Rett syndrome: historyRett syndrome: history
• 1966: 1966: Described by Described by Andreas RettAndreas Rett
• 1983: 1983: Described in Described in English by English by Bengt HagbergBengt Hagberg
Andreas Rett, Andreas Rett, MDMD1924-19971924-1997
Worldwide average of 1:15,000 Female Births
• Scotland: 1:15,000• Japan: 1:10,000• France: 1:18,000• USA: 1: 23,000• Sweden: 1: 15,000
RETT SYNDROMEWHAT DO WE KNOW? GENETIC DISORDER MAINLY IN FEMALES
VARIABLE CLINICAL EXPRESSION
PERVASIVE GROWTH FAILURE
SIGNIFICANT LONGEVITY
CONSISTENT NEUROPATHOLOGY >95% OF FEMALES MEETING CONSENSUS
CRITERIA HAVE MECP2 MUTATIONS
CLINICAL AND CLINICAL AND MOLECULAR DIAGNOSISMOLECULAR DIAGNOSIS• ClinicalClinical Relies on a set of Relies on a set of
diagnostic criteria diagnostic criteria that are based that are based on the “typical” pattern of on the “typical” pattern of development seen in children development seen in children with Rett syndromewith Rett syndrome
• MolecularMolecular - DNA test can - DNA test can confirm it in about 95% of confirm it in about 95% of casescases
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/squeezing; Hand clapping/tapping/rubbing; Hand mouthing
Gait dysfunction: Impaired (dyspraxic) or failing locomotion
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%
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
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 (<<1% of total) MAJORITY DUE TO LARGE DELETION
MECP2MECP2 Mutation Mutation Phenotypes in FemalesPhenotypes in Females • Infantile encephalopathy• Classic Rett syndrome• Angelman syndrome phenotype• Mental retardation with
seizures • Autism• Mild mental retardation• Learning disability• Normal
Rett SyndromeMale MECP2 Phenotypes
• Fatal Encephalopathy
• Rett/Klinefelter Syndrome
• X-Linked MR/Progressive Spasticity
• Somatic Mosaicism/NDD
• MECP2 Duplications and X-linked MR
Q19X
D97E
P101LP101HP101T
R106W (12)R106Q
R133C (7)
S134C (2)
411delG
Y141X
P152R (6)
F155IF155S
D156E
F157L
T158M (16)
R168X (37)
Q170X
R198X
P225R (3)
R255X (23)
K256X
620insT
654del4677insA
705delG
803delG (6)807delC
R270X (16)R294X (15)
P302AP302RP302L
R306C (19)R306H (2)
P322A
X487C
1364insC
258delCA
splice (2)
407del507+ ins GCTTTTAG
1053ins10
1096del101
1098del70
1116del841120del69
1141del55
1147del170ins31152del411152del441156del171157del321157del411157del441158del10
1159del431162del261163del261163del35
1165del26
1182del7
1189insA
1193insT
1194insT
P322L
missense
truncating
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
Mutations
• Mutations in MeCP2 found in >95% “classical” Rett syndrome
• Missense, nonsense, frameshift, large scale rearrangements
Two girls with the same Two girls with the same mutation can be very mutation can be very differentdifferent. .
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
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
RESEARCH UPDATE● Rare Disease Consortium
● Longevity Study
● Mouse Models● Reversibility Studies ● Anxiety and its Implications
● Therapeutic Horizons• PTC 124• Anxiety studies• Ampakines
Genetic Genetic counselingcounseling issues issues
• These are general guidelines, These are general guidelines, individual cases should individual cases should alwaysalways be done through a professional be done through a professional genetic counselor/geneticist genetic counselor/geneticist who examines the pedigree to who examines the pedigree to assess specific risks.assess specific risks.
• AsymptomaticAsymptomatic children are not children are not tested for genetic diseases.tested for genetic diseases.
Reproductive issuesReproductive issues• Parents who are not carriers, have Parents who are not carriers, have
~1% risk of a second affected child ~1% risk of a second affected child but if parent is carrier, risk is 50% for but if parent is carrier, risk is 50% for each pregnancy.each pregnancy.
• Family planningFamily planning– Individual decisions about Individual decisions about
subsequent pregnanciessubsequent pregnancies– Prenatal testing optionsPrenatal testing options– Pregnancy termination optionsPregnancy termination options
My (child, sister, brother) has Rett My (child, sister, brother) has Rett syndrome, but the MECP2 test was syndrome, but the MECP2 test was negative, what is the chance that I negative, what is the chance that I will have a(nother) child with Rett will have a(nother) child with Rett syndrome?syndrome?
