DEMYSTIFYING MEDICINE FRAGILE X SYNDROME & RELATED DISORDERS March 31, 2009 Walter E. Kaufmann

1. DEMYSTIFYING MEDICINE FRAGILE X SYNDROME & RELATED DISORDERS March 31, 2009 Walter E. Kaufmann

2. One Gene (FMR1): Three (or More) Disorders M: 1:800, F: 1:250 M: 1:4000, F: 1:6000 ID, ASD, LD? Hagerman et al. Pediatrics 123:378-90, 2009

3. One Gene (FMR1): Multiple disorders in the same family Hagerman. J Dev Behav Pediatr 27:63-74, 2006

4. Fragile X Syndrome: One gene, Three Major Disorders Fragile X syndrome: in males and females with full mutation (200-2,000 repeats) or mosaicism (full mutation+premutation). Life-long disorder. Fragile X tremor ataxia syndrome (FXTAS): predominantly older (>50 years) males with premutation (61-199 repeats). Manifestations: gait ataxia, intention tremor, cognitive impairment (frontal lobe dementia). Premutation-related disorders: POI, females with emotional problems and perseverative thinking, children (mainly boys) with ADHD, intellectual disability and/or autism. Intermediate or gray zone (41-60 repeats) : ??

5. FMRP Patterns CONT MOS FM PM Fragile X Syndrome FMR1 Mutation Diagnosis by FMR1Southern blot and PCR FMRP quantifications providecomplementary information Cytogenetics Kaufmann et al. Am J Med Genet 83:286-295, 1999 X-linked: Males more Affected than Females Kaufmann and Reiss. Am J Med Genet 88:11-24, 1999

6. Fragile X Phenotype • Affects about 1:4000 males, 1:6000 females • Neuro Phenotype (VARIABLE) • Mild/Moderate MR • ADHD • Autism • Social Withdrawal • Aggressive Behavior • Hyperarousal • Seizures • Non-Neuro Phenotype • Facial characteristics (non-diagnostic) • Connective tissue abnormalities (joint laxity, mitral valve prolapse) • Strabismus • Recurrent OM • GER From Fragile X Research Foundation website Adapted from Kaufmann & Reiss. Am J Med Genet 88:11-24, 1999

7. Fragile X syndrome as a Major Cause of Intellectual Disability PRACTICE PARAMETERS for GDD (CNS & AAN): Shevell et al. Neurology 60:367-380, 2003.

8. Fragile X as a Major Cause of Intellectual Disability Mild to Moderate ID vs. Moderate to Severe in Other Genetic Disorders Down Syndrome Fragile X Syndrome Capone et al. Am J Med Genet 134A:373-380, 2005 Carter et al. Am J Med Genet 144B:87-94, 2007 Kaufmann et al. Am J Med Genet 129A:225-234, 2004 Budimirovic et al. Am J Med Genet 140A:1814-1826, 2006

9. Fragile X syndrome as a Major Cause of Autism Schaefer & Mendelsohn. Genet Med 10:301-5, 2008/ACMG Practice Guidelines Typical Fragile X Fragile X + Autism

10. Fragile X syndrome as a Major Cause of Autism KKI Research Program on Autism in FXS

11. Autism in Fragile X and Down Syndromes Low IQ per se has a minimal influence upon ASD status in ID DS+ASD vs. DS Typical FXS+ASD vs. FXS Typical p=0.99 p=0.54 IQ/DQ IQ/DQ ASD ASD p=0.001 p=0.79 ABCstereo ABCleth ASD ASD p<0.0001 p<0.0001 AutBehav rel ADIrecs ASD ASD % Variance IQ/DQ: 0% ABCstereo: 13% AutBehav rel: 27% % Variance IQ/DQ: 0.5% ABCleth: 0.1% ADIrecs: 53%

12. Autism in Fragile X 16-50% prevalence of Autism/ASD in Fragile X Syndrome Example of Research in Autism in Fragile X: Determining Behavioral Profiles 1. Delayed/impaired adaptive socialization is the primary determinant of FraX+ASD. CORTEX Kaufmann et al. Am J Med Genet 129A:225-234, 2004 Budimirovic et al. Am J Med Genet 140A:1814-1826, 2006 Hernandez et al. Am J Med Genet: in press.

13. Autism in Fragile X 16-50% prevalence of Autism/ASD in Fragile X Syndrome Example of Research in Autism in Fragile X: Determining Behavioral Profiles 2. Severe social withdrawal (indifference) is an important secondary contributor. LIMBIC SYSTEM Kaufmann et al. Am J Med Genet 129A:225-234, 2004 Budimirovic et al. Am J Med Genet 140A:1814-1826, 2006 Hernandez et al. Am J Med Genet: in press.

