures, do not need to treat abnormal EEG
• 2. stop 2 years after last seizure
• 3. single drug regimen, lowest effective dose
  best
• 4. dose guide is effectiveness and toxicity
• 5. Match drug to seizure type, patient
  characteristics
• 6. Use drugs with less effect on cognition and
  behavior
• 7. EEG is adjunct for deciding which drug, how
  much, and how long
• 8. more drug is not necessarily more effective

27
Educational Treatments (behavior will be a
problem if the optimal educational setting,
curricula and approach style are not implemented)
28
FXS Curriculum and Teaching Style Matched to
Cognitive Profile

• New concept - disease specific curricula/teaching
  (different from categories like autism)
• Requires identification and testing of enough
  patients to identify disease-specific cognitive
  profile produced by the particular gene defect
• Fragile X is common so cognitive profile is known
  - can match curriculum

29
Fragile X Syndrome Characteristic cognitive
pattern with prominent executive function deficits

• Weaknesses
• Auditory processing
• Sequencing
• Abstraction
• Short-term memory
• Topic maintenance/ "connectedness"
• Mathematics
• Working memory
• Coordination/praxis

• Strengths
• Receptive vocabulary
• Syntax
• Imitation
• Grammaticalstructure
• Visual memory
• Simultaneous processing
• Experiential learning

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Why is Math so hard in FXS?
31
Academic Skills in FXS

• Strengths
• General knowledge
• Ability to utilize experiential information
• Reading decoding
• Weaknesses
• Prewriting and writing skills
• Visuospatial/math skills
• Rate of academic growth slows with time
• most in core academics (reading/math)
• Less in broad based tasks
• Autistic behavior and maternal education related
  to academic achievement and receptive vocabulary
  less than non-verbal IQ

32
FXS Cognition and Educational Program Placement

• IQ generally lower than academic achievement IQ
  taps areas of weakness
• Concrete, fact-based tasks easier than abstract
• IQ tests are limited by effort, attention,
  anxiety and often do not give full picture
• K-ABC is best
• If minimally verbal Leiter can be good
• Placement decision should not be made
  predominantly on basis of IQ as gives
  underestimate of what FXS individual can do
• Individuals with FXS often do better placed with
  higher functioning peers

33
Fragile X Syndrome Educational Strategies

• Characteristic cognitive profile dictates
  specific educational strategies that will
  maximize learning at school
• Emphasize
• Visual learning
• Simultaneous processing
• Imitation
• "Real life" learning

34
Fragile X Syndrome Educational Strategies

• Circumvent or Minimize Problems with
• Attention
• Sequential processing
• Auditory learning
• Anxiety/overstimulation
• Novelty
• Graphomotor skills

35
General Components of the Educational Approach

• Early intervention
• Speech therapy
• OT/sensory integration therapy
• Structure/routines
• Schedule/message boards - visual cues (pictures
  of normal day events) to help understand schedule
• Inclusive program - when possible , maximize
  imitation of normal behaviors

36
General Components of the Educational Approach

• Classroom modification - minimize overstimulation
• Environmental - seat away from distraction, quiet
  area in room, natural lights
• Instruction - co-operative learning in small
  groups, peer tutoring, high teacher-to-student
  ratio, one-on-one instruction
• Curriculum - appropriate task complexity, text
  enlargement, high interest/daily life topics
• Behavior management - behavior modification,
  calming, medications
• Aide to deliver specialized curriculum, carry out
  behavior and sociaization interventions

37
FXS Curriculum Matched to Cognitive Profile

• Learning based on visual memory - visual cues to
  all instructions
• Use of whole language, logos or picture-word
  association rather than phonics for reading
• Edmark reading curriculum
• Use of computer-assisted writing

38
FXS Curriculum Matched to Cognitive Profile

• Demonstration and real-life activities
• Concrete, hands-on math with visual
  representation of number manipulatives (eg. Math
  Their Way, Touch-Point, number lines)
• Focus on functional life-math eg. money, time,
  recipes

39
FXS Teaching Style Matched to Cognitive Profile

• Use incidentally acquired knowledge integrated
  into teaching format
• Present novel tasks in a familiar format
• Assist with task initiation
• Indirect instruction
• Associative learning - use interest areas
• Use token boards to help understand when tasks
  will be done
• DO NOT FORCE EYE CONTACT!!!!