• Your Child?Your Child?– Difficult to say- risk may be Difficult to say- risk may be
somewhat higher than 1% for somewhat higher than 1% for another childanother child
• Your Sister or brother?Your Sister or brother?– Low but not zeroLow but not zero– Possibly increased if parents are Possibly increased if parents are
blood relativesblood relatives– Need for individual counselingNeed for individual counseling
My sister has Rett syndrome and My sister has Rett syndrome and an MECP2 mutation, should I bean MECP2 mutation, should I be tested?tested?
Adult brother:Adult brother:
not really, your not really, your risk of having a risk of having a child with Rett child with Rett is population is population risk- would arise risk- would arise by new mutationby new mutation
My daughter with Rett syndrome has My daughter with Rett syndrome has a MECP2 mutation. Should I test my a MECP2 mutation. Should I test my other kids?other kids?
Typically developing:Typically developing:
No, not until they are No, not until they are adults and can decide on adults and can decide on their own whether they their own whether they want to be testedwant to be tested
•Insurability issuesInsurability issues•Bias, understanding Bias, understanding the implicationsthe implications
Developmental disorder: Developmental disorder: possibly, need to discuss possibly, need to discuss with their physicianwith their physician
My sister has Rett syndrome and My sister has Rett syndrome and an MECP2 mutation, should I be an MECP2 mutation, should I be tested?tested?
Adult sister: Adult sister: PossiblyPossibly
Low risk but it is Low risk but it is possible to carry possible to carry it silently. it silently.
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
IRSA North American Database• 85.5% were typical
• 13.4% were atypical
• 1.1% had MECP2 mutations but did not have RS
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
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
North American Database
Total enrolled 1928
Typical 1648 (85.5 %)
Atypical 259 (13.4 %)
Not RS (MECP2 positive)
21 (1.1 %)
North American Database
Group Total
Mutation
No mutatio
n
Unknown
Typical 1648
791 (91%)
79 (9%) 778
Atypical
259 94 (58%)
68 (42%)
97
Not RS 21 21 (100%)
0 0
North American DatabaseMutation N % RettBase
%
T158M 109 11.9 9.1
R168X 86 9.4 8.8
R255X 83 9.0 7.9
R270X 66 7.2 6.9
R306C 62 6.8 4.6
R133C 59 6.4 4.4
R294X 57 6.2 5.6
R106W 40 4.4 3.4
North American Database
Mutation N %
Large deletions
59 6.4
C-terminal del 81 8.8
Other deletions
54 5.9
Insertions 26 2.8
All others 136 14.8
North American DatabaseMutation
TypeN % % France
(Philippe et al.)
Missense 356 38.8 35.6
Nonsense 323 35.2 37.3
Frameshift 161 17.5 12.0
Complex deletion
59 6.4 5.8
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
LONG TERM CARE
Physical therapy
Occupational therapy
Communication therapy
Nutritional support
Orthopedic support
Seizure management
Self-abusive behaviors
Managment Issues:Managment Issues:Respiratory IrregularitiesRespiratory Irregularities• Breath holding can be Breath holding can be dramaticdramatic
•Several minutesSeveral minutes in durationin duration•Desaturation toDesaturation to 45% (normal- 95-45% (normal- 95-100%100%
– If they faint, they will breatheIf they faint, they will breathe..• Can induce seizuresCan induce seizures• Treatment- difficult to stopTreatment- difficult to stop
•Magnesium citrate, Prozac, Magnesium citrate, Prozac, Buspar, DesipramineBuspar, Desipramine
• Breath holding can be Breath holding can be dramaticdramatic•Several minutesSeveral minutes in durationin duration•Desaturation toDesaturation to 45% (normal- 95-45% (normal- 95-100%100%
– If they faint, they will breatheIf they faint, they will breathe..• Can induce seizuresCan induce seizures• Treatment- difficult to stopTreatment- difficult to stop
•Magnesium citrate, Prozac, Magnesium citrate, Prozac, Buspar, DesipramineBuspar, Desipramine
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
Managment Issues:Managment Issues:Gastroenterologic Problems• Weight loss• Constipation• Bruxism• GI reflux• Swallowing, chewing difficulties• Calcium deficiency• Treatment: Nutritionist, therapist to
aid in feeding, multivitamins, gastrostomy tube
Management Issues:Management Issues: SeizuresSeizures• More than More than 80% have EEG 80% have EEG
abnormalitiesabnormalities• Some have clinical seizuresSome have clinical seizures• 25-50%25-50%• Distinguishing “true” seizures Distinguishing “true” seizures
from “behaviors”from “behaviors”• Video EEG monitoring extremely Video EEG monitoring extremely
usefuluseful
Management Issues:Management Issues: SeizuresSeizures• Treat the child not the EEGTreat the child not the EEG• ‘‘Usual’ antiepileptic drugsUsual’ antiepileptic drugs• The seizures often improve The seizures often improve
with agewith age
What do I do if my child has a What do I do if my child has a seizure?seizure?11. . Stay calmStay calm
2. Safe position2. Safe position
3. On side to prevent 3. On side to prevent aspirationaspiration
4. Don't put anything 4. Don't put anything in the mouthin the mouth
5. Note duration of 5. Note duration of seizureseizure
6. 6. What is moving?What is moving?
