Outline Williams Syndrome and Fragile X • Overview of Fragile X Syndrome • Overlap of Fragile X Syndrome and Autism Cheryl Klaiman, PhD • Adaptive Behavior Profiles in Fragile X Syndrome Miriam Lense, PhD Marcus Autism Center Leo Kanner (1943) History of Fragile X Syndrome • 1943 • James Purdon Martin and Julia Bell • Particular form of intellectual disability was X-linked. • Family had 11 individuals with severe intellectual disability Marcus Autism Center Marcus Autism Center History of Fragile X Syndrome What is Fragile X Syndrome? • In 1969, Herbert Lubs developed the chromosomal test for • FXS was first known example of a trinucleotide repeat Fragile X disorder • In 1991, gene responsible for FXS was identified by Verkerk and colleagues, including Stephen Warren From: Garber, Visootsak & Warren, 2008. European Journal of Human Genetics Marcus Autism Center Marcus Autism Center More on Fragile X Syndrome Phenotype – Males • Varying degrees of symptoms ranging from mild to severe • X-linked dominant condition – Females: • 1/3 have intellectual disability • Leading inherited cause of developmental disability in males • More common – learning difficulties and emotional problems • Affects 1:4000 males and 1:8000 females – Physical features • Large ears, long face, soft skin, macroorchidism in post-pubertal males, connective tissue problems – Behavioral Features • ADHD, autism and autistic behaviors, social anxiety, hand-biting and/or flapping, poor eye-contact, sensory disorders, increased risk for aggression Marcus Autism Center Marcus Autism Center Phenotypic Screening Checklist (Maes et al, Checklists 2000) – To identify individuals with undiagnosed developmental 1. Narrow and elongated face 16. Gaiety, cheerfulness delay who would be appropriate candidates for the FXS 2. High forehead 17. Hypersensitivity for changes 3. Prominent lower jaw 18. Hand biting molecular testing 4. Large, protruding ears 19. Stereotypic hand movements 5. Macroorchidism 20. Flapping hands and arms – However, as many children do not have apparent physical 6. Hyperextensible finger joints 21. Avoiding eye contact 7. Hyperextensible joints (other) 22. Turning away the face features, it is best practice to recommend testing for FraX 8. Hyperactivity 23. Tactile defensiveness in all children with developmental delay, intellectual 9. Sensory oversensitivity 24. Rapid speed of language disability or autism. 10. Impulsivity 25. Being talkative 11. Being chaotic 26. Perseveration 12. Shyness 27. Echolalia 13. Being too helpful 28. Imitation of own language 14. Approach-avoidance conflict 15. Fearfulness Marcus Autism Center Marcus Autism Center Phenotypic Screening Checklist (Maes et al, Fragile X and Autism 2000) 1. Narrow and elongated face 16. Gaiety, cheerfulness • Many behavioral features similar to behaviors 2. High forehead 17. Hypersensitivity for changes 3. Prominent lower jaw 18. Hand biting commonly seen in ASD 4. Large, protruding ears 19. Stereotypic hand movements • FXS increasingly considered a subtype of ASD or even 5. Macroorchidism 20. Flapping hands and arms 6. Hyperextensible finger joints 21. Avoiding eye contact one of the ‘autisms’ 7. Hyperextensible joints (other) 22. Turning away the face • Approximately 1/3 of boys with FXS meet DSM-IV 8. Hyperactivity 23. Tactile defensiveness 9. Sensory oversensitivity 24. Rapid speed of language criteria for ASD and 1/3 more met criteria for 10. Impulsivity 25. Being talkative PDDNOS 11. Being chaotic 26. Perseveration 12. Shyness 27. Echolalia • Excess of repetitive behaviors may account for many 13. Being too helpful 28. Imitation of own language of the ASD symptoms associated with FXS 14. Approach-avoidance conflict – i.e., stereotypical manipulation of objects differentiates 15. Fearfulness children with FXS and ASD from those without an ASD Marcus Autism Center diagnosis Marcus Autism Center BUT h f f RRB h l i i SI Core ASD Symptoms Empirical Data on ASD symptoms • Social Behaviors • Study by Wolff et al, 2012, JAACAP – Social avoidance and failure to recognize social cues may drive a diagnosis of ASD in FXS – HOWEVER, impairments on a continuum in FXS regardless of the comorbid condition – Social avoidance and anxiety are common to children with FXS generally thus may not reliably distinguish those with from those without ASD – Difference could be due to minor degrees of difference in social performance Marcus Autism Center Marcus Autism Center RRB Symptom Overlap Continuum of ‘Autism’ impairments Marcus Autism Center Marcus Autism Center Summary of Wolff et al, 2012 findings Fragile X and Autism Overlap • Is it hyperexpression of the FXS behavioral • Repetitive behaviors phenotype – Greatest degree of symptom overlap in repetitive motor behaviors (stereotypy, self-injury) – Significantly less compulsive or ritual behaviors in boys with • Children with FXS+ASD may be more attuned to FXS+ASD social cues than those with ASD • Repetitive motor behaviors are linked to developmental