40
Curricula for FXS Academics

• Reading
• Logo Reading (Marsha Braden)
• Edmark Reading Program, Level 1
• Cloze Stories for Reading
• Developing Everyday Reading Skills
• Math
• I Can Plus and Minus
• Touch Math
• Math Equivalence Board (Marsha Braden)
• Good Apple Math Book

41
Curricula for FXS Academics

• Spelling
• I Can Print
• Spell Master
• Writing
• Handwriting Without Tears
• Functional Skills
• Stepping Out Cues
• Life Skills Game Series

42
Therapy Treatments(important part of behavioral
management need therepy to communicate, perform
ADLs, and manage sensory issues)
43
Speech Therapy

• Various goals depending on age, functional level
  of child with FXS
• Younger oromotor issues, speech production,
  vocabulary, intelligibility
• Middle increasing length of utterance, speech
  rate, sentences, limiting perseverative speech
  and cluttering
• Older conversational language, language
  pragmatics, hidden meanings, limiting
  perseverative speech

44
Speech Therapy

• Can be delivered in classroom, with classroom
  activity designed to bring out language such as
  acting out a story
• Calming techniques before session
• Can combine with OT especially for younger boys
• Visual cues and demonstration
• Make use of mimicking of things thay hear in TV
  shows, videos, songs to work on increasing
  phrases or sentences and appropriate use

45
Speech Therapy

• Non-verbal individuals with FXS may need
  augmentative communication device
• Often can use these well because receptive skills
  and visual memory are so good
• Can use to link picture to written words
• Some individuals who do not talk can read words
  and make sentences with communication device

46
Occupational Therapy

• Sensory integration
• Provide sensory diet
• Help with substituting chewing, biting, other
  undesired behaviors child is using for
  input/calming for more acceptable means of
  acquiring input
• Help with establishing calming routines when
  tantrum building

47
Occupational Therapy

• Work on fine motor deficits
• Writing practice
• Help with curricular adaptations to reduce amount
  of writing without limiting output (eg.
  dictation, circling answers, verbal testing)
• Teach use of alpha-Smart or Co-writer if
  possible, if child can generate sentences but
  slowed by writing skills
• Teach keyboarding early if possible
• Work on daily living fine motor skills and
  adaptations eg. buttons, tying, zipping, etc

48
Socialization Therapy

• play to facilitate social cue interpretation
• build tolerance for interaction
• modeling, rehearsals, self-regulation
• facilitate peer interactions
• social autopsy
• goal when child can interpret cues behind
  situation, intervention will be effective
• Deliver therapy through school and also outside
  of school if needed

49
Social Curricula

• Comic Strip Conversations (Carol Gray)
• The Thinking Story
• Think Aloud
• Stop, Think, Relax
• I Can Behave
• Social Skills for Daily Living - teenagers
• Social Compass Marsha Braden
• Public and private behaviors
• Sexuality issues
• Manners and social skills

50
Social Interventions in School

• Individual socialization therapy
• Group socialization therapy (modeling social
  interactions with normal peers)
• Social stories
• Videos of appropriate social behaviors for
  behaviors that are problematic
• Peer tutoring
• Circle of Friends

51
Other Therapies

• Vision therapy for tracking, visual attention
• Listening therapy for auditory attention
• Music therapy
• Equitherapy (other animal therapy)
• Aquatherapy
• ABA/Lovaas may not be good if forces too much
  eye contact
• Vitamins/herbals/gluten-free-casein-free
  diet/numerous alternative products
• Many others

None are proven effective in FXS certain ones
may be helpful for some FXS individuals
52
Behavioral Treatments and Psychotherapy
53
Causes of Difficult Behavior in FXS

• Anxiety
• Aberrant behavior may be only strategy FXS
  individual has to deal with anxiety
• Anxiety about novel exposures, separation, being
  unable to do something, not doing it right, other
  specific phobias, no particular thing
• Anxiety increases with age fear learning is
  enhanced in FXS fear without threat
• FXS individual learns what is difficult and
  becomes increasingly anxious about lack of
  success and novelty

