Fragile What? –An Overview of Fragile X Syndrome and its Associated Disorders

Matt RhodesParent Contact - LINKS LeaderFragile X Association of Alabama

Fragile X Associated DisordersFXS –

Fragile X Syndrome

FXTAS – Fragile X-Associated Tremor Ataxia Syndrome

FXPOI –Fragile X-Associated Primary Ovarian Insufficiency

FXS DEFINITION

Fragile X Syndrome

The world’s leading cause of inherited mental impairmentSymptoms ranging from learning problems to mental impairment and autismCan be accurately diagnosed with a simple blood test or DNA

INCIDENCE

PrevalenceAffects 1 in 3,600 males & 1 in 4,000- 6,000 females1 in 260 women are carriers1 in 800 men are carriersFragile X appears in all socioeconomic backgroundIn Alabama, carriers and full mutations are estimated at 15,978

Second only to Down’s Syndrome as a genetic cause of mental retardation

Unlike Down’s Syndrome, maternal age is not a factor

The most common known cause of autism

About 30% of individuals with Fragile X Syndrome have autism

2-6% of individuals with autism have Fragile X Syndrome

GENETICS

SCAN in page 14

X Y XX

Father Mother

X Y

Son

X Y XX

Father Mother

X X

Daughter

Parents – X’s and Y’s

Woman with a premutation on one of her two X chromosomes

Girl with out fragile X mutation

Girl with fragile X mutation

Plus father’s Y

Plus father’s Y

Plus father’s X Plus

father’s X

Egg cell without

a fragile X mutation

Egg cell with a fragile X mutation

Her egg cells

Boy with fragile X mutation

Boy with out fragile X mutation

Man with a premutation on his one X chromosome

Plus Mother’s X

Plus Mother’s X

Sperm cell without a Y sex

chromosome

Sperm cell with a fragile X mutation

His sperm cells

Boy with out fragile X mutation

Girl with premutated

carrier

Both Males and Females Can Have

Fragile X SyndromeBOYS

Approximately 85% of boys with F.M. have cognitive defects in the MR range (below 70)The production of FMR1 protein is usually shut down

GIRLSApproximately 70% of girls with F.M. have cognitive defects in borderline to M.R. range (below 70)Girls with more protein-producing cells tend to have higher IQs

Category

CGG repeats

Methylation of FMR1

Female

Male

Stable 6 to ~45 unmethylated Not affected

Not affected

Gray zone

~45 to ~55 unmethylated Not affected

Not affected

Pre-mutation

~55 to ~200 unmethylated Usually not affected

Usually not affected

Full mutation

>200 Completely methylated ~50% affected

All affected

Direct DNA Analysis for the Fragile X

Mutation

FatherXY

MotherXX

Pre-mutated MaleXY

Pre-mutated FemaleXX

Unaffected Female

XY XX XYXX XY

Unaffected Unaffected Unaffected

XY XX

XXXX

XX

1

2

3

4

5

6

CGGRepeats

INCREASINGX – Pre-mutation

X – Full Mutation

CLINICAL FEATURES

Physical Characteristics

Large earsLong, narrow faceProminent foreheadProminent, square chinHigh palate (roof of mouth)Hand callusesMitral valve prolapse (a leaky heart valve)SeizuresEye problems

Physical Characteristics Often

Seen in Young Children:Numerous ear infections

Flat feetHyper extensible jointsEye problems in 20%-25%: Refractive errors Strabismus Astigmatisms

Seizures Missing developmental milestones

Common Difficulties

SleepingToilet trainingSocializationPlay (spinning objects, play with exclusive toy, or part of toy)

CognitiveThe Fragile X mutation affects brain development and leads to a range of cognitive delays.

•Developmental delays

•Mental impairment

•Learning disabilities

Difficulties with frontal lobe functions

(“executive” functions)Organization of informationActing on that information in an effective mannerFocusing attentionForming a plan and carrying it out

BehaviorAttention deficits HyperactivityImpulsivityAutistic-like behaviors Repetitive behaviors Hand flapping Hand biting Gaze aversion

Extreme anxiety, shynessTransition problems, difficulty adjusting to change

Cognitive/ Behavioral Strengths

Strong visual memoryLong term memoryGood verbal imitative skillsDesire to be socialStrong appreciation of humorOften receptive to helping or working cooperatively

Speech and Language

CharacteristicsDelayed speech Problems with intelligibilityRapid, repetitive speech (perseveration)EcholaliaPoor conversation skillsGood verbal imitative skills

