Not Being Able to Talk IS NOT THE SAME As Not Having Anything To Say

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(No Transcript)
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Rett syndrome history

• 1966 Described by Andreas Rett
• 1983 Described in English by Bengt Hagberg

Andreas Rett, MD1924-1997
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RETT SYNDROME IS A DEVELOPMENTAL DISORDER
NOT degenerative
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Worldwide average of 115,000 Female Births

• Scotland 115,000
• Japan 110,000
• France 118,000
• USA 1 23,000
• Sweden 1 15,000

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RETT SYNDROMEWHAT DO WE KNOW?

• GENETIC DISORDER MAINLY IN FEMALES
• VARIABLE CLINICAL EXPRESSION
• PERVASIVE GROWTH FAILURE
• SIGNIFICANT LONGEVITY
• CONSISTENT NEUROPATHOLOGY
• gt95 OF FEMALES MEETING CONSENSUS CRITERIA HAVE
  MECP2 MUTATIONS

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CLINICAL AND MOLECULAR DIAGNOSIS

• Clinical Relies on a set of diagnostic criteria
  that are based on the typical pattern of
  development seen in children with Rett syndrome
• Molecular - DNA test can confirm it in about 95
  of cases

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RETT SYNDROME CONSENSUS CRITERIA - 2001

• Normal at birth
• Apparently normal early development (may be
  delayed from birth)
• Postnatal deceleration of head growth in most
• Lack of achieved purposeful hand skills
• Psychomotor regression Emerging social
  withdrawal, communication dysfunction, loss of
  learned words, and cognitive impairment
• Stereotypic movements Hand washing/wringing/squee
  zing Hand clapping/tapping/rubbing Hand
  mouthing
• Gait dysfunction Impaired (dyspraxic) or failing
  locomotion

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VARIANT EXPRESSIONS

• Delayed onset or forme fruste
• Preserved speech
• Early-onset seizures
• Diagnosis by variant consensus criteria
• Variant forms may account for 15-20
• MECP2 mutations in approximately 50

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RETT SYNDROME AND MECP2

• RETT SYNDROME IS A CLINICAL DIAGNOSIS
• RETT SYNDROME IS NOT SYNONYMOUS WITH MECP2
  MUTATIONS
• RETT SYNDROME MAY BE SEEN WITH MECP2 MUTATIONS
• RETT SYNDROME MAY BE SEEN WITHOUT MECP2 MUTATIONS
• MECP2 MUTATIONS MAY BE SEEN WITHOUT RETT SYNDROME

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MECP2 AND RETT SYNDROME

• 8 MUTATIONS ACCOUNT FOR 65 OF THOSE IN RETT
  SYNDROME
• SPORADIC RS MAJORITY APPEAR TO BE OF PATERNAL
  ORIGIN
• FAMILIAL RS (ltlt1 of total) MAJORITY DUE TO LARGE
  DELETION

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MECP2 Mutation Phenotypes in Females

• Infantile encephalopathy
• Classic Rett syndrome
• Angelman syndrome phenotype
• Mental retardation with seizures
• Autism
• Mild mental retardation
• Learning disability
• Normal

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Rett SyndromeMale MECP2 Phenotypes

• Fatal Encephalopathy
• Rett/Klinefelter Syndrome
• X-Linked MR/Progressive Spasticity
• Somatic Mosaicism/NDD
• MECP2 Duplications and X-linked MR

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T158M (16)
F157L
missense
D156E
F155I
F155S
P322L
R106Q
P322A
R106W (12)
R306H (2)
P152R (6)
R306C (19)
S134C (2)
P101T
R133C (7)
P302L
P101H
P302R
P101L
P225R (3)
P302A
X487C
D97E
splice (2)
1053ins10
1141del55
620insT
Q19X
258delCA
411delG
1096del101
654del4
677insA
1098del70
Y141X
1182del7
705delG
R168X (37)
1116del84
R255X (23)
Q170X
1120del69
K256X
1147del170ins3
R198X
1152del41
803delG (6)
1152del44
807delC
1364insC
truncating
1156del17
R270X (16)
1157del32
R294X (15)
1157del41
1194insT
1157del44
1193insT
1158del10
407del507 ins GCTTTTAG
1159del43
1189insA
1162del26
1165del26
1163del26
1163del35
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MUTATION TYPES