54
Why does anxiety increase - the amygdala is
over-wired in FXS easy threat response
55
Causes of Difficult Behavior in FXS

• Problems communicating
• Cannot express what is bothering them
• Only alternative may be aberrant behavior
• Lack of cognitive sophistication about
  interpreting problem and coming up with a
  solution
• Social misinterpretation (lack of understanding
  about when others are teasing etc)
• Poorly modulated emotional state
• Overarousal and hypersensitivity to everything
  noises, smells, facial expressions, temperature,
  flashing visual stimuli, something different in
  room, routine change

56
Things That Cause Overarousal in FXS
Precipitate Problem Behaviors

• Loud/chaotic environment
• Flashing/blinking lights
• Novelty
• Transitions or changes in schedule
• Being on the spot
• Prior aversive event in same setting

57
Physiological Antecedents to Behavioral
Deterioration Fight or Flight
Use to help identify when problem about to occur
and head off

• Red ears, face, neck
• Increased heart rate
• Increase in perspiration
• Rapid speech louder/cluttering
• Hand flapping, hand biting
• Eye aversion and fidgety/squirmy movements
• Hyperactivity
• Perseveration pattern of behavioral
  deterioration itself may become perseverative due
  to re-inforcement

58
Treatment of Behavioral/ Emotional Problems

• Behavior Modification
• Operant conditioning
• High interest, frequent re-inforcements
• Visual cueing/picture cards
• Photo series of behavior and consequences
• Calming techniques
• Need good behavior modification program
  implemented at school or group home, etc for most
  individuals with FXS
• Aide to carry out program male aide if possible

59
Treatment of Behavioral/ Emotional Problems

• Psychotherapy
• Visual cues paired with verbal interaction
• Non-confrontational
• Family therapy
• Videotaping of adaptive behavior

60
Behavior Plan for Agitation and Aggressive
Outbursts

• Remove, Relax, Refocus
• Place to go to calm down (goal is to teach
  patient to take self out) need to establish
  this area at school
• Engage in calming activity
• Physical activity to help re-focus
• Steps will have to be trained with goals of
  patient eventually doing them on own
• Reward for completing process successfully

61
Medication Treatments for Behavior
62
Psychopharmacology in Fragile X Syndrome

• Targets behavior to improve functioning
• Supportive, does not target underlying cognitive
  problem
• Only one prior controlled trial in FXS (N15)
  shows Ritalin effective in 2/3 of boys
• Therapeutic decisions based on target largest
  problem symptom complex(es) trial and error
• May need to treat multiple behavioral domains

63
FXS - Types of Medications and Indications
meds may be targeting several clusters
64
Decision to Use Behavioral Medication

• Individual engaging in dangerous behaviors
• Individual is dysfunctional from behavior
• Individual could accomplish more or be higher
  functioning if specific behavior is managed
• Increase ability to participate
• Able to be in more inclusive setting
• Not necessarily when all else fails
• ALWAYS an adjunct to behavioral, environmental
  measures

65
Supportive Psychopharmacology is Helpful in FXS
Rush Fragile X Clinic

Berry-Kravis and Sumis, 2006
but treating the underlying disorder would be
better
208 trials 136 patients
231 trials 123 patients
52 trials 52 patients
100 trials 58 patients
Anxiety Mood
Attention Hyperactivity
Aggression Irritability
Hyperarousal Oversensitivity
66
FMR1 The Fragile X Gene
Carrier state passed through many generations
before FXS
Simple DNA test to diagnose FXS measures repeat
size
67
FMRP Expression and Disability
100
Social anxiety/shyness
Distractibility/hyperactivity Executive deficits
Spatial perceptual deficits
FMRP
NVLD
Intellectual Disability
0
Disability
68
The Fragile X Mouse (Knockout K/O)

• fmr1 gene inactivated
• No active FMRP
• Subtle cognitive problems
• Audiogenic seizures
• Good neurobiological model to answer question
  WHAT DOES FMRP DO?

