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Fragile X A Family Affair

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					                Fragile X:
             A Family Affair
Mountain States Regional Genetic Conference 7- 14-07
                Randi Hagerman MD
       Endowed Chair in Fragile X Research
                 M.I.N.D. Institute
             UC Davis Medical Center
               Sacramento, California
Funding from NICHD, NINDS, NFXF, CDC
              Fragile X: A Family Affair
                  All generations may be involved

             Fragile X Syndrome: leading inherited
             of MR and leading single gene associated
             with autism : 1 in 3,600 with MR, also a cause of
             LD, anxiety disorders, mood instability.
             30% with autism; 2-6% with autism have FXS

             Premutation involvement: Leading single
              gene cause of POF and significant cause
             of ataxia and tremor in aging carriers
Fragile site (FXTAS): 1 in 129 females and 1 in 800 males
Expression of the FMR1 gene
 Relative FMR1 mRNA level             normal   gray       premutation           full mutation
                            10

                            8
                                                                                   unmethylated

                            6

                            4                                                 partially methylated

                            2
                                                                          hyper-methylated
                            0

                            1
FMRP level




                            0.5


                            0

                                  0            45 55                    200                     >1000
                                                      CGG repeat number
          The Fragile X Gene
               A family affair
Four generations                    89 yr       tremor/ataxia
                                                cognitive decline
                                                neuropathy
                                      61 yr
                                                    tremor/ataxia
                                                    nl cognition, POF

                                            38 yr      POF, anxiety
                                                       neuropathy
                                                       Muscle pain


                                         fragile X
                       proband          syndrome
                                 + autism            (mild)
Hyperactivity in most - 80%
Attention problems
Hyperarousal to stimuli
Sensory Modulation or Processing
        Problems in FXS


  Enhanced electrodermal responses
  to sensory stimuli which correlates
   inversely with FMRP levels
                          (Miller et al 1999)




                               FXS
    Normals
 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
 FMRP transports mRNAs
 to the synapse and regulates
 translation.




FMRP inhibits protein
translation with mGluR5
stimulation


                                Oostra 2006
mGluR5 stimulation
leads to LTD; FMRP
puts the brakes on this.             Bear et al 2004
So in FXS there is dramatically increased LTD
  Specific Psychopharmacological
            Interventions
• Ampakines: CX516 ampakine trial



• mGluR5 antagonists including MPEP have been
  tried in KO mice and in fragile X fruit flies and
  have improved cognition and seizures. Now
  lithium has been helpful for the fly, mouse and
  humans
                                    Berry-Kravis et al 2006
                                    Bauchwitz et al 2004
                                    McBride et al 2005
     Reversal of CNS Structural
         Pathology in FXS
• Drosophila model of FXS had structural reversal
  of pathology in CNS with MPEP (mGluR5
  antagonist)
• Hayashi et al 2007 PNAS: Inhibition of p21-
  activated kinase (PAK) will reverse dendritic
  spine changes and behavioral abnormalities in KO
  mouse (expression of double negative PAK
  transgene in KO mouse)
• Restivo et al 2006: in FX KO mice synaptic
  connections normalized with environmental
  stimulation
 Targeted Treatments for FXS
• mGluR5 antagonists:
  – Fenobam used in 1980s as anxiolytic, recently
    shown to be mGluR5 antagonist, needs FDA
    approval for FXS trials
  – STX 107 developed by Merck and licensed by
    Seaside Therapeutics. Animal studies funded by
    CAN, human trials in FXS within 2 years or so
  – Lithium: helpful in trial of 15 patients


• GABAA agonist:
  – Ganaxolone a neurosteroid that is effective in
    infantile spasms will likely be helpful in FXS.
     Anxiety is a key behavioral feature in FXS


