Fragile X Syndrome - Dayton Children`s Hospital
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Fragile X Syndrome - Dayton Children`s Hospital
Fragile X: A Family of Disorders with Targeted Treatments Meinhard Robinow Lecture 12-15 -10 Randi Hagerman MD Endowed Chair in Fragile X Research M.I.N.D. Institute University of California at Davis Medical Center Conflicts/Funding from NICHD, NINDS, NIA, Roche, Neuropharm, NFXF, FRAXA, Seaside Therapeutics, Novartis, Johnson and Johnson and Forest Fragile X Syndrome Leading heritable form of intellectual disability One in 130130-260 females and one in 250 250--800 males are carriers with new forms of involvement One in 2500 in general population with the full Involvement is broader than just ID and includes LD, ADHD, anxiety disorders, mood instability Leading (known) single gene associated with autism 3-6% of all children with autism have FXS Fragile site Approximately 30% of young children with fragile X syndrome have autism The clinical team for targeted treatments Thanks to all! 1 The Fragile X Mental Retardation 1 Gene (FMR1) Penagarikano et al 2007 FXS the most common inherited cause of ID 1/130-250 females 1/250-810 males Typical Premutation (CGG) < 45 (CGG) 55 - 200 1/2500-3600 Full mutation (CGG) > 200 mRNA FMRP Fragile X syndrome Clinical normal Primary Ovarian Insufficiency (POI) Fragile X-associated Tremor Ataxia Syndrome (FXTAS) Depression and anxiety ADHD and ASD The more FMRP you have the smarter you are 85% of males with the full mutation have ID or IQ< 70 25% of females have ID but 70% have an IQ<85 Loesch et al 2004 2 Expression of the FMR1 gene Relative FMR1 mRNA level normal gray 10 premutation full mutation FXTAS and POI 8 unmethylated 6 4 partially methylated 2 hyper-methylated 0 FMRP level 1 ___FXS__________ 0.5 0 0 45 55 200 >1000 CGG repeat number Expression of the FMR1 gene Relative FMR1 mRNA level normal 10 gray premutation full mutation FXTAS and POF 8 unmethylated 6 4 partially methylated 2 hyper-methylated 0 FMRP level 1 ___FXS__________ 0.5 0 0 45 55 200 >1000 CGG repeat number The Fragile X Mutation A family affair Four generations 89 yr FXTAS cognitive decline, dementia neuropathy 61 yr tremor/ataxia FXTAS nl cognition, POI 38 yr proband POI, anxiety neuropathy Muscle pain, lupus fragile X syndrome + autism (mild) 3 Handbiting 60% Handflapping 80% Poor eye Contact 90% Tactile 80% defensiveness Perseverative speech or behavior in almost allall-routines Unusual sensory responses to stimuli FXS in all racial and ethnic groups Sensory Modulation or Processing Problems in FXS Enhanced electrodermal responses to sensory stimuli which correlates inversely with FMRP levels Enhanced sympathetic activity (Miller et al 1999) 1999) Normals FXS 4 Emotional & Neurocognitive Features Hyperactivity, impulsivity and/or short attention span Executive function deficits: problems with organization, shifting set, planning, inhibition, tangential speech, perseveration Over reactivity to stimuli: enhanced electrodermal response to stimuli; enhanced cortisol release after stressors Anxiety Autism or ASD Mood instability: excessive outbursts, tantrums Hyperactivity, anxiety, aggression and ASD are key behavioral features that we work with daily but anxiety may be the primary problem Sympathetic hyerarousal GABA underactivity mGluR5 enhancement ANXIETY Avoidance Social deficits Selective mutism Aggression ASD or Autism Anxiety assessed with the ADIS (Cordiero et al submitted) 5 FXS Typicals Farzin et al 2009 Significant Pupil Dilation in FXS Children viewing faces b. * * * Change in Pupil Diameter (mm) 