69
FMRP in Dendrites (Brain Connections)
FMRP in RED in tip of neural dendrites and where
processes are forming
FMRP regulates proteins made at brain connections
(in dendrites) - proteins have to be made in
right amount for connection to mature and work
right.
70
Dendritic Spine Morphology Abnormal in FXS

• What happens when FMRP is not there?
• More immature dendrites
• Fewer mature dendrites
• More synapses
• Human FXS Cerebral Cortex K/O Mouse Cerebral
  Cortex
• Defective pruning/lack of synapse strengthening

As would predict, FMRP regulates structural
synaptic maturation
McKinney et al, AJMG -B Neuropsychiatric
Genetics, 2005
71
New Research is Leading to Future Treatments for
Fragile X

• Specific glutamate (group I mGluR) pathway
  regulated by fragile X protein (FMRP) in neurons
• Regulates strength of neural connections needed
  for learning
• Overactive when FMRP not there messes up
  connections
• Can block pathway with new drugs (mGluR blockers)
  being developed

Normal
Fragile X
Drug
72
Excessive LTD due to mGluR system overactivity
LTD
AMPA
AMPA
AMPA
AMPA
FMRP
AMPA
AMPA
FMRP
Dendrite
Normal Mature connection
Fragile X Immature connection (too weak)
mGluR Theory of Fragile X
73
4
3
AMPA
AMPA
Other systems
2
X
X
1
AMPA
AMPA
Excessive LTD due to mGluR system overactivity
Potential Mechanisms for New Treatments in FXS
Dendrite
Fragile X Immature connection (too weak)
74
Treatment of Cognition Fragile X as a Model

• Known single gene defect all patients have same
  mechanism of cognitive dysfunction
• Some info on synaptic deficits due to absence of
  FMRP have mouse and drugable targets
• Other developmental disorders more difficult - no
  info on brain deficits
• Aspects of FXS model ADHD, autism, LD
• Very exploratory IDEA - NO prior attempt at
  moderate/large clinical trial in FXS, NO prior
  clinical trials for cognition based on underlying
  neurobiology in any MR population

75
Stronger connection
Excessive LTD
AMPA
AMPA
Activate AMPA receptors Raise BDNF bring AMPA
receptors to synapse
AMPA
AMPA
AMPA
AMPA
Ampakine Mechanism 3
Fragile X Immature connection (too weak)
76
Excessive LTD
Stronger connection
AMPA
AMPA
Lithium blocks PI turnover, reduce mGluR
signalling through PL-C/PK-C cascade, directly
block protein synthesis by GSK3B block
Li
AMPA
AMPA
AMPA
AMPA
Lithium Mechanism 1
Fragile X Immature connection (too weak)
77
Lithium and FXS Models

• Lithium corrects courtship memory deficits in
  dfxr mutant fly McBride 2005
• Lithium corrects open field hyperactivity and
  decreases audiogenic seizures in fmr1 k/o mouse -
  Bauschwitz
• FX-specific effect - lithium is convulsant in
  normals
• Corrects several learning tests, LTD in mouse

Data from R. Bauschwitz
Audiogenic Seizures
78
FXS Open-Label Lithium Trial

• Test concept of mGluR pathway inhibition
  (reduction of excess translation)
• 13 better at 2 mo, minimal toxicity

RBANS List Learning (range 0-40) 8 of 10
improved, p 0.028 CX516 placebo change 0.0
ABC Total (range 0-174) 13 improved,
p0.005 Placebo change in CX516 study (N25) -4
Also significant improvement in CGI, VAS, and
Vineland Personal Daily Living Skills and
Maladaptive Behavior
79
Lithium Study Biomarker - ERK Activation in
Lymphocytes
ERK phosphorylation slower in K/O and FXS
Berry-Kravis et al, JDBP 2008
N11 Baseline mean 4.87 min 2 Month Treatment
mean 4.11 min (p0.007) (about 1 min is
difference FXS and control) 1 Year Treatment
mean 3.56 min (P0.00006)
baseline
2 mo
1 yr
80
GABA Agonists in FXS

• Glutamate toxic to dfxr mutant flies (excitatory)
  Warren lab 2006
• GABA and GABA activators spiked in food rescue
  toxicity (inhibitory)
• GABA receptors abnormal in FXS mouse
• Baclofen (available on market for spasticity) -
  GABA-A agonist that blocks presynaptic release of
  glutamate
• Preclinical data helps irritability in FXS and
  autism
• Ganaxolone GABA-B agonist used for seizures
  in late phase development