• Missense DNA code changed from one amino acid
  to another complete MeCP2 protein made example
  R133C
• Nonsense DNA code change does not code for
  amino acid incomplete MeCP2 made example R168X
• Frameshift insertion or deletion of coding
  material incomplete MeCP2 made
• Large scale rearrangements large portion of DNA
  missing incomplete MeCP2 is made

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Mutations

• Mutations in MeCP2 found in gt95 classical Rett
  syndrome
• Missense, nonsense, frameshift, large scale
  rearrangements

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Two girls with the same mutation can be very
different.
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MUTATIONS AND PHENOTYPE

• R294X Abnormalities of mood
• R225X and R270X Stereotypies of hand/face
• R133C and R306C Milder overall involvement and
  heightened anxiety and fear
• R168X more severe

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DOES MUTATION PREDICT OUTCOME?

• R133C, R294X, and R306C mutations and C-term
  truncations are associated with better outcome
• Lower severity scores
• Slower progression
• Preserved speech variants
• Greater anxiety/fear
• Missense mutations in C-terminal region
  associated with XLMR alone

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RESEARCH UPDATE

• Rare Disease Consortium
• Longevity Study
• Mouse Models
• Reversibility Studies
• Anxiety and its Implications
• Therapeutic Horizons
• PTC 124
• Anxiety studies
• Ampakines

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Genetic counseling issues

• These are general guidelines, individual cases
  should always be done through a professional
  genetic counselor/geneticist who examines the
  pedigree to assess specific risks.
• Asymptomatic children are not tested for genetic
  diseases.

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Reproductive issues

• Parents who are not carriers, have 1 risk of a
  second affected child but if parent is carrier,
  risk is 50 for each pregnancy.
• Family planning
• Individual decisions about subsequent pregnancies
• Prenatal testing options
• Pregnancy termination options

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My (child, sister, brother) has Rett syndrome,
but the MECP2 test was negative, what is the
chance that I will have a(nother) child with Rett
syndrome?

• Your Child?
• Difficult to say- risk may be somewhat higher
  than 1 for another child
• Your Sister or brother?
• Low but not zero
• Possibly increased if parents are blood relatives
• Need for individual counseling

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My sister has Rett syndrome and an MECP2
mutation, should I be tested?

• Adult brother
• not really, your risk of having a child with
  Rett is population risk- would arise by new
  mutation

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My daughter with Rett syndrome has a MECP2
mutation. Should I test my other kids?

• Typically developing
• No, not until they are adults and can decide on
  their own whether they want to be tested
• Insurability issues
• Bias, understanding the implications
• Developmental disorder possibly, need to discuss
  with their physician

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My sister has Rett syndrome and an MECP2
mutation, should I be tested?

• Adult sister Possibly
• Low risk but it is possible to carry it silently.
  

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Lifespan

• First 10 years just like other girls
• 95 survive to age 25
• 70 survive to age 35
• Lower than 98 of all females
• Higher than the 27 survival of others with
  profound motor and cognitive disabilites

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IRSA North American Database

• 85.5 were typical
• 13.4 were atypical
• 1.1 had MECP2 mutations but did not have RS

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N AMERICAN DATABASE 1,928 PATIENTS Lived to AGE
TOTAL LIVING 30   
254         187 40   
82            48 50   
17            11 60  
5             1 70   
1               0
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Longevity Study

• Data gathered on 1928 girls and women
• Completion of data gathering and filling in
  missing data
• Analysis of longevity underway
• Databank very informative
• Appears representative

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North American Database
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North American Database
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North American Database
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North American Database
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North American Database
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Causes of Death Reported

