1. Fragile What? – An Overview of Fragile X Syndrome and its Associated Disorders
Matt Rhodes Parent Contact - LINKS Leader Fragile X Association of Alabama

2. Fragile X Associated Disorders
FXS –
Fragile X Syndrome
FXTAS – Fragile X-Associated Tremor Ataxia Syndrome
FXPOI –
Fragile X-Associated Primary Ovarian Insufficiency
One gene does all three.

3. FXS DEFINITION

4. Fragile X Syndrome
The world’s leading cause of inherited mental impairment
Symptoms ranging from learning problems to mental impairment and autism
Can be accurately diagnosed with a simple blood test or DNA

5. INCIDENCE

6. Prevalence Affects 1 in 3,600 males & 1 in 4,000- 6,000 females
1 in 260 women are carriers
1 in 800 men are carriers
Fragile X appears in all socioeconomic background
In Alabama, carriers and full mutations are estimated at 15,978
Recent statistics may reveal that the prevalence in women may be as high as 1 in Alabama statistics are women and men.

7. Unlike Down’s Syndrome, maternal age is not a factor
Second only to Down’s Syndrome as a genetic cause of mental retardation
Unlike Down’s Syndrome, maternal age is not a factor
Again fxs is inherited

8. 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
Boys seem to have higher incidence rates of autism or on spectrum. James is on the spectrum.

9. GENETICS

10. SCAN in page 14

11. Parents – X’s and Y’s Father Mother Father Mother X Y XX X Y XX Son
Daughter
Basic genetics and inheritance
X Y
X X

12. Woman with a premutation on one of her two X chromosomes
Her egg cells
Egg cell
without
a fragile X
mutation
Egg cell
with
a fragile X
mutation
Plus
father’s X
Plus
father’s X
Plus
father’s Y
Plus
father’s Y
Define mosaic.
Girl with out fragile X mutation
Girl with fragile X mutation
Boy with out fragile X mutation
Boy with fragile X mutation

13. Boy with out fragile X mutation Girl with premutated carrier
Man with a premutation
on his one X chromosome
His sperm cells
Sperm cell
without
a Y sex chromosome
Sperm cell
with
a fragile X
mutation
Plus
Mother’s X
Plus
Mother’s X
Boy with out fragile X mutation
Girl with premutated carrier

14. Both Males and Females Can Have Fragile X Syndrome
BOYS
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
GIRLS
Approximately 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
Mosaic boys and protein, activation ratios in girls

15. Direct DNA Analysis for the Fragile X Mutation
Category
CGG repeats
Methylation of FMR1
Female
Male
Stable
6 to ~45
unmethylated
Not affected
Gray zone
~45 to ~55
Pre-mutation
~55 to ~200
Usually not affected
Full mutation
>200
Completely methylated
~50% affected
All affected
Briefly explain the absence of protein

16. CGG Repeats INCREASING XX XY XY XX XY XY X – Pre-mutation1 2 3 4 5 6
Father XY
Mother XX
CGG
Repeats
INCREASING
Pre-mutated Male XY
Pre-mutated Female XX
Unaffected Female XX XY XY XX XY
Unaffected
Unaffected
Unaffected
Try to convey how it goes silently through the generations. XY XX XX
X – Pre-mutation
X – Full Mutation XX XX

17. CLINICAL FEATURES

18. Physical Characteristics
Large ears
Long, narrow face
Prominent forehead
Prominent, square chin
High palate (roof of mouth)
Hand calluses
Mitral valve prolapse (a leaky heart valve)
Seizures
Eye problems
Physical characteristics range in display. Also can become more prominent as child ages.

19. Physical Characteristics Often Seen in Young Children:
Numerous ear infections
Flat feet
Hyper extensible joints
Eye problems in 20%-25%:
Refractive errors
Strabismus
Astigmatisms
Seizures
Missing developmental milestones
Weak connective tissue

20. Common Difficulties Sleeping Toilet training Socialization
Play (spinning objects, play with exclusive toy, or part of toy)

21. Cognitive
The Fragile X mutation affects brain development and leads to a range of cognitive delays.
Developmental delays
Mental impairment
Learning disabilities

22. Difficulties with frontal lobe functions (“executive” functions)
Organization of information
Acting on that information in an effective manner
Focusing attention
Forming a plan and carrying it out

23. Behavior Attention deficits Hyperactivity Impulsivity
Autistic-like behaviors
Repetitive behaviors
Hand flapping
Hand biting
Gaze aversion
Extreme anxiety, shyness
Transition problems, difficulty adjusting to change

24. Cognitive/ Behavioral Strengths
Strong visual memory
Long term memory
Good verbal imitative skills
Desire to be social
Strong appreciation of humor
Often receptive to helping or working cooperatively
Desire to be social