0.04 0.03 FXS 0.02 Controls happy 0.01 0 250 500 750 1000 1250 1500 1750 2000 2250 2500 2750 3000 -0.01 0.04 * ** * * 0.03 fearful 0.02 0.01 0 250 500 750 1000 1250 1500 1750 2000 2250 2500 2750 3000 Farzin et al 2009 -0.01 Time (ms) MRI Comparison of Autism to FXS • Hazlett et al 2009 JND: 52 boys with FXS, 63 autism,19 DD, 31 TD ages 18-42 mo • FXS had enlarged caudate • Autism had enlarged amygdala but FXS did not, even those with FXS plus autism • Behavior features were similar in those with autism without FXS and autism with FXS but the underlying brain structure was different. So many paths to autism 6 Obvious Second Hits Leading to Autism • Additional genetic disorder; n or Down syn; the Prader Willi Phenotype • Birth trama or Cerebral Palsy • Seizures in 13 to 22% of males and 4 to 5% of females (Musumeci et al 1999; Berry-Kravis et al 2002) The PraderPrader-Willi Phenotype (PWP) of Fragile X Syndrome Bardoni & Mandel, 2002 Those with the PWP have a higher rate of autism (50-70%) than those with FXS alone and lower CYFIP levels 7 FMRP has many functions and its absence causes dysregulation of several systems known to be associated with autism • Transporter of mRNAs to the synapse • Controls (usually suppression of) translation of many mRNAs related to synaptic plasticity • Absence of FMRP causes increased protein production throughout the brain • Up regulation of mGluR5 pathways leading to LTD • Down regulation of GABAA receptors • Dysregulation of dopamine pathways • Enhanced APP production • Increased oxidative stress damage to neurons FMRP regulates the translation of many genes at the synapse • • • • • • • • Neuroligins Neurorexins Arc Map1Kinase PSD95 Matrix metalloproteinase 9 (MMP9) CamKinase ll Many others leading to down regulation of PTEN and up regulation of mTOR Proteins Controlled by FMRP Darnell et al 2009 Trends Neurosci. 2002 May;25(5):251 8 Lowered Brain FMRP levels in Psychiatric Disorders Fatemi et al Schizophrenia Research 2010 FMRP Deficit in Adult Autism Brains Fatemi and Folsom 2010 Neuropharmacology The Role of FMRP: binds and transports mRNAs And regulates translation usually through inhibition FMRP transports mRNAs to the synapse and regulates translation. FMRP inhibits protein translation with mGluR5 stimulation Oostra 2006 9 mGluR5 theory of intellectual disability in FXS mGluR5 stimulation leads to LTD; FMRP Bear et al 2004 puts the brakes on this. So in FXS there is dramatically increased LTD mGluR5 antagonists for FXS – Fenobam : we have shown improvement in PPI and behavior in single dose with 12 adults with FXS (Berry-Kravis et al 2009 JMG) – Roche mGluR5 antagonist RO4917523 currently in controlled trials at multiple centers including MIND – Novartis AFQ056 finished European trial and now initiating US trials at multiple centers including the MIND – STX 107 an mGluR5 antagonist licensed by Seaside Therapeutics; human trials in FXS begin in January 2011 R-Baclofen= Arbaclofen: 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 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 10 mGluR Theory Excessive Glutamatergic Transmission STX209 GABA-B FMRP Pre-synaptic Proteins Proteins Post -synaptic Seaside Therapeutics Study 22001: Overview STX209 STX209 Period 2 Period 1 Screening Follow-up Washout Placebo Placebo • Double-blind, randomized, placebo-controlled, 2-period crossover • Endpoints o Global: CGI-I; CGI-S; blinded treatment preference o Focused: Aberrant Behavior Checklist - Irritability (ABC-I) scale; ABC-Total & other subscales; Vineland Adaptive Behavior Scale; Visual Analog Scale of top 3 problem behaviors; other • Down titration after completion of 4 week period Study 22001: Design details • Key inclusion/exclusion criteria o Fragile X full mutation o Age 6 – 40 years o +/- Autism Spectrum Disorder o ABC-Irritability criterion at Screening & Visit 1 • ≥ 12 for ages 6-11 years • ≥ 9 for ages 12-40 years o 3 or fewer psychoactive medications (stable dose x 4 weeks) • Flexible titration over 2 weeks, to optimal titrated dose (OTD) o Starting dose: 1 mg BID, then 2 BID, 3 BID, 5 BID, 10 BID (10 mg TID permitted for subjects ≥ 12 years) o OTD continued for remainder of 4 week treatment period o www.clinicaltrials.gov NCT00788073 11 Study 22001: Analysis populations • Full “safety” population, n = 63 (55 M, 8 F) – 56 (89%) completers o 3 discontinuations due to AE (1 arbaclofen; 2 PBO) o 1 each: lost to f/u; withdrew consent; protocol deviation; other • Per Protocol population, n = 54 – 5 excluded for prohibited concomitant medication – 2 for failure to meet ABC-I criterion; 2 for other • FXS + Autism subgroup (pediatric), n = 22 (19 M, 3 F) o DSM-IV + ADI-R criteria for autism o Analogous to subjects in risperidone/autism study • “Low sociability” subgroup, n = 27 (24 M, 3 F) o ABC-Social Withdrawal subscale ≥ 8 at screening and baselines o Autism: 18 yes, 9 no o Motivation: Frequent reports of improvements in sociability CGI-Improvement: Autism subgroup “Responders” 44% vs. 6% (p < 0.05) CGI-Improvement: “Lower sociability” subgroup 58% vs. 19% p < 0.01 12 Efficacy scores: “Lower sociability” subgroup STX209 Placebo n=27 (mean ± SD) n=27 (mean ± SD) p-value CGI-I 2.7 ± 1.1 3.5 ± 1.2 < 0.01 CGI-S -1.0 ± 1.1 -0.3 ± 0.9 = 0.01 Treatment preference (clinician) 63% 19% < 0.01 Treatment preference (parent) 67% 19% = 0.001 ABC-Social Withdrawal Vineland Socialization domain (raw score) Responders (CGI-I =1 or 2, and ABC-SW improvement ≥ 25%) -4.3 ± 6.3 -0.4 ± 7.1 < 0.05 14.2 ± 19.0 4.6 ± 10.8 < 0.05 42% 7% < 0.01 Targeted Treatments must be combined with innovative educational programs • If synaptic connections are improved with targeted treatment we must enhance these connections with educational interventions • Combine treatment trials with educational interventions, computer programs, AT devices etc. Co-Writer and write out loud FX tracking game CHAT Alt CHAT 40 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 13 Minocycline treatment induces spine maturation with enhanced mushroom spines in the KO mouse Bilousova et al 2008 JMG Minocycline Studies in FXS or Autism • • • • • There was dramatic response from families after the Bilousova paper was out on line in 2008 Agustini Utari MD surveyed 50 families whose child was tx with minocycline for >2wks and found 70% positive response especially in language and limited side effects (Utari et al 2010 AJIDD). Positive open trial in FXS in Toronto with Paribello age > 13 years Trial of minocycline in autism at NIMH Controlled double blind trial of minocycline for FXS (each arm lasts 3 months) at the MIND (NFXF funded) 19 yo boy with FXS took minocycline for 1 year Targeted Treatment of Fragile X Syndrome cAMP Agonists others GABA Agonists Ganaxolone Arbaclofen Antioxidants Vit E, C, folate NAC, omega 3s mGluR5 Antagonists Fenobam STX107 AFQ056 RO4917523 Minocycline 14 Autism in premutation carriers: is there a developmental component of the premutation ? Tassone et al 2000 Aziz et al 2003 Goodlin-Jones et al 2004 Farzin et al 2006 Boys with the premutation are at high risk for ADHD and autism or ASD: A developmental form of RNA toxicity? • • ADHD (CGI>15 and DSM-IV) – 93% (13/14) of probands – 38% (6/13) of nonprobands – 