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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. Fragile X Syndrome. Form of X-linked MR/ID discovered by Martin and Bell 1943 Lubs fragile site 1969

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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

fragile x syndrome
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 – 1:4000 males and females
  • Carriers – 1:250 females, 1:800 males
  • All ethnic groups worldwide


features of fragile x syndrome
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
growth in fragile x syndrome
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
fragile x syndrome eye problems
Fragile X SyndromeEye Problems
  • Hyperopia (59%)
  • Strabismus (30%)
  • Myopia (17%) - like general population
  • Congenital nystagmus - increased but occasional
  • No ocular health problems
epilepsy in fragile x
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, >80% 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

fragile x syndrome intellectual disability
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

fragile x syndrome characteristic cognitive pattern with prominent executive function deficits
Fragile X SyndromeCharacteristic cognitive pattern with prominent executive function deficits


Receptive vocabulary




Visual memory

Simultaneous processing

Experiential learning


Auditory processing



Short-term memory

Topic maintenance/ "connectedness"


Working memory


fragile x syndrome developmental problems
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
developmental problems
Developmental Problems
  • Parents most frequently become concerned first about speech delay
  • Other concerns that may lead to child’s 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 don’t recognize problem or are in denial
developmental screening in fxs
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
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


Less abnormal






Fragile X Syndrome - Pattern of Speech/Language Deficits
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
language in fxs vs autism
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)
fxs socialization deficits
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
behavior problems in fxs
Behavior Problems in FXS


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

Behavior in fragile X often

out-of-proportion to cognitive level

fragile x syndrome distinguishing behaviors
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
fxs female affecteds
FXS - Female Affecteds
  • More mildly involved
  • Average IQ 80
  • NVLD, VIQ>PIQ, 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
supportive fragile x syndrome treatment 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

Supportive Fragile X SyndromeTreatment/Therapy in Clinic

Rush FXS Clinic since 1992:

Now about 400 patients

eye problems
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
ear infections
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 T&A
    • If fluid and hearing loss without overt infections – need tubes
  • Need to be aggressive – hearing loss will add to speech problems
sleep apnea
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
flat pronated feet
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
seizures basic principles of seizure management in fxs
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

Educational Treatments (behavior will be a problem if the optimal educational setting, curricula and approach style are not implemented)
fxs curriculum and teaching style matched to cognitive profile
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
fragile x syndrome characteristic cognitive pattern with prominent executive function deficits29
Fragile X SyndromeCharacteristic cognitive pattern with prominent executive function deficits


Receptive vocabulary




Visual memory

Simultaneous processing

Experiential learning


Auditory processing



Short-term memory

Topic maintenance/ "connectedness"


Working memory


academic skills in fxs
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
fxs cognition and educational program placement
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
fragile x syndrome educational strategies
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
fragile x syndrome educational strategies34
Fragile X Syndrome Educational Strategies
  • Circumvent or Minimize Problems with
    • Attention
    • Sequential processing
    • Auditory learning
    • Anxiety/overstimulation
    • Novelty
    • Graphomotor skills
general components of the educational approach
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

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
fxs curriculum matched to cognitive profile
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
fxs curriculum matched to cognitive profile38
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
fxs teaching style matched to cognitive profile
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
curricula for fxs academics
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
curricula for fxs academics41
Curricula for FXS Academics
  • Spelling
    • I Can Print
    • Spell Master
  • Writing
    • Handwriting Without Tears
  • Functional Skills
    • Stepping Out Cues
    • Life Skills Game Series
Therapy Treatments(important part of behavioral management – need therepy to communicate, perform ADLs, and manage sensory issues)
speech therapy
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
speech therapy44
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
speech therapy45
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
occupational therapy
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
occupational therapy47
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
socialization therapy
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
social curricula
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
social interventions in school
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
other therapies
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

causes of difficult behavior in fxs
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
causes of difficult behavior in fxs55
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
things that cause overarousal in fxs precipitate problem behaviors
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
physiological antecedents to behavioral deterioration fight or flight
Physiological Antecedents to Behavioral Deterioration – “Fight or Flight”
  • 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

Use to help identify when problem about to occur and “head off”

treatment of behavioral emotional problems
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

treatment of behavioral emotional problems59
Treatment of Behavioral/ Emotional Problems


Visual cues paired with verbal interaction


Family therapy

Videotaping of adaptive behavior

behavior plan for agitation and aggressive outbursts
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
psychopharmacology in fragile x syndrome
Targets behavior to improve functioning

Supportive, does not target underlying cognitive problem

Only one prior controlled trial in FXS (N=15) 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

Psychopharmacology in Fragile X Syndrome
fxs types of medications and indications
FXS - Types of Medications and Indications*

*meds may be targeting several clusters

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

Decision to Use Behavioral Medication
supportive psychopharmacology is helpful in fxs
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

52 trials

52 patients

231 trials

123 patients

100 trials

58 patients

Anxiety Mood

Attention Hyperactivity

Aggression Irritability

Hyperarousal Oversensitivity


FMR1: The Fragile X Gene

Carrier state passed through many generations before FXS

Simple DNA test to diagnose FXS – measures repeat size

fmrp expression and disability
FMRP Expression and Disability


Social anxiety/shyness


Executive deficits

Spatial perceptual deficits



Intellectual Disability



the fragile x mouse knockout k o
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?
fmrp in dendrites brain connections
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.

