DEMYSTIFYING MEDICINE FRAGILE X SYNDROME & RELATED DISORDERS March 31, 2009 Walter E. Kaufmann
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Transcript of DEMYSTIFYING MEDICINE FRAGILE X SYNDROME & RELATED DISORDERS March 31, 2009 Walter E. Kaufmann
One Gene (FMR1):Three (or More) Disorders
ID, ASD, LD? Hagerman et al. Pediatrics 123:378-90, 2009
M: 1:800, F: 1:250 M: 1:4000, F: 1:6000
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 emotionalproblems and perseverative thinking, children (mainlyboys) with ADHD, intellectual disability and/or autism.
Intermediate or gray zone (41-60 repeats) : ??
FMR1 Mutation
X-linked: Males more Affected than Females
Fragile X Syndrome
Diagnosis by FMR1 Southern blot and PCR
Cytogenetics
Kaufmann and Reiss. Am J Med Genet 88:11-24, 1999
CONT MOS FM PM
FMRP Patterns
FMRP quantifications providecomplementary information
Kaufmann et al. Am J Med Genet 83:286-295, 1999
Fragile X Phenotype
Adapted from Kaufmann & Reiss. Am J Med Genet 88:11-24, 1999
• 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
Fragile X syndrome as a Major Cause of Intellectual DisabilityPRACTICE PARAMETERS for GDD (CNS & AAN):
Shevell et al. Neurology 60:367-380, 2003.
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
Kaufmann et al. Am J Med Genet 129A:225-234, 2004Budimirovic et al. Am J Med Genet 140A:1814-1826, 2006
Capone et al. Am J Med Genet 134A:373-380, 2005Carter et al. Am J Med Genet 144B:87-94, 2007
0
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% o
f sub
ject
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<25 25-39 40-54 55-70
Cognitive Level (IQ)
DS+ASD DS+SMD DS Typical
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% o
f su
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<25 25-39 40-54 55-70 70+
Cognitive Level (IQ)
FXS+ASD FXS Typical
Fragile X syndrome as a Major Cause of Autism
Typical Fragile X
Schaefer & Mendelsohn. Genet Med 10:301-5, 2008/ACMG Practice Guidelines
Fragile X + Autism
Autism in Fragile X and Down Syndromes
% VarianceIQ/DQ: 0%ABCstereo: 13%AutBehav rel: 27%
DS+ASD vs. DS Typical
ASD
ASD
ASD
IQ/DQp=0.99
ABCstereop=0.001
AutBehav relp<0.0001
FXS+ASD vs. FXS Typical
ASDIQ/DQp=0.54
ASDABClethp=0.79
ASDADIrecsp<0.0001
% VarianceIQ/DQ: 0.5%ABCleth: 0.1%ADIrecs: 53%
Low IQ per se has a minimal influence upon ASD status in ID
Autism in Fragile X
1. Delayed/impaired adaptive socialization is the primary determinant of FraX+ASD. CORTEX
Kaufmann et al. Am J Med Genet 129A:225-234, 2004Budimirovic et al. Am J Med Genet 140A:1814-1826, 2006Hernandez et al. Am J Med Genet: in press.
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
16-50% prevalence of Autism/ASD in Fragile X Syndrome
Example of Research in Autism in Fragile X: Determining Behavioral Profiles
Kaufmann et al. Am J Med Genet 129A:225-234, 2004Budimirovic et al. Am J Med Genet 140A:1814-1826, 2006Hernandez et al. Am J Med Genet: in press.
Autism in Fragile X
Behavioral Features in FXS: Diagnostic ChallengesShy temperament: misdiagnosis Social Anxiety: missing diagnosis (Social Anxiety is the mostcommon psychiatric co-morbidity in “Idiopathic” Autism
• Avoidance of eye contact• Hyperactivity• Perseverative speech• Hand flapping• Distractibility
Autism in Fragile X
Roberts et al. JADD 37:1748-60, 2007
The Social Approach Scale paradigm identifies dynamics of social avoidance and indifference that can distinguish Autism from Social Anxiety in Fragile X
Autism in Fragile X
Behavioral Basis
Cognitive trajectory distinguishes FXS+ASD
Hernandez et al. Am J Med Genet: in press
Autism in Fragile X
1. Hyperplasia of the posterior-superior vermis in boys with FXS+Autism (vs. FXS Typical)(Kaufmann et al. J Child Neurol 18:463-470, 2003)
Fragile X
LOB VI-VII
LOB VIII-X
LOB I-V
LOB VI-VII
LOB VIII-X
LOB I-V
Fragile X + AUT
FXS Typical FXS+Autism
2. 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)
Biological Bases
Autism in Fragile X
Symptomatic Treatment: Specific Manifestations
CNS Stimulants: ADHD• Methylphenidate• Dextroamphetamine Alpha-adrenergic agonists: ADHD, hyperarousal• Clonidine• GuanfacineAtypical 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
Treatment of Fragile X
Treatment of Fragile X
Targeted Treatments: Neurobiologically-BasedMultiple 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
Amiri et al. Arch Neurol 65:19-25, 2008
Diagnostic and Clinical Features of FXTAS
Fragile X-Associated Tremor/Ataxia Syndrome
Courtesy of Dr. R. Hagerman
Brunberg et al. AJNR 23:1757-1766, 2002
Neuroimaging of FXTAS
MCP sign
Fragile X-Associated Tremor/Ataxia Syndrome
Amiri et al. Arch Neurol 65:19-25, 2008
Cultured neural cells: nuclear lamin IR
Normal CGG88
G
N
Neuropathology of FXTAS
Intranuclear inclusions
Fragile X-Associated Tremor/Ataxia Syndrome
Premature Ovarian Failure/Primary Ovarian InsufficiencyPOF/POI
Wittenberger et al. Fertil Steril 87:456-465, 2007
~15% of women with FMR1 premutation0.8-7.5% FMR1 premutation in sporadic POI
13% FMR1 premutation in familial POI
Coffey et al. Am J Med Genet 146A:1009-1016, 2008
Adult females with Premutation
The Other Premutation-Related Disorders
Fragile X Gene Related Disorders
1. Key to understanding ID and ASD.2. Contributory to neurobiology of
synaptic development andmaintenance.
3. Key to understanding RNA toxicity and formation of neuronal and glial inclusions.
4. Contributory to the clinical study of neurodegenerative disorders.
Chechlacz & Gleeson.Pediatr Neurol 29:11-17, 2003
Conclusions
The Postsynaptic Density:convergence of RTT, FXS & XLMR
XLMRs are associated to mutations in signaling and synaptic proteins
The X-linked mental retardation protein oligophrenin-1is required for dendritic spine morphogenesis.Govek et al. Nat Neurosci 7:364-372, 2004.Knock-down of OPHN1 levels in CA1 neurons in rathippocampal slices significantly decreases spine length.Reduced OPHN1 levels affect spine length by increasingRhoA and Rho-kinase activities. There is an interactionbetween OPHN1 and the postsynaptic adaptor Homer.
Chechlacz & Gleeson.Pediatr Neurol 29:11-17, 2003