14. Autism in Fragile X Behavioral Features in FXS: Diagnostic Challenges Shy temperament: misdiagnosis Social Anxiety: missing diagnosis (Social Anxiety is the most common psychiatric co-morbidity in “Idiopathic” Autism • Avoidance of eye contact • Hyperactivity • Perseverative speech • Hand flapping • Distractibility

15. Autism in Fragile X The Social Approach Scale paradigm identifies dynamics of social avoidance and indifference that can distinguish Autism from Social Anxiety in Fragile X Roberts et al. JADD 37:1748-60, 2007

16. Autism in Fragile X Behavioral Basis Cognitive trajectory distinguishes FXS+ASD Hernandez et al. Am J Med Genet: in press

17. FXS+Autism FXS Typical Autism in Fragile X Biological Bases Hyperplasia of the posterior-superior vermis in boys with FXS+Autism (vs. FXS Typical)(Kaufmann et al. J Child Neurol 18:463-470, 2003) Abnormalities in the cytoplasmic FMR1 interacting protein 1 (CYFIP1) pathway in lymphoblasts from boys with FXS+ASD (vs. controls and dup15q):GPR155 in FXS, CYFP1 & JAKMIP1/MARLIN-1 in dup15q(Nishimura et al. Hum Mol Genet 16:1682-1698, 2007)

18. Treatment of Fragile X Symptomatic Treatment: Specific Manifestations • CNS Stimulants: ADHD • Methylphenidate • Dextroamphetamine • Alpha-adrenergic agonists:ADHD, hyperarousal • Clonidine • Guanfacine • Atypical antipsychotics:Aggressive behavior, stereotypic behavior, anxiety (*) • Risperidone • Aripiprazole* • Selected Serotonin Reuptake Inhibitors (SSRIs):Anxiety, autistic symptoms • Fluoxetine • Sertraline • Anticonvulsants & Mood stabilizers:Seizures, mood disorders • Carbamazepine • Valproic Acid. • Lithium Carbonate

19. Treatment of Fragile X Targeted Treatments: Neurobiologically-Based Multiple Cognitive & Behavioral Symptoms • mGluR5 antagonists: multiple ongoing trials, initial trial completed • GABA agonists: on initial trial • Ampakines: initial trial completed • Lithium: initial trial completed • Other synaptic modulators (minocycline): on initial trial

20. Fragile X-Associated Tremor/Ataxia Syndrome Diagnostic and Clinical Features of FXTAS Amiri et al. Arch Neurol 65:19-25, 2008 Courtesy of Dr. R. Hagerman

21. Fragile X-Associated Tremor/Ataxia Syndrome Neuroimaging of FXTAS MCP sign Brunberg et al. AJNR 23:1757-1766, 2002

22. Fragile X-Associated Tremor/Ataxia Syndrome Neuropathology of FXTAS Intranuclear inclusions G Normal CGG88 N Cultured neural cells: nuclear lamin IR Amiri et al. Arch Neurol 65:19-25, 2008

23. Premature Ovarian Failure/Primary Ovarian Insufficiency POF/POI ~15% of women with FMR1 premutation 0.8-7.5% FMR1 premutation in sporadic POI 13% FMR1 premutation in familial POI Wittenberger et al. Fertil Steril 87:456-465, 2007

24. Primary Ovarian Insufficiency Wittenberger et al. Fertil Steril 87:456-465, 2007

25. The Other Premutation-Related Disorders Children Farzin et al. J Dev Behav Pediatr 27:137-144, 2006

26. The Other Premutation-Related Disorders Children Aziz et al. Am J Med Genet 121B:119-127, 2003

27. The Other Premutation-Related Disorders Adults

28. The Other Premutation-Related Disorders Adult females with Premutation Coffey et al. Am J Med Genet 146A:1009-1016, 2008

29. Fragile X Gene Related Disorders Conclusions Key to understanding ID and ASD. Contributory to neurobiology of synaptic development andmaintenance. Key to understanding RNA toxicity and formation of neuronal and glial inclusions. Contributory to the clinical study of neurodegenerative disorders. • Chechlacz & Gleeson. • Pediatr Neurol 29:11-17, 2003

30. The Postsynaptic Density: convergence of RTT, FXS & XLMR XLMRs are associated to mutations in signaling and synaptic proteins • Chechlacz & Gleeson. • Pediatr Neurol 29:11-17, 2003 • The X-linked mental retardation protein oligophrenin-1 • is required for dendritic spine morphogenesis.Govek et al. Nat Neurosci 7:364-372, 2004. • Knock-down of OPHN1 levels in CA1 neurons in rat • hippocampal slices significantly decreases spine length. • Reduced OPHN1 levels affect spine length by increasing • RhoA and Rho-kinase activities. There is an interaction • between OPHN1 and the postsynaptic adaptor Homer.