The FXTAS Complex. Tremor Ataxia. hypertension Psychological Neuropathy problems Limb pain

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1 The FXTAS Complex Tremor Ataxia hypertension Psychological Neuropathy problems Limb pain migraines fibromyalgia impotence dysinhibition Urinary problems: urgency, incontinence Hypothyroidism, testosterone deficiency

2 Treatment of Symptomatic Carriers Treat depression and anxiety with SSRIs Exercise and SSRIs stimulate neurogenesis to repair the brain: a dynamic process in aging Treat hypertension and hypothyroidism Avoid stress and elective surgery when possible Stop smoking and drinking excessively Antioxidants ie vit C, folate, vit E, fresh fruit, acai berry, green tea Treatment of FXTAS: tremor-consider primidone, beta blockers, botox injections; cognitive changesmemantine for memory, confusion and neuroprotection venlafaxine (Effexor XR) to enhance attention,ef, 1 case of Chantrix improving tremor in a smoker Deep brain stimulation can improve tremor

3 Treatment for Fragile X Syndrome Multiple individual therapies speech & language, PROMPT therapy developed by Deborah Hayden at OT SI & PT behavioral therapy, family counseling, ABA if autism too Special education inclusion when possible, often with aide individual help with academics especially math computers: word processing & software for academics Medications enhance attention and concentration-stimulants decrease impulsivity, hyperactivity, and aggression decrease anxiety and OCD symptoms- SSRIs stabilize mood-risperidone, aripiprazole (Abilify), lithium anticonvulsants: depakote, lamotrigine (Lamictal) Genetic Counseling

4 Treatment of ADHD in FXS with Stimulants

5 Alpha Agonists to Decrease ADHD and Hyperarousal in FXS Clonidine Guanfacine And alpha 2A agonist

6 Clonidine in Fragile X Survey of 35 children with FXS treated with clonidine (Hagerman et al 1995) 89% treated for ADHD, 37% for tantrums, 40% for aggression, 49% for anxiety, 37% for sleep disturbances 63% said very helpful 20% said somewhat helpful 6% said no effect 11% said worse on clonidine

7 Selective Serotonin Reuptake Inhibitors SSRIs

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9 Fragile X specific treatments: Targeted treatments for FXS may also be helpful for other neurodevelopmental disorders with similar Glutamate and GABA abnormalities including a subgroup of patients with autism

10 Neurobiology of Long Term Depression (LTD) through mglur5 Internalization of AMPA mglur5 Internalization of AMPA mglur5 Internalization of AMPA mglur5 Antagonist Normal protein synthesis Gene transcription FMRP activates mrna translation Excess protein synthesis FMRP activates mrna translation Normal protein synthesis FMRP activates mrna translation Nucleus DNA Typical Development Nucleus DNA Fragile X syndrome Nucleus DNA Rescued Phenotype Chonchyia, Schneider and Hagerman 2009 Advances in Pediatrics

11 A Model for FMRP function The mglur hypothesis Gradual weakening of synapses Too many immature spines Receptor loss

12 Specific Psychopharmacological Interventions mglur5 antagonists mglur5 antagonists including MPEP and fenobam have been tried in KO mice and in fragile X fruit flies and have improved synaptic structure, cognition and seizures. devrij et al 2007 Bauchwitz et al 2004 McBride et al 2005 Yan et al 2005

13 Targeted Treatments for FXS mglur5 antagonists: Fenobam used in 1980s as anxiolytic, recently shown to be mglur5 antagonist, has FDA approval for FXS trials (Berry-Kravis et al 2009 JMG) STX 107 developed by Merck and licensed by Seaside Therapeutics. Animal studies funded by CAN, human trials in FXS within 1-2 years Novartis has finished European study of mglur5 Roche will initiate studies in FX adults Some GABA agonists may down regulate mglur5 pathway: R-Baclofen-trial in progress 6 sites for FXS Minocycline can be helpful for the KO mouse by lowering MMP9 and also helpful in a survey in FXS

14 Prepulse Inhibition (PPI) Studies Startle Alone Trials 50 ms 105 db white noise Auditory stimulus Obicularis Oculi EMG Latency Amplitude (volts) Prepulse Trials 50 ms 105 db white noise Prepulse: 50 ms, 75 db 1000Hz tone Auditory stimuli Obicularis Oculi EMG Prepulse interval: 60, 120, or 240 ms Amplitude (volts)

15 Prepulse Inhibition in Fragile X Syndrome: Outcome Measure Ready for Treatment Trials Test-Retest Reliability Group Effect: F(1, 74) = 36.00, p < !! Alphas =.88 (control),.85 (FXS),.89 overall!!!