• Unexpected causes may be related to
• autonomic nervous system dysfunction
• Prolonged QT interval
• Intestinal volvulus
• Other, individual causes
• Causes related to level of disability
• Aspiration pneumonia
• Nutritional state

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LONG TERM CARE Physical therapy Occupational
therapy Communication therapy Nutritional
support Orthopedic support Seizure
management Self-abusive behaviors
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Managment IssuesRespiratory Irregularities

• Breath holding can be dramatic
• Several minutes in duration
• Desaturation to 45 (normal- 95-100
• If they faint, they will breathe.
• Can induce seizures
• Treatment- difficult to stop
• Magnesium citrate, Prozac, Buspar, Desipramine

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AUTONOMIC NERVOUS SYSTEM

• Hands and feet tend to be cool to cold
• More likely in lower extremities not only cold
  but red or purple discoloration involving much of
  lower extremity
• Thought to be due to increased threshold of
  sympathetic nervous system
• Does not appear to cause discomfort
• No specific treatment available

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Managment IssuesGastroenterologic Problems

• Weight loss
• Constipation
• Bruxism
• GI reflux
• Swallowing, chewing difficulties
• Calcium deficiency
• Treatment Nutritionist, therapist to aid in
  feeding, multivitamins, gastrostomy tube

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Management Issues Seizures

• More than 80 have EEG abnormalities
• Some have clinical seizures
• 25-50
• Distinguishing true seizures from behaviors
• Video EEG monitoring extremely useful

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Management Issues Seizures

• Treat the child not the EEG
• Usual antiepileptic drugs
• The seizures often improve with age

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What do I do if my child has a seizure?
1. Stay calm 2. Safe position 3. On side to
prevent aspiration 4. Don't put anything in the
mouth 5. Note duration of seizure
6. What is moving? 7. If it lasts gt 5 minutes or
there is a color change or breathing difficulty,
call 911 8. Otherwise, call the pediatrician or
take them to the ER after
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Management Issues Respiratory irregularities

• Hyperventilation, breathholding, or both are
  common may notice forced air expulsion
• Occur while awake
• Modified by hunger, agitation, other stress
• Typically reach maximum in school years
• Significant air swallowing may occur
• Effective treatment may be elusive

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Respiratory irregularities

• Breath holding can be dramatic
• Several minutes in duration
• Desaturation to 45 (normal- 95-100)!!!
• If they faint, they will breathe.
• Can induce seizures
• Treatment- difficult to stop
• Magnesium citrate, Prozac, other meds

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Management Issues Behaviors

• Teeth grinding, air swallowing
• Stereotypies (splinting, restraints)
• Poor sleep patterns
• Self injurious behaviors
• Screaming spells
• Pain? Frustration? Gall bladder?

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Management Issues Anxiety

• Recently recognized
• Pronounced in mouse models
• Clinical trials in mice
• Stress hormone elevated
• Cortisol
• Medications in development
• Antidepressants

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Managment IssuesStereotypies

• Interfere with purposeful hand use
• Worse when stressed
• Can and do injure themselves
• What can you do?
• Restrain the dominant hand for abuse
• Restrain the non-dominant hand for use
• wrist or elbow restraint
• weights
• Velcro

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Management IssuesBruxism

• Can interfere with nutrition
• Dental damage
• Tends to diminish or disappear after school age
• Occurs in almost all girls or women
• Varies in frequency and intensity
• May increase with anxiety or excitement

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Bruxism
Intervention?? Separate the teeth bite guard
chew towel or toy Deter the behavior Electric
toothbrush
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Management IssuesNutrition

• Poor weight gain
• Supplements
• Gastrostomy tubes
• Many have GE reflux
• Constipation Probably neurologic in origin
• Can be severe, judicious use of stimulant
  laxatives
• Miralax powder (Glycolax)

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What is Reflux?

