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Fragile X: A Family of Disorders
Dianne M. McBrien, MD
Clinical Associate Professor of Pediatrics
University of Iowa Hospitals and Clinics
• Sequence of bases
codes for proteins
• Proteins then facilitate
or inhibit various
reactions related to
physiology
• Change or abnormality
in the sequence is
called a mutation
Triplet repeat expansion mutation
• Normal number of CGG
repeats at site is less
than 50
• Premutation consists of
55 to 200 repeats
• The mutation consists
of >200 repeats
• Number of repeats can
increase with
generations
What is fragile X?
• Family of genetic
conditions
• Mutations in what is
now known as FMR1
gene, discovered 1991
• Xq27.3
• Involves unstable series
of trinucleotide repeats
FMR1 status can be:
• Normal (<45 repeats)
• Grey zone allele (45-54 repeats)
• Premutation (55-200 repeats)
• Full mutation (>200 repeats)
• When we talk about a patient with fragile X syndrome,
we are generally referring to an individual with the full
mutation. When we talk about a patient who is a carrier,
we are referring to an individual with the premutation.
What makes the premutation expand to a full
mutation in the next generation?
• Female carrier
• Number of repeats (more repeats, more unstable)
• Association with AT base pairs
What makes the premutation expand to a full
mutation in the next generation?
• Female carrier
• Number of repeats (more repeats, more unstable)
• Association with AT base pairs
Full expansion of the gene induces methylation,
which silences FMRP production
• The cognitive and
behavioral
phenotype is
attributed to the
complete or partial
loss of FMRP
What does FMRP do?
• Binds mRNAs
• Helps to transport them along the neuron to where they are
needed
• Inhibits translation of these templates until the right signal
arrives
• Helps in synaptic plasticity
What does FMRP do?
FXS: Problems associated with the full
mutation
• Cognitive deficits
• Autistic-like features
• Severe social anxiety
• AD/HD
• Behavioral problems
• Sleep disruption
Other medical issues
• Hypotonia
• Seizures in at least
17% of males
• Ear and sinus
infections
• Joint hypermobility
• Flat feet
• Mitral valve prolapse
• PWS-like phenotype
in some patients
Connective tissue dysplasia cont’d.
• Hernias
• Recurrent ear
infections
• Frequent sinusitis
• Mitral valve prolapse
• Unusually soft skin
Cognitive function
• Range is quite wide
• 50-60% within moderate to severe range of MR
• Function of how methylated (silenced) FMR1 gene is as well as
possible mosaicism
• Characteristic neuropsychological profile
Strengths and weaknesses
• Strong verbal labeling and comprehension—may
understand more than rest of abilities would suggest
• Strong at long-term memory and simultaneous
processing
• Weak at several measures of short-term memory and
arithmetic
• Executive function poor
Strengths and weaknesses
• Strong verbal labeling and comprehension—may
understand more than rest of abilities would suggest
• Strong at long-term memory and simultaneous
processing
• Weak at several measures of short-term memory and
arithmetic
• Executive function poor
Autism in FXS
• More problems with
eye contact than
children with autism
and no FXS dx
• More social relatedness
• Extremely high degree
of social anxiety
Speech and language
• Poor articulation
consistent with
cognitive age
• Rapid, dysrhythmic
rate—”cluttering”
• Self-repetitions
(palilalia) c/w autistic
individuals without
FXS
Girls and women with FXS
• Physical features are
milder than in males,
more common in
patients with full
mutation
• Borderline or mild MR
IQ, LD, attentional
problems, impulsive
behavior, poor eye
contact in girls with FM
Characteristic appearance
• May not be present
in infants and young
children
• May develop over
time
• Absence of which
cannot be used to
rule out FXS
Premutation carriers
• Mutation is between 55
and 200 repeats
• Premutation carriers
once thought to be
asymptomatic
Fragile X tremor-ataxia syndrome
(FXTAS)
• Seen in 25-30% men >
50 years old who have
the premutation
• Limb and truncal ataxia,
tremor, cognitive
symptoms
• Misdiagnosed as
Parkinson’s disease
Premature ovarian insufficiency
(POI)
• 25% of women with premutation
• Infertility
• Reduced bone density
• Irregular menses
• Menopause prior to 40 years
Other problems associated with the
premutation
•
•
•
•
•
•
ADHD, autism spectrum d/o, learning issues
Social anxiety, phobias, and depression
SLE, other autoimmune disease
Thyroid dysfunction
Hypertension
Chronic muscle pain syndrome
What’s going on?
• FMRP mRNA in WBCs 2 to 8 times normal
• High levels of FMRP mRNA in FXTAS inclusions
• Not toxic in itself
• Thought to induce a state of oxidative
stress”heat shock” proteins
Targeted treatments: Promise,
uncertainty
Animal models for fragile X
The mGlur5 theory
• Activation of
mGlur5LTD of synaptic
responses
• LTD much more
pronounced in the KO
mouse than in wild
mouse (Huber et al,
2002)
• Neuropsychiatric
phenotype response to
exaggerated mGlur5
response
Knockout mouse
Wild type mouse
In the knockout mouse,
mGlur5 blockers have shown:
• correction of dendritic spinal abnormalities
• correction of seizure threshold
• improvement in several measures of
learning
mGlur5 blockade: Human trials
• Fenobam (BerryKravis et al, 2009):
Improved
communication, eye
contact, PPI deficit
• AFQ056: Response
on ABC, CGI, as well
as a measure of
repetitive behaviors
mGlur5 antagonist clinical trials
• R04917523 (FX trial
in adults, now
closed)
• Same compound in
children—the Foxtail
study, still enrolling
Phase II study
• Double blinded, randomized placebo trial
• Three arms: 0.5 mg, 1 mg, and placebo
• WISC-IV, ADOS, Vineland, Social
Responsiveness Scale, ADOS, ABC, CGI-S
and CGI-I, VAS, Vineland, RBANS, Caregiver
Burden Inventory
The role of GABA
• Lower levels of
GABA-A receptors
• Abnormally low
GABA activity in
amygdala
• GABA-B agonists
block glutamine
release
• Arbaclofen
Arbaclofen
• Potent GABA-B agonist
• Improvements in ABC social withdrawal score, Vineland
Play and Leisure Scale, and Visual Analog Scale, as well
as improvement on CGI
• Well tolerated, with minimal side effects
• Trial was discontinued abruptly
Lithium
• Inhibits GSK3B, which is
a kinase
• Overactive in the KO
mouse
• Li normalizes its levels
• Reverses a number of
behavioral abnormalities
in the KO mouse, along
with dendritic spinal
abnormality and seizure
threshold
Human trials of lithium in FXS
• 15 patients with FXS
• Improvements in Total ABC score, Hyperactivity, Inappropriate
Speech and Lethargy (Social Withdrawal) subscales
• The Maladaptive Behavior subscore from the VABS
• A parent visual analog scale for target behaviors
• CGI scale
• RBANS list learning task
• Subgroup continued on Li for a year with persistent
improvement on ABC-C and VABS
• (Berry-Kravis et al. 2008)
Minocycline
• Treatment of KO
hippocampal cell culture
improves dendritic spine
maturity
• Treatment of nursing KO
dams improves
hippocampal dendritic
spine anatomy in pups
• Reduced anxiety in
exposed pups
Human trials of minocycline
• Paribello et al:
Positive effects in a
group of boys 13
years and older
• Currently a
controlled trial going
on at UC-Davis for
children from 3.5 to
16 years
Center for Disabilities and Development
University of Iowa Fragile X Clinic