16 Fenobam: An anti An anti-anxiety anxiety med studied in the 1980s and now found to be an mglur5 antagonist (Porter et al 2005) FDA approved orphan drug for FXS and safety trial funded by Neuropharm and FRAXA Single dose study with AE screening and PK in FXS 6 males and 6 females 3 each at Rush and UC Davis stable doses of SSRIs,, antipsychotics, alpha-agonists agonists allowed, stimulants held for baseline and dosing days Baseline visit for exam, screening labs, PPI, CPT Dosing visit in weeks with AE monitoring, PPI/CPT, PK blood draws for 5 hours Primary endpoint safety; PPI, CPT as exploratory efficacy outcome measures (Berry-Kravis et al JMG 2009)

17 MIND Institute Patient Prepulse Inhibition (PPI) measures at baseline and after 2 weeks IV stayed in for 5 hours For PK studies

18 We celebrated the results of the first and subsequent patients

19 P=0.03

20 R-Baclofen Rescues Audiogenic Seizures in the FX-KO Mouse (Pacey et al 2009 on line Molecular Pharmacology) R-Baclofen (1 or 2 mg/kg i.p.) rescued audiogenic seizures in 27 to 30 day old FMR1 KO mice There was a 67% (1 mg/kg dose) to 79% (2 mg/kg dose) decrease in seizure incidence compared to vehicle controls Effect seen in both male and female KOs

21 R-Baclofen: STX209 Baclofen is racemic Both isomers are selective GABA-B agonists GABA-B: R:S potency ratio 15:1 in vivo: R:S potency ratio :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

22 mglur Theory Excessive Glutamatergic Transmission STX209 mglur5 GABA-B FMRP Proteins mglur5 Pre-synaptic Post -synaptic Seaside Therapeutics

23 Controlled R-Baclofen Trial funded by Seaside Therapeutics Enrolling individuals with FXS 6 years and older with irritability scale >9 on ABC- Aberrant Behavior Checklist Escalation of dose from 1 mg bid gradually to optimal dose but no higher than 10 mg tid over a 4 week period then washout and crossover for a second 4 weeks Outcome measures include CGI, visual analogue, ABC, PPI, eye tracking Trial taking place at 6 centers in the US including MIND Institute, Rush University, UCLA, Indiana University, Vanderbilt and UNC

24 Lithium could inhibit mglur-activated translation through 2 mechanisms Lithium FMRP

25 FXS Open-Label Lithium Trial Test concept of mglur pathway inhibition (reduction of excess translation) Test drug responsiveness for outcome measures Results to help inform study design for mglur5 blocker trials in FXS 15 FXS subjects 2 mo, 1 year extension Rapid titration to levels of Behavioral, cognitive, biopysiological,, biomarker outcomes at baseline and 2 mo 13 better at 2 mo, minimal toxicity

26 Absence of FMRP upregulates other proteins throughout the brain including MMP 9 (Bilousova et al 2009) Matrix metalloproteinase 9 (MMP 9) one of a family of proteins important for synaptic structure and plasticity MMP9 is significantly elevated in FXS Minocycline will lower MMP 9 levels and mature synaptic connections in cultured hippocampal cells Studies in the FX mouse demonstrate that minocycline treatment for 1 month at birth will rescue the synaptic abnormalities in vivo Improvements also seen in anxiety on the elevated plus maze and more strategic exploratory behavior on the Y maze

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28 Minocycline matures the spines in KO FX mouse

29 Minocycline treatment induces spine maturation with enhanced mushroom spines in the KO mouse Bilousova et al 2008 JMG

30 Minocycline 1948: Tetracycline introduced as a broad spectrum antibiotic 1963: FDA and ADA acknowledged dental abnormalities related to periods of active calcification (TCNs chelate Ca ++ and incorporate into bone and teeth) and recommended avoidance during pregnancy and early childhood 1967: Minocycline introduced, benefits are Little phototoxicity, greater GI absorption, lipid soluable, CNS penetrance, less calcium binding so less frequent tooth staining, anti-inflammatory and neuroprotective (Sanchez et al 2004; LaPorta et al 2005)

31 Dental Staining with Minocycline Overall thought to be 2 to 6% (Laporta et al 2005) Cascio et al 2004: followed 41 children ages 0.5 to 7.9 y mean 5yo treated with minocycline for brucellosis for 3 weeks (2.5 mg/kg bid). No increase in dental abnormalities compared to controls at 11yo Minocycline can stain tissues also in addition to bone and teeth. Oxidation brings out color and inhibited with simultaneous treatment with vit C (Bowles 1998) Other side effects include pseudotumor cerebri so discontinue if headaches or emesis is a problem; lupus like rash can occur with long term use

32 Porcelain plated upper teeth Sanchez et al 2004

33 Timing of calcification of deciduous teeth Calcification of permanent teeth begins at 6 months of age So window of opportunity In the first 6 months Sanchez et al 2004