• When stomach contents move up into the esophagus
• can lead to pain, irritability, poor feeding,
  vomiting, ulcers in esophagus, problems with
  weight gain
• Diagnosis pH probe, swallow study
• Treatment medical, surgical

http//www.gerd.com
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OSTEOPENIA

• Occurs in almost all girls or women
• Worse with poor calorie-protein intake
• Fractures much more common may be unrecognized
• Unexplained immobility of limb a red flag
• Regardless of age, use of oral calcium
  supplementation should be considered

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Management IssuesScoliosis

• May progress rapidly
• More risk if non-ambulatory
• What can you do??
• Encourage weight bearing standers, walkers,
  assisted walking
• Regular orthopedic evaluations
• Bracing or surgery

http//www.spine-health.com/
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The Autonomic Nervous System

• Automatic control of things like breathing, heart
  rate, intestinal function, blood pressure
• Does not function properly in Rett
• Brainstem nerve cells involved
• Possible imbalance of signals

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CARDIAC CONDUCTION SYSTEM

• Cardiac conduction may be immature
• Prolonged QT interval may be observed
• At diagnosis, an electrocardiogram (EKG) should
  be obtained likely to be normal
• If abnormal, a cardiologist should be seen
  medical treatment should be effective
• If abnormal, other family members should be
  checked

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The Heart EKG Changes

• The heart is structurally normal
• Prolonged QTc interval, increases with age (50
  in Late Motor Stage)
• Loss of normal heart rate variability
• Proposed as cause of sudden, unexpected death

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Management IssuesSleep Disturbances

• Night waking, screaming, laughing
• Increased daytime sleep with age delayed onset
  of sleep at night
• Treatment Behavioral modalities
• Sleep Medications

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SLEEP AIDS

• Antihistamines limited effectiveness
• Melatonin may induce sleep, but not prevent
  arousals
• Trazodone and zolpidem may promote full night of
  sleep
• Chloral hydrate effective but unpalatable
• Private pharmacy may formulate as suppository or
  capsule

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Management IssuesOrthopedic Abnormalities

• Early truncal ataxia
• Legs abducted
• Hypotonic early hyperreflexive and rigid later
• Scoliosis (64 prevalence)
• 10 require surgery
• Treatment Brace/surgery for scoliosis,
  orthopedic and intensive physical therapy,
  special computers and toys

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AMBULATION

• 80 learn to walk
• About 25 lose this ability with regression
• Overall, 60 remain ambulatory
• Orthotic devices may be needed for toe walking
• Great effort should be exerted to maintain
  ambulation
• Standing frames, walkers, or parallel bars should
  be used at home and school for those who do not
  walk

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OTHER MOTOR SYSTEMS

• Hypotonia the rule during infancy
• Strength typically normal
• After puberty, motor activities may slow and
  muscle tone is often increased
• In addition to hand stereotypies, other movements
  may be seen
• Tremor, myoclonus, or choreiform
• Dystonia may be prominent with age
• Drug Treatment available to relieve pain

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Management IssuesPathologic Fractures

• Reported to occur in 40 by 15 yrs
• More common in children who have never walked,
  who take AEDs
• Bone loss or lack or normal bone growth?
• Interleukin 1 from brain needed for normal bone
  density?

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Causes of PAIN

• Gastroesophageal reflux (GERD)
• Constipation
• Gall bladder disease
• Pancreatitis
• H pylori bacteria
• Air swallowing
• Menstrual cramps
• Fractures
• Toothache
• Dystonia

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Management IssuesGynecologic Concerns

• Usually normal onset of puberty, but delayed
  menarche possible due to decreased body fat
• Monitor for UTIs and Candida infections
• Management of periods
• Depo Provera
• Birth control pills
• Hysterectomy
• Endometrial ablation

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Adults

• May see resolution of seizures
• Loss of motor abilities-?Parkinsonism
• Premature aging?
• Fixed joint deformities (preventable?)
• Breathing better
• Feeding abilities stable

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Severe Dyspraxia - Motor Planning Difficulty

