Fragile X: A Family of Disorders

Dianne M. McBrien, MDClinical Associate Professor of PediatricsUniversity 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

mGlur5LTD 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 (Berry-

Kravis 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