81
R-Baclofen (STX209) Trial

• Baclofen is racemic
• Both isomers are selective GABA-B agonists
• GABA-B RS potency ratio 151
• in vivo RS potency ratio 10-1001
• R-Baclofen kinetics comparable when given alone
  or as part of racemic mixture (with S-baclofen)
• R-Baclofen is more potent in blocking presynaptic
  release of glutamate and therefore may be
  helpful in FXS and perhaps in autism
• Reverses phenotypes in FXS mouse
• Clinical trial 2009 of R-baclofen in FXS/autism

82
Stronger connection
Excessive LTD
AMPA
AMPA
mGluR5 blocker Fenobam
Li
AMPA
AMPA
AMPA
AMPA
mGluR5 Blocker Mechanism 1
Fragile X Immature connection (too weak)
83
mGluR5 Blockers and Fragile X

• mGluR5 negative modulators potent anxiolytics,
  also anticonvulsant
• MPEP is prototype but not for humans
• Being developed for anxiety disorders,
  neuropathic pain, irritable bowel syndrome
• Like lithium, would correct mGluR overactivity in
  most areas of brain and would correct
  oversynthesis of all FMRP-regulated proteins
• Unlike lithium, specific for mGluR system

84
Phenotypes in dfxr mutant fly Normalized by MPEP

• Courtship memory deficits
• Mushroom body beta lobe fusion
• Lack of survival on commercial food
  (glutamate-containing)
• Odor shock long-term memory deficits

McBride et al. 2005
Warren 2006
Bolduc 2007
85
Phenotypes in FXS Knockout Mouse Normalized by
MPEP
Bauschwitz, 2006

• Audiogenic seizures
• Epileptiform bursts
• Open field behavior
• Prepulse inhibition
• Dendritic spine shape
• AMPA receptor internalization
• Excessive protein synthesis

Wong et al. 2006
These and other phenotypes in the fmr1 K/O mouse
also all reversed by crossing fmr1 K/O to mGluR5
heterozygous mutant
86
AMPA Receptor Rescue by MPEP
Internal GluR1
Surface GluR1
Nakamoto et al. 2007
FMRP
Control
GluR1 AMPA receptors that drive strength of
neural connections
siRNA to block FMRP translation
siRNA and MPEP
87
mGluR5 Negative Modulators in Development

• Fenobam
• Old molecule No major toxicity
• Reduced anxiety in some adult phase II trials
• Dropped - short half life/erratic
  pharmacokinetics (PK)
• Found to be mGluR5 blocker (Porter et al. 2005)
• The first mGluR5 blocker used in FXS 2008
  orphan drug status for FXS - Neuropharm
• STX107 Seaside (from Merck)
• Good tox profile so far, better half life and PK
• In preclinical testing trials expected in 2009

88
mGluR5 Negative Modulators in Development

• AFQ056 Novartis
• Randomized double-blind clinical trial in Europe
  now 30 subjects
• 28 day treatment after dose titration
• Primary outcome behavioral improvement on ABC
• Cognitive measures investigated
• Other molecules Roche, Addex, AstraZeneca

89
TRIAL Open Label Escalating Single Dose Trial of
Fenobam in FXS
RUSH and UC Davis (Neuropharm and FRAXA) safety
trial of 1 dose (50-150 mg), 12 adult FXS (6M,
6F), age 18-38, IQ 36-85

• TRIBULATIONS
• CPT good reproducibility and can be done by low
  functioning FXS children, but higher functioning
  adults ceiling effect

• POSITIVES
• PPI improved 25 in 6/12 subjects (control
  test-retest group 2/13, p0.03), looks like good
  measure for smaller early studies
• Observation of positive behavioral changes in
  9/12 subjects
• No fenobam-related adverse events

90
Prepulse Inhibition (PPI) Studies
91
Hessl et al. AJMG 2008
92
PPI improved on fenobam
Berry-Kravis et al. JMG 2009
P0.03
93
Potential Future TRIALS

• Longer term mGluR agonist (Mechanism 1), placebo
  control with extension-for-all option
• Fenobam, AFQ, STX207, others
• Move down age increments as preliminary safety
  established in next older population
• Placebo-control lithium Mechanism 1
• GABA agonists Mechanism 4
• Better ampakines Mechanism 3
• ?minocycline Mechanism 2
• Combinations

Still need work on design and outcome measures
for these, many steps, but benefit may be overlap
with autism pathways treatments for autism too
94
Is There a Premutation Phenotype?