• Limits her ability to coordinate speech
• Limits her ability to gesture
• May interfere with the ability to
• eye gaze
• touch a switch

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Physical Status

• Affects her communicability
• Walking to the bathroom
• Walking to the faucet
• Reaching objects to touch

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On The Other Hand

• Sometimes those with more physical
  challenges are more communicative
• Their eyes say it first
• Attention is not so focused on how to move, so
  they are able to focus on what is said

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Receptive language is always greater than
expressive language

• Input is greater than output

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Arm, Hand or Elbow Splints

• Non- dominant hand
• Can make a big difference
• ability to use the dominant hand
• operate a switch
• choose a picture, object or word by touch

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Processing Takes Time

• We give up when she is still trying
• Give her lots of time

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Fluctuations

• Attention
• Behavior
• Day to Day
• Hour to Hour

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A Rett Syndrome Truth

• The most consistent aspect of Rett syndrome is
  inconsistency

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Health Status

• Concentration may be difficult
• Reflux
• Seizures
• Scoliosis
• Breathing

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Making It Easier

• Be alert to her body language
• Be sensitive about what you say in front of her
• Explore different kinds of communication
  strategies
• She may not comply because youre asking for what
  YOU want, not what SHE wants

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Making It Easier

• Make the communication motivating and exciting.
• Be alert to her visual cues and body language
• Minimize distractions
• Allow for comfortable seating

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Do Not Underestimate Her

• She has not lost the will to speak, only the way
  to speak
• Understanding and responding are two different
  things
• Knowing It and Showing It are Different

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Oftentimes, the greatest statements are made
insilence

• Listen with your heart

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MOUSE MODELS

• Knock-out mouse Mecp2 deleted
• Knock-in mouse Insertion of human mutation in
  Mecp2

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KNOCK-OUT MUTANT

• Note
• hind-limb clasping
• Guy et al.
• Nature Genetics 200127322-326

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Reversibility Studies Knock-out Mutant

• Is Mecp2 knock-out reversible?
• Using estrogen receptor controlled Mecp2
  promoter
• Mecp2 knock-out phenotype reversed in both
  immature male and mature male and female mice
  with estrogen analog, tamoxifen
• Rapid re-expression in immature males resulted in
  death in 50
• Guy et al. Science 20073151143-1147

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KNOCK-IN MUTANT

• Note humped back and fore-limb clasping
• Young and Zoghbi, Am J Hum Genet 200474511-520

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KNOCK-IN MUTANT

• Impaired hippocampus-dependent social, spatial,
  and contextual fear memory
• Impaired long-term potentiation and depression
• Reduced post-synaptic densities
• No change in BDNF expression
• Moretti et al. J Neurosci 200626319-327

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ANXIETY STUDIES

• Following recognition of heightened anxiety in
  individuals with Rett syndrome, recent studies in
  the knock-in mouse model provide valuable
  information that is being pursued in the animal
  model and in humans

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KNOCK-IN MUTANT

• Enhanced anxiety and fear based on
• Elevated blood corticosterone levels
• Elevated corticotropin-releasing hormone in
  hypothalamus, central nucleus of amygdala, and
  bed nucleus of stria terminalis
• MeCP2 binds to Crh promoter methylated region
• McGill et al. PNAS 200610318267-18272

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KNOCK-IN MUTANT

• Implications of Crh over-expression
• Anxiety plays central role in clinical RS
• Amygdala has direct input into hypothalamus and
  brainstem autonomic nuclei correlating with
  clinical problems of respiration, GI function,
  and peripheral sympathetic NS
• Suggests strategies for therapeutic intervention

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Therapeutic Horizons

• PTC 124 Small molecule capable of reading
  through stop codons (nonsense mutations) to
  produce full length proteins
• Currently in clinical trials for cystic fibrosis
  and Duchenne muscular dystrophy
• Pre-clinical studies on-going in cell systems and
  in near future in R168X knock-in mouse model
• Anxiety studies