13% (2/16) of controls ASD (DSM-IV and ADOS/ADI) – 73% (11/14) of probands* • 29% (4/14) Full autism • 50% (7/14) PDDNOS – 8% (1/13) of nonprobands • 8% (1/13) Full autism – None of controls Farzin et al, 2006 J Dev Beh Pediatrics Two brothers with the FMR1 premutation ages 6 and 7. Boy on right presented as proband with autism and ADHD and his brother has anxiety and ADHD. Follow-up after 4 years brothers with the premutation • Youngest brother with ADHD, anxiety and social deficits responded well to sertraline: “miracle drug” now in normal classroom, friends and normal IQ • Oldest brother with autism and ADHD did not do well with sertraline (activation so D/C), developed seizures, now with severe autism and low verbal abilities 15 Bailey et al 2008 study of >1,200 FXS families Spectrum of Premutation Involvement Background gene effects Cellular dysregulation Upregulation of heatshock proteins Kinase activation FMR1 CGG-repeat Sequestration of toxic RNA “trigger” DROSHA, Sam68 Mitochondrial dysfunction Inclusion formation Neuropathology Environmental effects Neurodevelopmental problems Social anxiety → ASD ADHD Cognitive deficits Psychiatric involvement Anxiety Stress Depression Endocrine dysfunction FXPOI Immune dysregulation Hypothyroidism Fibromyalgia Lupus- MS features Neurological problems Neuropathy Migraine Memory problems, foggy thinking Hypertension ,erectile dysfunction FXTAS tremor, ataxia, Parkinsonism autonomic dysfunction, EF deficits, memory and cognitive decline Adult Male Carriers • 45% with Masters or higher education (Grigsby et al 2006) • Verbal comprehension significantly higher than controls (Loesch et al 2003) • Older male carriers (40% Jacquemont et al 2004 JAMA) and some female carriers (8% Coffey et al 2008-16% RodriquezRavenga et al 2009) have the fragile X-associated tremor/ataxia syndrome (FXTAS) 16 CGG repeats Fragile XX-associated Tremor Ataxia Syndrome (FXTAS) excess, toxic mRNA ( < 45 (normal) nucleolus 55 55--200 Current Research Efforts: inclusion Loss of brain volume Intranuclear inclusions • How does the RNA trigger the disease process? New targets for treatment • Treatment trials ongoing/planned based on our current Distribution of the Intranuclear Inclusions in FXTAS Strong parallels in human and mouse Broad distribution throughout brain and spinal cord - in brain, exclusively in nuclei of neurons and astrocytes Also found in numerous peripheral tissues - ganglion cells of adrenal medulla - dorsal root ganglia - paraspinal sympathetic ganglia - myenteric ganglia of the stomach/intestine - subepicardial autonomic ganglia of the heart - testicular (Leydig) cells - anterior and posterior pituitary - thyroid - islets of langerhans (glucagon producing cells) Greco et al., 2002 Brain; Willemsen et al., 2003 Hum Mol Genet; Greco et al., 2006 Brain Greco et al., 2007 J Urology; Brouwer et al., 2008 Psychoneuroendocrinology Godken et al., 2009 Neuropathology Medical history of 146 women with the premutation:20.6-84.5y (mean 45.3 y) 69 controls ages 18-87 (mean 51.9y) (Coffey et al 2008 AJMG) 17 Medical History 146 women carriers Control N=69 Non FXTAS N=128 Control N=39 0% 0% 0% 100% POF 5.6% 19.0%** 5.9% 13.3%** FXTAS FXTAS N=18 Thyroid Problems 10.1% 17.3% 15.4% 50.0% ** Diabetes 0.0% 3.9% 0% 11.1% Lupus 0.0% 2.4% 0% 5.9% Hypertension 10.1% 16.4% 18% 61.1% ** MS 0.0% 4.8% 0% 17.7% Fibromyalgia 5.0% 8.3% 9.4% 43.8% ** Muscle Pain 8.9% 25.6%** 10.7% 76.5% ** Tremor 1.5% 11.7%** 0% 89%** Problems Walking/Balance 1.5% 8.6% 2.6% 83.3%** Neuropathy Sx 11.9% 45.2%** 18.9% 83.3%** **Fisher’s exact test for 2×2 contingency table analysis