25. Speech and Language Characteristics
Delayed speech
Problems with intelligibility
Rapid, repetitive speech (perseveration)
Echolalia
Poor conversation skills
Good verbal imitative skills
LOGO reading, signs and billboards

26. Sensory Processing Characteristics
Tactile defensiveness
Visual defensiveness
Olfactory defensiveness
Oral defensiveness
Gravitational/ postural insecurity
Tactile = touch, Visual = too bright, olfactory = smells, oral = flavors, textures (may overstuff or gag), grav / post = feet on ground

27. Sensory processing often seen in infants and young children
Excessive mouthing and drooling
Mouth stuffing
“picky” eaters
Difficult to calm and comfort
Over sensitivity to sounds
Mouth stuffing and gagging. Makes family dining difficult.

28. Gross Motor Characteristics
Low muscle tone
Delays in gross motor skills
Uncoordinated, clumsy
What we thought low muscle tone meant

29. Fine Motor Characteristics
Low muscle tone
Hyper extensible finger joints
Difficulties with fine motor joints
Self feeding
Dressing
handwriting

30. Characteristics Often Seen in Females With FX
Attention deficits
Shyness and anxiety
Selective mutism
Problems with math
Increased risk for mental health issues such as depression, bipolar disorder, and obsessive compulsive disorder
25% premature ovarian failure (early menopause)
Carrier and Full mutation

31. INTERVENTIONS

32. Early/ Preschool Interventions
Speech and language therapy
Occupational therapy
Occasional physical therapy
Settings with consistency, structure and routine
Total communication program
Simultaneous not sequential
Visual learners
Incidental learners
Peer interaction. Immerse in language

33. 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
Routines and schedules are difficult to maintain at an early intervention level because of therapists schedules and parent-daycare. Timers in activites.

34. Managing Hyperarousal
Nervous system over stimulated
Evokes fear/flight responses
Anxiety can lead to hyperarousal
Use calming, coping and comfort to help self-regulation
Manage environment
Although subtle, can be a mild as gaze avoidance but can be go and hide. And even agression.

35. Reducing Anxiety Beginning and ending clearly defined
Picture schedules
Calm environment
Maintaining schedule
Use of various types of picture schedules or items that count remaining task. Example of swimming laps.

36. 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

37. Structure Needs Teaching strategies
Predictable routines, rules and expectations
Consistent physical layout of classroom
Minimize auditory distractions
Teaching strategies
Picture schedule
Visual communications system (PECS)
Augmentative communication
computers

38. Middle/ High School Interventions
Continue therapies if appropriate
Relevant and functional reading and learning experiences
Social skills training
Introduce pre-vocational opportunities
Recreational/ extracurricular
(Special Olympics, choirs, other musical venues)

39. Adult Opportunities Employment Independent living options
Socialization and adult relationships
Recreation

40. Suggested Recreational Opportunities
Trampolines
Bicycling
Swimming
Bowling
Soccer
Gym/Fitness Center
Softball
Martial Arts
Scouts
Choirs or other musical venues
Special Olympics
Challenger sports

41. Medications Attention-related problems Hyperactivity/ impulsivity
Mood disorders/ depression
Anxiety/ panic
Aggression
Obsessive/ compulsive symptoms
Bedwetting
Sleep disorders
Seizures
Self injury
I am not a doctor.

42. FXTAS Symptoms and Diagnosis
FXTAS usually develops between the ages of 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, and 3) Magnetic Resonance Imaging (MRI) findings that are known to be related to FXTAS, including white matter changes or decreased size of the brain.
Dementia or parkinson’s

43. FXPOI FXPOI: Fragile X-Associated Primary Ovarian Insufficiency
Affects female pre-mutation carriers ( CGG repeats)
Female with the full mutation do not appear to be at risk
While mother and family are dealing with child mother may be experiencing the effects of fxpoi while her father is dealing with fxtas

44. 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 .
Early menopause is prior to the age of 45.

45. Fragile X Research & Clinic Consortium
More clinics are planned. Goal would be to have a clinic in about 250 mile range.

46. Linking Individuals in Knowledge and Support

47. Fragile X Advocacy Day March 3, 2010 in Washington, D.C.
Photo is from last year’s advocacy day.
March 3, 2010 in Washington, D.C.

48. The National Fragile X Foundation
P.O. Box
San Francisco, CA
For more information and I would like to thank….

49. Fragile X Association of Alabama
Matt Rhodes
2710 Wellington Circle
Pelham, AL 35124
Alabama’s info can be linked to from fragilex.org.

50. The National Fragile X Foundation
Questions?
Serving the Fragile X community since 1984