 Synpathetic                             Avoidance
hyperarousal                             Social
                                         deficits
 GABA                                    Selective
                      ANXIETY
underactivity                            mutism
 Amygdala                                Aggression
hyperconnectivity                        ASD or
                                         Autism
 Fragile X as a model of autism
• Many children with FXS have autism (30%) and
  many children with autism (2-6%) have fragile X
• Both disorders have big heads and rapid brain
  growth early in childhood
• FXS has problems with hyperarousal and anxiety
  so it models this subtype of autism
• Both disorders have problems with facial
  processing ie avoiding looking at the eyes which
  overactivates the amygdala
• Both disorders have decreased AMPA receptors
• Those with FXS and autism have lower IQ than
  FXS alone
   Detailed Genetic Evaluation of
   Autism (Schaefer and Lutz, Genet Med 2006:8:549)
• Detailed genetic assessments in 32 children
  referred for autism
   – High resolution cytogenetic studies and FISH testing
     for 22q, 15q, 17p, and subtelomeric, methylation
     studies, dysmorphology eval, MRI, EEG
   – FMR1 DNA testing
   – metabolic studies ie AA, OA, ammonia, acyl-carnitine
     and uric acid
   – MECP2 sequencing
• 41% or 13/32 with an identifiable genetic disorder
                  Group Classifications for Individual
                     Measures and Overall Group
                         Assignment (n=63)
             60
                  51   49   51
             50
                                       41
percentage




             40                                     40
                                              35
                                  32                   3030
             30                                                    none
                                         24
             20              17                                    PDD
                                                                   Autism
             10
              0
                  ADI-R     ADOS       DSM-IV       Overall

                                                   Harris et al 2006
Communication and Social Deficits are Continuous
                                                ADOS Module 1


               25
               20
A D O S S c o re




               15                                                               Comm-Soc
                              Autism
               10                                                               RB
                                                       PDDNOS
                   5
                   0
                       0        10         20          30       40         50
                           Subjects: lowest comm-soc to highest comm-soc

                                                                Harris et al 2006
Study of 80 children with FXS with and without ASD




                                  Chiu et al 2006
      Autism and Fragile X
may be caused by genes that are epistatic with FMRP




                              Autism with limited interest in
Autism with no interest
                              social interactions but anxiety
in social interactions
                              interferes with interactions
Obvious Second Hits
 Leading to Autism
• Down Syndrome
• 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)
                            Description of the secondary medical/genetic problems




                                                            3.1
                                                           12.1                      7.0
                              100%
                                                            3.0                     28.1
                               90%
                               80%
                                                                                      3.5
                               70%
                               60%
            Percentage of                                  81.8
                               50%                                                  61.4
               patients        40%
                               30%
                               20%
                               10%
                                0%
                                       FXS alone (n=33)       FXS+ASD (n=57)


                                 No medical problems              MRI abnormalities

                                 Seizures                         Genetic abnormalities

                                                                                            Chi-Square Test
                       FXS Alone (n = 33)                    FXS+ ASD (n = 57)                 (p-value)
                          n     percentage                      n    percentage
Full mutation            19         57.6                       37       64.9                      .14
Mosaic                   14         42.4                       20       35.1                      .18
No medical problems      27         81.8                       35       61.4                      .04
Seizures                  4         12.1                       16       28.1                      .15
MRI Abnormalities         1          3.0                        2        3.5                      .90
Genetic Abnormalities     1          3.1                        4        7.0                      .43
Total Medical Problems    6         18.2                       22       38.6                      .04
                                                                                 Garcia et al 2006
The Prader-Willi Phenotype
   of Fragile X Syndrome




              Bardoni & Mandel, 2002


 Those with the Prader-Willi Phenotype
 often have autism (54%) or ASD (69%)
    CYFIP1 Expression in PWP
•   11 with PWP m=0.21 SD 0.16
•   8 with FXS only m= 1.80 SD 1.46
•   19 normals m=0.61 SD 0.14
•   T tests
    – Normals vs PWP p<0.00001
    – FXS only vs PWP p=0.0033
    – Normals vs FXS only p=0.0013
FMRP is an RNA binding protein (involved in synaptogenesis)
Binds to CYFIP1 which maps on 15q (BP1-BP2)
CYFIP1 interact with Rac1 GTPase (neurite outgrowth and
regulation of synaptic connectivity)
      Fragile X and Autism
    Mechanisms of Association