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

Dendritic Spine Morphology Abnormal in FXS

As would predict, FMRP regulates structural synaptic maturation

McKinney et al, AJMG -B: Neuropsychiatric Genetics, 2005

new research is leading to future treatments for fragile x
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


Fragile X



Excessive LTD – due to mGluR system overactivity


















Mature connection

Fragile X

Immature connection

(too weak)

mGluR Theory of Fragile X









Other systems







Excessive LTD – due to mGluR system overactivity

Potential Mechanisms for New Treatments in FXS


Fragile X

Immature connection

(too weak)

treatment of cognition fragile x as a model
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









Stronger connection

Excessive LTD



Activate AMPA receptors

Raise BDNF – bring AMPA receptors to synapse






Mechanism 3

Fragile X

Immature connection

(too weak)








Excessive LTD

Stronger connection



Lithium blocks PI turnover, reduce mGluR signalling through PL-C/PK-C cascade, directly block protein synthesis by GSK3B block







Mechanism 1

Fragile X

Immature connection

(too weak)

lithium and fxs models
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

fxs open label lithium trial
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, p=0.005

Placebo change in CX516 study (N=25): -4

Also significant improvement in CGI, VAS, and Vineland Personal Daily Living Skills and Maladaptive Behavior

lithium study biomarker erk activation in lymphocytes
Lithium Study Biomarker - ERK Activation in Lymphocytes

ERK phosphorylation slower in K/O and FXS

Berry-Kravis et al, JDBP 2008


Baseline mean: 4.87 min

2 Month Treatment mean: 4.11 min (p=0.007)

(about 1 min is difference FXS and control)

1 Year Treatment mean: 3.56 min (P=0.00006)


2 mo

1 yr

gaba agonists in fxs
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

r baclofen stx209 trial
R-Baclofen (STX209) Trial

Baclofen is racemic

Both isomers are selective GABA-B agonists

GABA-B: R:S potency ratio 15:1

in vivo: R:S potency ratio 10-100:1

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









Combination: Fragile X

connection corrected

Stronger connection

Excessive LTD



mGluR5 blocker









Mechanism 1

Fragile X

Immature connection

(too weak)

mglur5 blockers and fragile x
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

phenotypes in dfxr mutant fly normalized by mpep
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

phenotypes in fxs knockout mouse normalized by mpep
Phenotypes in FXS Knockout Mouse Normalized by MPEP

Audiogenic seizures

Epileptiform bursts

Open field behavior

Prepulse inhibition

Dendritic spine shape

AMPA receptor internalization

Excessive protein synthesis

Bauschwitz, 2006

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

ampa receptor rescue by mpep
AMPA Receptor Rescue by MPEP

Surface GluR1

Internal GluR1

Nakamoto et al. 2007



GluR1 = AMPA receptors that drive strength of neural connections

siRNA to block FMRP translation

siRNA and MPEP

mglur5 negative modulators in development
mGluR5 Negative Modulators in Development


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

mglur5 negative modulators in development88
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

trial open label escalating single dose trial of fenobam in fxs
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


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


  • PPI improved 25% in 6/12 subjects (control test-retest group 2/13, p=0.03), looks like good measure for smaller early studies
  • Observation of positive behavioral changes in 9/12 subjects
  • No fenobam-related adverse events
prepulse inhibition ppi studies
Prepulse Inhibition (PPI) Studies

50 ms 105 db white noise

Startle Alone Trials

Auditory stimulus


Amplitude (volts)

Obicularis Oculi


Prepulse Trials

50 ms 105 db white noise

Prepulse: 50 ms, 75 db 1000Hz tone

Auditory stimuli

Prepulse interval:

60, 120, or 240 ms

Obicularis Oculi


Amplitude (volts)


PPI improved on fenobam

Berry-Kravis et al. JMG 2009


potential future trials
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


Still need work on design and outcome measures for these, many steps, but benefit may be overlap with autism pathways – treatments for autism too

is there a premutation phenotype
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
fragile x related primary ovarian insufficiency fxpoi
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 don’t fully stop menses by 40 years, increased FSH
  • Risk for POF increases gradually for CGG<80, 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)
poi infertility and fxs the trouble with triplets
POI, Infertility and FXSThe Trouble with Triplets






Likely Premutation


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/


Mild ID



Severe ID

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


Reproductive Options in Fragile X Syndrome
fxtas in premutation carrier males
FXTAS in Premutation Carrier Males

Multidimensional tremor


Parkinsonian symptoms


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

newborn screening for fxs
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)

FRAXA Research Foundation


Kiwanis Spastic Paralysis Foundation

National Fragile X Foundation


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


Ok-Kyung Kim

Chinton DeSai

Ravi Iyengar

Hazel Perry


Sue Leurgans PhD

Joanna Wuu MS

Cortex Pharmaceuticals

Steve Johnson PhD

Roger Stoll PhD

Seaside Pharmaceuticals

Randy Carpenter PhD

Study Co-ordinators off site

Tristan Jardini

Penelope Decle

Jennifer Cogswell

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