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 – 1:4000 males and females • Carriers – 1:250 females, 1:800 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, >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

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 SyndromeCharacteristic cognitive pattern with prominent executive function deficits Strengths Receptive vocabulary Syntax Imitation Grammaticalstructure Visual memory Simultaneous processing Experiential learning Weaknesses Auditory processing Sequencing Abstraction Short-term memory Topic maintenance/ "connectedness" Mathematics Working memory Coordination/praxis

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 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

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. 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 Fragile X Syndrome - Pattern of Speech/Language Deficits

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 THE BIGGEST PROBLEM FOR MANY FAMILIES • 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

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, 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

20. 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

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 T&A • 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 SyndromeCharacteristic cognitive pattern with prominent executive function deficits Strengths Receptive vocabulary Syntax Imitation Grammaticalstructure Visual memory Simultaneous processing Experiential learning Weaknesses Auditory processing Sequencing Abstraction Short-term memory Topic maintenance/ "connectedness" Mathematics Working memory Coordination/praxis

30. 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