• Lack of FMRP leads to up
  regulation of multiple genes with a
  negative impact on:
  – Synaptic plasticity
  – The balance of inhibitory vs
    stimulatory systems ie glutamate vs
    GABA systems
  – Disruptions in interconnectivity in
    the CNS
       Autism
in premutation carriers
    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
                                              Two brothers with the FMR1 premutation ages 6 and 7.
     – None of controls                       Boy on right presented as proband with autism and ADHD
                                              and his brother has anxiety and ADHD.
    Farzin et al, 2006 J Dev Beh Pediatrics
 Spectrum of Involvement in Adult
     Carriers without FXTAS
• Moore et al 2004: Adult male carriers have
  deficits in several domains of memory and
  executive function compared to age matched
  controls
• Cornish et al 2005: Adult male carriers have
  deficits on social cognition, obsessive compulsive
  traits and deficits in inhibitory control
• Johnston et al 2001: Women with >100 repeats
  have higher rates of depression and interpersonal
  sensitivity
• Hessl et al 2005: higher rates of OCD and
  psychopathology correlated with mRNA levels
                           Psychological Symptoms on the SCL-90-R
                   65                                                            OCD Symptoms:
                                 Obsessive Compulsive                            • Highest scores in all
                                 Anxiety                                           pM groups, differs sig.
                                 Psychoticism
                                                                                   from norm
                   60            Global Severity
                                                                                 • The only symptom
                                                                                   type that differed from
                                                                                   norm in subjects with
SCL-90-R T Score




                   55                                                              pM without FXTAS
                                                                                 • Associated with
                                                                                   FMR1 mRNA in
                                                                                   premutation males
                   50




                   45




                   40                                                               Hessl et al 2005
                        Control Female   pM Female      Control Male   pM Male
                                                                                    Neuropsy genetics
     Amygdala Dysfunction in fMRI studies- lack of activation
     to fearful faces compared to controls in 12 premutation men




                                            Hessl et al 2006


                                        Amygdala did fine with
                                        Calm faces

Psychophysiological studies
also demonstrated amygdala
 dysfunction with lack of startle
in viewing fearful faces
        Adult Male Carriers
• 45% with Masters or higher education
  (Grigsby et al 2006)
• Verbal comprehension significantly higher
  than controls (Loesch et al 2003)
• Adult male carriers with deficits in social
  cognition and OCD traits (Cornish et al 2005)

                      Older male carriers and some
                      female carriers have the
                      fragile X-associated tremor/
                      ataxia syndrome (FXTAS)
            FXTAS Features
•   Intention tremor that is progressive
•   Ataxia and/or frequent falling
•   Parkinsonian features: masked facies, intermittent
    resting tremor, increased tone or response to L-dopa
•   Cognitive deficits: memory problems & executive
    function deficits – decrease in PIQ first
•   Autonomic Dysfunction: Orthostatic hypotension,
    hypertension, urine and bowel incontinence, impotence
•   Psychological features: disinhibition, anxiety, mood
    liability, outbursts, depression and reclusive behavior
•   Peripheral neuropathy: decreased reflexes and
    sensation in lower extremities
•   MRI global brain atrophy, white matter disease and
    MCP sign
 California Family Study of the
     prevalence of FXTAS
• Jacquemont et al JAMA 29:460, 2004:
  – 123 families with FXS in the Northern and
    Southern Fragile X Associations
  – in 192 individuals who are >50 and either
    premutation carriers or controls the penetrance
    in male carriers was 17% in the 50s; 38% in the
    60s; 47% in the 70s; 75% in the 80s
  – some may be stable for decades and others have
    a more rapid progression
Multiple Sclerosis diagnosis made in
3 of 105 Premutation females (Zhang et al 2004 AAN)

                               A 4th case of MS and the premutation
                               died and autopsy demonstrated
                               classical lesions of MS in addition
                               to FXTAS inclusions

                                 FXTAS occurs rarely in females
                                 (Hagerman et al 2004;Berry-
                                 Kravis et al 2005 Jacquemont et al
                                 2005; Zulhke et al 2005)



                                  4 sisters (50 to 36 years)
                                    with the premutation
                                the oldest two have FXTAS
                                and the younger ones have
                                intermittent tremor and ataxia
                                all have anxiety and mood
                                          problems
 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 2007)
               Results – Medical History
                           Control      Non FXTAS           Control   FXTAS
                            N=69          N=128              N=39      N=18
   FXTAS                     0%              0%               0%       100%

   POF                      5.6%          19.0%**            5.9%     13.3%**

   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                 1.5%            8.6%             2.6%     83.3%**
   Walking/Balance
   Neuropathy Sx            11.9%         45.2%**            18.9%    83.3%**