Sensory Processing Characteristics

Tactile defensivenessVisual defensivenessOlfactory defensivenessOral defensivenessGravitational/ postural insecurity

Sensory processing often seen in infants and young childrenExcessive mouthing and droolingMouth stuffing“picky” eatersDifficult to calm and comfortOver sensitivity to sounds

Gross Motor Characteristics

Low muscle toneDelays in gross motor skillsUncoordinated, clumsy

Fine Motor Characteristics

Low muscle toneHyper extensible finger jointsDifficulties with fine motor jointsSelf feeding Dressinghandwriting

Characteristics Often Seen in

Females With FXAttention deficitsShyness and anxietySelective mutismProblems with mathIncreased risk for mental health issues such as depression, bipolar disorder, and obsessive compulsive disorder25% premature ovarian failure (early menopause)

INTERVENTIONS

Early/ Preschool Interventions

Speech and language therapyOccupational therapyOccasional physical therapySettings with consistency, structure and routineTotal communication programSimultaneous not sequentialVisual learnersIncidental learners

Interventions Strategies

Sensory-based Strategies Sensory Diets Self-Regulation

Routines-based Strategies Maintain schedules Maintain routines Maintain Structure

Language-based Strategies Side Dialogues/Self Talk (Incidental Learning) Social Stories Video Modeling

Managing Hyperarousal

Nervous system over stimulatedEvokes fear/flight responsesAnxiety can lead to hyperarousalUse calming, coping and comfort to help self-regulationManage environment

Reducing AnxietyBeginning and ending clearly definedPicture schedulesCalm environmentMaintaining schedule

Elementary School Interventions

Intervention services Speech therapy Occupational therapy Extracurricular (sports, scouts, dance,

martial arts)

Classroom options Full inclusion with support Mainstreaming Self-contained programs

Structure Needs Predictable routines, rules and expectations Consistent physical layout of classroom Minimize auditory distractions

Teaching strategies Picture schedule Visual communications system (PECS) Augmentative communication computers

Middle/ High School Interventions

Continue therapies if appropriateRelevant and functional reading and learning experiencesSocial skills trainingIntroduce pre-vocational opportunitiesRecreational/ extracurricular (Special Olympics, choirs, other musical

venues)

Adult Opportunities

EmploymentIndependent living optionsSocialization and adult relationshipsRecreation

Suggested Recreational Opportunities

TrampolinesBicyclingSwimmingBowlingSoccerGym/Fitness Center

Softball Martial ArtsScoutsChoirs or other musical venuesSpecial OlympicsChallenger sports

MedicationsAttention-related problems Hyperactivity/ impulsivityMood disorders/ depressionAnxiety/ panicAggression

Obsessive/ compulsive symptomsBedwettingSleep disordersSeizuresSelf injury

FXTAS Symptoms and DiagnosisFXTAS usually develops between the ages of 50-80. Symptoms that family

members may notice, but often attribute to aging, include:

• "Intention" tremors -- shaking that often occurs when reaching for or pouring something

• Balance problems (ataxia) that cause falling or instability while walking

• Numbness in the extremities (neuropathy)

• Mood instability, irritability, and other changes in personality

• Short-term memory loss and gradual intellectual decline The diagnosis is based on 3 factors:1) Positive carrier testing for the FMR1 premutation,2) A neurological exam that affirms the above characteristics, and3) Magnetic Resonance Imaging (MRI) findings that are known to be related to FXTAS, including white matter changes or decreased size of the brain.

FXPOIFXPOI: Fragile X-Associated Primary Ovarian Insufficiency

Affects female pre-mutation carriers (55-200 CGG repeats)

Female with the full mutation do not appear to be at risk

FXPOI Symptoms and Diagnosis

• FXPOI causes decreased ovarian function

• 23% experience early menopause (prior to age 40)

• 20-28% experience ovarian insufficiency

• many experience decreased fertility

• many women with pre-mutations are able to conceive

• decreased ovarian function is detectable by blood tests that measure specific hormones, particularly FSH .

Fragile X Research &

Clinic Consortium

Linking Individuals in Knowledge and Support

Fragile X Advocacy Day

March 3, 2010 in Washington, D.C.

The National Fragile X

FoundationP.O. Box 190488

San Francisco, CA 94119-0048

800-688-8765

www.FragileX.org

Email: NATLFX@FragileX.org

Fragile X Association of Alabama

Matt Rhodes

2710 Wellington Circle

Pelham, AL 35124

www.fxalabma.org

Email: mattr@fxalabama.org

The National Fragile X

Foundation

Serving the Fragile X community since 1984