34 Minocycline is available now by prescription There was dramatic response from families after the Bilousova paper was out on line Agustini Utari MD, a fellow in pediatrics from Indonesia working at the MIND surveyed 50 families whose children with FXS have been treated for >2weeks on minocycline (3 were treated for less than 2 wks) with a likert scale (very much better, somewhat better, no improvement, somewhat worse, very much worse) for behavioral and cognitive changes in the follow-up of our patients Open trial in Toronto with Dr Carlo Paribello

35 Sex Results Characteristics of Participants 43 Male, 7 Female DNA Full mutation 39 (78%), mosaic 9 (18%), premutation 2 (4%) Autism Autism 12 (24%), PDD-NOS 14 (28%) Diagnosis Age Mean : 13.3 ± 6.2 y (range years) Full Scale IQ Mean : 62.6 ± 14.5 (range 40-91) Duration of Mean : 3.5 months (range months) Treatment Dosage mg /day, orally

36 Outcome in 50 patients

37 Side Effects Percentage of side effects (n=53) 11.3% (6 patients) discontinued minocycline because of the side effects.

38 SIDE EFFECTS n=53

39 Gray color in finger and toe nails pigmentation of the nails in a 19 year-old male after one year on minocycline. The color change involved only some nails. Intense staining is seen on his index fingers and 2nd toes. The color change appeared after about months of use of minocycline and has not worsened in the subsequent year. A fungal culture was negative.

40 The Tobii eye tracker allows testing in babies with FXS

41 We demonstrated a significant impairment in detecting second-order, moving stimuli in FXS babies. Farzin et al 2008 First-order (luminance defined) Second order (texture defined)

42 Mullen Scales can detect improvement post minocycline in babies with FXS Changes in Mullen Scores age in months Visit 1 Visit 2 Visit 3 Pre Mino Visit 4 Post Mino CA MA Gross Motor Visual Reception Fine Motor Receptive Language Expressive Language Prominent increases, post-minocycline, in Expressive Language and Visual Reception

43 Targeted Treatment of Fragile X Syndrome camp agonists GABA Agonists Ganaxolone R-Baclofen MGluR5 Antagonists Fenobam STX107 others Antioxidants Vit E, C, folate NAC Minocycline

44 Alpha Tocopherol (Vit E) and N-acetyl L Cystine Protects Against Oxidative Stress in FXKO Mouse and Improves Behavior, Learning and Macroorchidism (de Diego-Otero et al 2009 Neuropsychopharmacology 34:1011

45 Targeted Treated Treatments must be combined with innovative educational programs If synaptic connections are improved with minocycline we must enhance these connections with educational interventions Develop improved education programs with assistive technology, virtual reality and computer games. Using Write Out Loud Co-writer word prediction programs

46 Greg Niemeyer s games to improve attention executive finction abilities will be utilized in the interventions Track FX and Balance Game

47 Assistive Technology includes Augmentative and Assistive Communication (AAC) Devices for those who are non verbal LAMP Training has been helpful for a subgroup of Children with FXS who are nonverbal

48 Who to Test with FMR1 DNA Any child or adult with intellectual disability or autism or ASD of unknown etiology Children with borderline IQ or learning disabilities or ADHD with features of FXS Women with reproductive or fertility problems with elevated FSH ACMG: Those with late onset tremor or cerebellar ataxia of unknown origin Neurological disorders: cerebellar ataxia in males and females over 50 years (2% with pre) MSA-C (Kamm et al 2005) Atypical Parkinsonism (Ceravolo et al 2005)

49 The National Fragile X Foundation has Treatment Information on line Next conference Detroit July 2010 PO Box San Francisco, CA USA Telephone: Fax: NATLFX@FragileX.org Web:

50 M.I.N.D. Institute Susan Rivera Louise Gane Susan Harris Faraz Farzin Weeresak Chonchiaya David Hessl Jennifer Cogswell Agustini Utari Patrick Adams Michele Ono Sarah Coffey Dept. Radiology James Brunberg Dept. Pathology Claudia Greco Dept. Chemistry Carlito Lebrilla Hyun-Joo An Eric Dodds Dept. Neurology Lin Zhang Charles DeCarli Ricardo Maselli Grace Fenton-Farrell Farrell Dept of Psychiatry Jim Bourgeois Andreea Seritan Collaborators UC Davis School of Medicine Dept. Biochem & Molec. Medicine Paul Hagerman Flora Tassone Chris Iwahashi Anna Ludwig Dolores Garcia-Arocena Greg Mayeur Chris Raske Dept. Biostatistics Danh Nguyen University of Washington and UC Davis Fragile X Research Center NICHD Funded Charles Laird Mike Guralnick Gwen Glew University of Colorado Health Sciences Center (Denver) Maureen Leehey Deborah Hall James Grigsby RUSH-Presbyterian Presbyterian-St. Luke s s Medical Center (Chicago) Elizabeth Berry-Kravis Christopher Goetz Latrobe University, Melbourne Australia Danuta Loesch Richard Huggins Support: NICHD, NINDS, NIA, NFXF, CDC UC Davis M.I.N.D. Institute