**Fisher’s exact test for 2×2 contingency table analysis p<0.05
    The FXTAS Complex


              Tremor
              Ataxia

        hypertension
                   Psychological
      Neuropathy
                   problems
      Limb pain
                          fibromyalgia
   impotence      dysinhibition
     Urinary problems: urgency, incontinence
Hypothyroidism, testosterone deficiency
 Premature ovarian failure and the
           premutation
• Approximately 20% of individuals with the
  premutation have POF; additional 23% with
  menopause before age 45
• In sporadic POF 1-7.5% have the pre;
  Familial POF 4-17% have the pre (Bussani et al
  2004;Murray et al 1998;Marozzi et al 2000)
• Women with 59-79 repeats have menopause
  2.5 years earlier than non-carriers. Women
  with >80 repeats have menopause 4 years
  earlier than those with 59-79 repeats (Sullivan et
  al 2005)
• FSH higher throughout cycle in pres vs nls
  (Welt et al 2004)
        Treatments for Carriers
• Treat hypertension early to avoid hypertensive
  CNS disease; check thyroid and testosterone levels
• Treat psychiatric problems, reduce stress and
  exercise daily (fluoxetine and exercise stimulate
  stem cells)
• Neurons vulnerable to oxidative stress
  In FXTAS avoid unnecessary general anesthesia
  Consider folate, vit E, C, B12
• Lithium and memantime: to study for
  neuroprotection
• In FXTAS-gabapentin helps neuropathic pain
   – Aricept and Nemanda help with cognition
   – Effexor XR often helps with processing, EF,
     and dysinhibition; Cymbalta for pain and SNRI
   Tx info anecdotal see Hall et al 2006 review
Who to Test with FMR1 DNA
• Any child or adult with mental retardation 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)
   – Parkinsonism with nl dopamine studies with SPECT
     (Ceravolo et al 2005)
            High risk screening
               for research
• Psychiatric populations
  – Anxiety disorders ie social phobia
  – Selective mutism
  – Overanxious disorder
• Neurological populations beyond ataxia
  –   Multiple sclerosis
  –   Normal pressure hydrocephalus
  –   Neuropathy
  –   Pain clinics
• Population screening ie
  – prenatal
  – newborn
Link Between FXS and Alzheimers
      Westmark and Malter 2007, PLOS Biology


• FMRP binds to and regulates the translation of
  amyloid precurser protein (APP) mRNA through
  mGluR activation
• Soluable beta amyloid (primary constituent of
  plaques and cleaved from APP) are significantly
  higher in multiple strains of KO mice
• The aging research in FX has just begun, the
  science is in its infancy and the big question is
  whether dementia is seen in FXS with age, can we
  reverse these problems and what is the best
  treatment
The National Fragile X Foundation has Treatment
              Information on line

  PO Box 190488
  San Francisco, CA 94119 USA
  Telephone: 800-688-8765
  Fax: 925-938-9315
  Email: NATLFX@FragileX.org
  Web: www.FragileX.org
 M.I.N.D. Institute
     Randi Hagerman               Collaborators
     Louise Gane
                               UC Davis School of Medicine
     Sebastien Jacquemont
     Susan Harris                   Dept. Biochem & Molec. Medicine
     Faraz Farzin                     (Paul Hagerman lab)
     Steve Nowicki                       Flora Tassone            Chris Iwahashi
     David Hessl                         Dag Yasui                Brooke Babineau
     Jennifer Cogswell                   Kendra Nannen            Lisa Becker
     Susannah Cohen                      Li-Sheng Chen            Nelly Won
     John and Patrick Adams              Sasha Beilina            Anna Ludwig
     Michele Ono                         Dolores Garcia-Arocena   Ruiqin Pan
     Sarah Coffey                        Greg Mayeur              Chris Raske
 Dept. Radiology                    Dept. Biostatistics
    James Brunberg                        Danh Nguyen              Laurel Beckett
 Dept. Pathology              University of Colorado Health Sciences Center (Denver)
     Claudia Greco             Dept. Neurology                Dept. Medicine
 Dept. Chemistry                  Maureen Leehey                James Grigsby
     Carlito Lebrilla             Deborah Hall
     Hyun-Joo An              RUSH-Presbyterian-St. Luke’s Medical Center (Chicago)
     Eric Dodds                Dept. Pediatrics                      Dept. Neurology
 Dept. Neurology                   Elizabeth Berry-Kravis               Christopher Goetz
     Lin Zhang                Children’s Hospital of Orange County
     Charles DeCarli              Philip Schwartz
     Ricardo Maselli
     Grace Fenton             Latrobe University, Melbourne Australia
Dept of Psychiatry                 Danuta Loesch
     Jim Bourgeois
                                                    Support: NICHD, NINDS, NIA, NFXF, CDC
                                                              UC Davis M.I.N.D. Institute

				
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