disability in – In ASD social deficits are likely a result of an inability to general - not specific to ASD attend to relevant social information but in FXS+ASD social • Social behaviors initiation deficits may reflect social anxiety common to – Boys with FXS+ASD significantly less impairment on children with FXS measurements of social response – Overall patterns most similar for social initiation items Marcus Autism Center Marcus Autism Center Neuroanatomical Differences Overview – Williams Syndrome • Neuroanatomy backs up FXS+ASD being different • Physical Features of Williams Syndrome from ASD – FXS+ASD show highly enlarged caudate and small amygdala • Genetics of Williams Syndrome – ASD show modest caudate and amygdala enlargement – In FXS, social avoidance been associated with • Cognitive-Behavioral Profile of Williams Syndrome neuroendocrine dysfunction; in ASD social indifference or inattention associated with amygdala overgrowth and dysfunction – THUS, neurodevelopmental pathways leading to seemingly similar but qualitatively different social deficits between ASD and FXS+ASD may also differ with respect to the brain. Marcus Autism Center Marcus Autism Center Williams Syndrome Physical Characteristics • First identified in 1961 • Facial features – Periorbital fullness, long philtrum, full lips, short nose • Incidence: 1 in ~10,000 live births (under diagnosed) • “De novo” deletion of ~26-28 genes on chromosome 7 • Cardiovascular disease Genetics of WS – Supravalvular aortic stenosis (SVAS; ~70%) – High blood pressure (50%) • Typically deletion of 1.5 or 1.8 million base pairs • Endocrine – Early puberty, glucose intolerance, subclinical hyperthyroidism, • 2-3% of patients have atypical deletions hypercalcemia • Gastrointestinal, weight issues • Soft skin, premature graying of hair • Hoarse voice, recurrent ear infections, strabismus, sensorineural hearing loss, high frequency hearing loss • Short stature • Dental problems – Microdontia, malocclusion • Musculoskeletal – Joint hypermobility, joint contractures, awkward gait Genotype-Phenotype Relations (Pober, 2010; Schubert, 2010) Cognitive Profile • ELN: hypertension, arteriopathy with vascular stenoses, vascular smooth-muscle-cell overgrowth; soft skin with Language Spatial premature aging, hoarse voice, hernias, facial features • STX1A: impaired glucose tolerance • LIMK1: visuospatial impairments? • GTF21 family: craniofacial features, social behavior, intellectual disability, neurocognitive profile, impaired visual responses? • Dup7 cases: expressive language difficulties, social anxiety Bellugi et al., 2000 Language: Visuospatial Processing Strengths and Weaknesses • Delayed language development } Socially-expressive language • Early phonologic delays (SW vs WS) } Linguistic affect • Produce more words than understand • Lies vs. jokes Sociability “Everyone in the world is my friend” • 䇾…Jenny locked her eyes onto the stranger’s from the time the stranger entered the room. After the stranger was repeatedly unable to entice Jenny to attend to something else, she tried to force Jenny to direct her attention elsewhere by waving a stuffed kitty in front of her face. Jenny glanced briefly at the kitty but then immediately looked around the kitty to resume staring at the stranger.䇿 – (Mervis 2003) Mean adjusted time looking at partner Video Examples Social Approach/Vulnerability Is it good to be so social? – Rate “happy faces” as more approachable than controls (Friegeiro et al., 2006) • Dyadic vs. Triadic Interactions (Laing et al., 2002) – Parents rate their children with WS as more willing to approach strangers (Doyle et al., 2004) • Parental Questionnaire (Dykens and Rosner, 1999): – 䇾often initiates interactions䇿 – 䇾never goes unnoticed in groups䇿 – Work supervisors and parents report vulnerability, – 䇾feels terrible when others are hurt䇿 potential for exploitation (Udwin et al., 1998) • Social Impairments (Elison et al., 2010): – Teach “stranger danger” skills (Fisher, 2015): – 1/3 of adults have problems making friends • 41% of adults agreed to go with a stranger at least once before – ~50% have poor concept of friendship training vs.11% after training – 40% never had romantic relationship • 9% said “no” and walked away before training vs. 54% after training Social Impairment on ADOS Psychopathology • 10-50% of individuals with WS meet criteria for ASD on ADOS Mod 1 Children/Adolescents Adults – Majority fall in PDD-NOS/ASD range rather than - ADHD (65%) - Specific Phobia (35% Dx, Autism - Specific Phobia >80% symptoms) (54%) - GAD (18-35%) • Common difficulties in WS: declarative pointing, - GAD (12%) - Distractibility (85%) showing objects, giving - No diagnosis (22%) - Overaffectionate, - Attention Seeking, • Less common difficulties: Directed vocalizations hyperacusis, compulsions, and facial expressions, modulated eye contact, obsessions, obsessions, over- attention seeking activity initiating joint attention • Repetitive play skills Questions? .