p<0.05 Coffey et al 2008 AJMG RNA toxicity can start before FXTAS and the premutation mice develop inclusions after 21 weeks well before neurological symptoms Accumulative toxicity Developmental toxicity Childhood Toxicity to The limbic system and reproductive system Mid adulthood Hypertension Neuropathy Impotence Autonomic Dysfunction Tremor, Ataxia Cognitive decline FXTAS Geriatrics Increasing age White matter disease in the pons In FXTAS 18 RNA Toxicity occurs even before FXTAS • Higher rates of psychopathology in adults reported by Roberts et al 2008 • Bourgeois et al 2010: utilization of the SCID: Lifetime mood disorder in 65% of FXTAS and 42% of non FXTAS pres; lifetime anxiety disorder in 52% of FXTAS and 47% of non FXTAS pres • Insula sign of white matter disease can occur even before the onset of FXTAS Insula Sign on T2 in early FXTAS A B 62 yo 52, 68 repeats Probable FXTAS 57 yo 52 repeats Diabetes, hypertension, migraine Subclinical tremor tandem walk instability Only Premutation Involvement No Full Mutations 61 y C D E 3 37 yo 56 repeats Anxiety, Depression Breast cancer, Thyroid tumor, Uterine tumors Mitral valve prolapse 39 yo 54 repeats Anxiety Benign thyroid tumors 34 yo 67 repeats Anxiety, Depression Mathematics problems Hypertension, Raynaud’s phenomenon F 2 12 yo 6 mo 61 repeats Autism ADHD Anxiety 11 yo 69 repeats ASD ADHD Anxiety 9 yo 7 mo 69 repeats Anxiety ADHD Shyness = FXTAS = Carrier A summarized pedigree of a family with fragile X premutations demonstrating a broad spectrum of clinical involvement throughout generations (Chonchiaya et al 2009 JDBP) 19 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; Duloxetine (Cymbalta) for fibromyalgia or pain sxs. • Deep brain stimulation can improve tremor Aging in FXS No FXTAS but we have seen Parkinsonism and this is reported in other disorders e.g. 22q11 del syndrome Utari et al 2010 JND Loss and Disorientation of Purkinje Cells in the Cerebellum Greco et al 2010 submitted H&E, 400x, 20 Calbindin binding studies in the cerebellum in older males with FXS CONTROL CASE #3 Case 3 40X 40X 100X 100X Newborn Screening for FX mutations initiated in 11-2008 in Sacramento (UCDMC) and Chicago (Rush University) utilizing the Tassone blood spot method (Tassone et al J Molecular Diagnostics 2008) Language Seeing and Hearing Mental Images Higher Reasoning Facial Recognition Memory What is the best intervention for babies with FXS ? Combining intensive intervention ( Denver Early Start Program) with targeted Rxs 21 The National Fragile X Foundation has Treatment Information on line Next Conference: Miami July 2012 PO Box 190488 San Francisco, CA 94119 USA Telephone: 800800-688688-8765 Fax: 925925-938938-9315 Email: [email protected] Web: www.FragileX.org 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 TonySimon Dept. Radiology James Brunberg Dept. Pathology Claudia Greco NTRI Researchers Isaac Pessah Rob Williamson Rob Berman Dept. Neurology Lin Zhang John Olichney Ricardo Maselli Grace FentonFenton-Farrell Dept of Psychiatry Jim Bourgeois Andreea Seritan Collaborators UC Davis School of Medicine Dept. Biochem & Molec. Molec. Medicine Paul Hagerman Flora Tassone Chris Iwahashi Anna Ludwig Dolores GarciaGarcia-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 RUSH Presbyterian--St. Luke’s Medical Center (Chicago) Elizabeth BerryBerry-Kravis Christopher Goetz Waisman Center Center--University of Wisconson Len Abbeduto *Latrobe University, Melbourne Australia* Danuta Loesch Richard Huggins Support: NICHD, NINDS, NIA, NFXF, CDC, NFXF Neuropharm,, Roche, Novartis, Seaside Therapeutics Neuropharm 22