• Women
• prominent ears
• no difference in cognitive functioning/depression
• increased anxiety, social phobia
• premature ovarian failure (24)
• Men
• increased anxiety, neuroticism, social phobia
• prominent ears
• Fragile X-Associated Tremor/Ataxia Syndrome
  (FXTAS) discovered 2001

95
Fragile X-Related Primary Ovarian Insufficiency
(FXPOI)

• 15-22 of female premutation carriers have POF
  (early menopause)
• 0.8-7.5 of women with POF have FMR1 premutation,
  13 if FHx of POF
• Now called POI because many have ovarian
  dysfunction early but dont fully stop menses by
  40 years, increased FSH
• Risk for POF increases gradually for CGGlt80,
  rapidly 80-100 and then levels off or decreases
• Need to test all women with POF, also with
  infertility but no menopause especially if
  increased FSH (before fertility treatment or IVF)

96
POI, Infertility and FXSThe Trouble with Triplets
Tremor Psychological dysfunction Gait changes

• Is infertility a sign of FXPOI and when?
• Who should have an FMR1 DNA test before fertility
  drugs or IVF?
• How often does FXS occur due to fertility
  interventions?
• Research to guide Ob/Gyn practice

LD, Severe anxiety/ behavior
Mild ID ADHD
Non-verbal Severe ID
97
Reproductive Options in Fragile X Syndrome

• Prenatal diagnosis and carrier testing made
  possible by discovery of FMR1
• Prenatal testing - CVS, amnioscentesis
• Egg donation
• Preimplantation genetics (some successful cases)
  difficult
• Adoption

98
Moms provide link between FXS and FXTAS
99
FXTAS in Premutation Carrier Males

• Multidimensional tremor
• Ataxia
• Parkinsonian symptoms
• Neuropathy
• Executive function problems and cognitive
  deterioration
• Characteristic MRI with white matter changes and
  MCP sign
• Neuronal inclusions
• Severity of movement disorder, neuropathy,
  inclusions, MRI changes, age of onset all
  increase with CGG repeat length
• Women (about 10) can get milder form

100
FMR1 Revisited
101
Newborn Screening for FXS
Pilot program (30,000 births) in California,
Illinois

• Need follow up for positives with early
  intervention and genetic counseling at FXS clinic
• Benefits
• in early intervention right away
• avoid long process of diagnosis, extra tests
• avoid second (or third) affected child
• get diagnosis for symptomatic premutation
  carriers through cascade analysis of family
• Problems
• what to do with asymptomatic premutation carriers
• no cure
• If new treatments give partial cure newborn
  screening will be key (treatments may work better
  earlier)

102
Acknowledgements

• FRAXA Research Foundation
• NIH NINDS
• Kiwanis Spastic Paralysis Foundation
• National Fragile X Foundation
• Collaborators
• Sue Ellen Krause PhD
• Sandy Block MS
• Steve Guter MS
• Ed Cook MD
• Randi Hagerman MD
• Maureen Leehey MD
• Paul Hagerman MD PhD
• Chris Goetz MD
• Don Bailey PhD
• Glenn Stebbins PhD
• Pete Van der Klish PhD

• Lab Research Associate
• Lili Zhou MD
• Study Co-ordinators
• Kristina Potanos
• Dahlia Weinberg
• Rebecca Lara
• Foster Lewin
• Allison Sumis
• Crystal Hervey
• Students
• Ok-Kyung Kim
• Chinton DeSai
• Ravi Iyengar
• Hazel Perry
• Statistics
• Sue Leurgans PhD
• Joanna Wuu MS
• Cortex Pharmaceuticals
• Steve Johnson PhD

Steve Porges PhD Mina Johnson PhD Isabel Boutet
PhD Steve Hooper PhD Ivan Jean Weiler PhD Bill
Greenough PhD Ning Weng PhD Mark Bear PhD Emily
Osterweil PhD
FXS Families