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DEMYSTIFYING MEDICINE FRAGILE X SYNDROME & RELATED DISORDERS March 31, 2009 Walter E. Kaufmann PowerPoint Presentation
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DEMYSTIFYING MEDICINE FRAGILE X SYNDROME & RELATED DISORDERS March 31, 2009 Walter E. Kaufmann. 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. One Gene ( FMR1 ):

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slide1

DEMYSTIFYING MEDICINE

FRAGILE X SYNDROME & RELATED DISORDERS

March 31, 2009

Walter E. Kaufmann

slide2

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

slide3

One Gene (FMR1):

Multiple disorders in the same family

Hagerman. J Dev Behav Pediatr 27:63-74, 2006

slide4

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) : ??

slide5

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

slide6

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

slide7

Fragile X syndrome as a Major Cause of Intellectual Disability

PRACTICE PARAMETERS for GDD (CNS & AAN):

Shevell et al. Neurology 60:367-380, 2003.

slide8

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

slide9

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

slide10

Fragile X syndrome as a Major Cause of Autism

KKI Research Program on Autism in FXS

slide11

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%

slide12

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.

slide13

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.

slide14

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
slide15

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

slide16

Autism in Fragile X

Behavioral Basis

Cognitive trajectory distinguishes FXS+ASD

Hernandez et al. Am J Med Genet: in press

slide17

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)

slide18

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
slide19

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
slide20

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

slide21

Fragile X-Associated Tremor/Ataxia Syndrome

Neuroimaging of FXTAS

MCP sign

Brunberg et al. AJNR 23:1757-1766, 2002

slide22

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

slide23

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

slide24

Primary Ovarian Insufficiency

Wittenberger et al. Fertil Steril 87:456-465, 2007

slide25

The Other Premutation-Related Disorders

Children

Farzin et al. J Dev Behav Pediatr 27:137-144, 2006

slide26

The Other Premutation-Related Disorders

Children

Aziz et al. Am J Med Genet 121B:119-127, 2003

slide28

The Other Premutation-Related Disorders

Adult females with Premutation

Coffey et al. Am J Med Genet 146A:1009-1016, 2008

slide29

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
slide30

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.