7. If it lasts > 5 7. If it lasts > 5 minutes or there is minutes or there is a a color changecolor change or or breathing difficulty,breathing difficulty, call 911call 911
8. Otherwise, call the 8. Otherwise, call the pediatrician or take pediatrician or take them to the ER them to the ER afterafter
Management Issues: Management Issues: Respiratory irregularitiesRespiratory 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
Respiratory irregularitiesRespiratory irregularities• Breath holding can be Breath holding can be dramaticdramatic
•Several Several minutesminutes in durationin duration•Desaturation toDesaturation to 45% (normal- 95-45% (normal- 95-100%)!!!100%)!!!
– If they faint, they will breatheIf they faint, they will breathe..• Can induce seizuresCan induce seizures• Treatment- difficult to stopTreatment- difficult to stop
•Magnesium citrate, Prozac, other Magnesium citrate, Prozac, other medsmeds
• Breath holding can be Breath holding can be dramaticdramatic•Several Several minutesminutes in durationin duration•Desaturation toDesaturation to 45% (normal- 95-45% (normal- 95-100%)!!!100%)!!!
– If they faint, they will breatheIf they faint, they will breathe..• Can induce seizuresCan induce seizures• Treatment- difficult to stopTreatment- difficult to stop
•Magnesium citrate, Prozac, other Magnesium citrate, Prozac, other medsmeds
Management Issues: Management Issues: BehaviorsBehaviors• Teeth grinding, air swallowingTeeth grinding, air swallowing• Stereotypies (splinting, Stereotypies (splinting,
restraints)restraints)• Poor Poor sleepsleep patterns patterns• Self injurious behaviorsSelf injurious behaviors• Screaming spellsScreaming spells
– Pain? Frustration? Gall Pain? Frustration? Gall bladder? bladder?
• Teeth grinding, air swallowingTeeth grinding, air swallowing• Stereotypies (splinting, Stereotypies (splinting,
restraints)restraints)• Poor Poor sleepsleep patterns patterns• Self injurious behaviorsSelf injurious behaviors• Screaming spellsScreaming spells
– Pain? Frustration? Gall Pain? Frustration? Gall bladder? bladder?
Management Issues:Management Issues: AnxietyAnxiety
• Recently recognizedRecently recognized• Pronounced in mouse modelsPronounced in mouse models• Clinical trials in miceClinical trials in mice
– Stress hormone elevatedStress hormone elevated– CortisolCortisol
• Medications in developmentMedications in development– AntidepressantsAntidepressants
Managment Issues:Managment Issues:StereotypiesStereotypies• Interfere with purposeful hand useInterfere with purposeful hand use• Worse when Worse when stressedstressed• Can and do injure themselvesCan and do injure themselves• What can you do?What can you do?
– Restrain the Restrain the dominantdominant hand for abuse hand for abuse– Restrain the Restrain the non-dominantnon-dominant hand for use hand for use
•wrist or elbow restraintwrist or elbow restraint•weightsweights•VelcroVelcro
Management Issues:Management Issues:BruxismBruxism• Can interfere with nutritionCan interfere with nutrition• Dental damageDental 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
BruxismBruxism
Intervention??Intervention??Separate the Separate the
teethteethbite bite
guardguard “ “chew chew
towel” or toytowel” or toyDeter the Deter the
behaviorbehavior
Electric Electric toothbrushtoothbrush
Management Issues:Management Issues:NutritionNutrition• Poor weight gainPoor weight gain
•SupplementsSupplements•Gastrostomy tubesGastrostomy tubes•Many have GE refluxMany have GE reflux
• Constipation: Constipation: Probably Probably neurologicneurologic in in originorigin
•Can be severe, judicious use of Can be severe, judicious use of stimulant laxativesstimulant laxatives
•Miralax powder (Glycolax)Miralax powder (Glycolax)
What is Reflux?What is Reflux?• When stomach contents move When stomach contents move
up into the esophagusup into the esophagus– can lead to pain, irritability, can lead to pain, irritability,
poor feeding, vomiting, poor feeding, vomiting, ulcers in esophagus, ulcers in esophagus, problems with weight gainproblems with weight gain
• Diagnosis: pH probe, swallow Diagnosis: pH probe, swallow studystudy
• Treatment: medical, surgicalTreatment: medical, surgicalhttp://www.gerd.com
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
Management IssuesManagement IssuesScoliosisScoliosis
• MayMay progress rapidlyprogress rapidly• More risk if non-More risk if non-
ambulatory ambulatory • What can you do??What can you do??
– Encourage weight Encourage weight bearing: standers, bearing: standers, walkers, assisted walkers, assisted walkingwalking
– Regular orthopedic Regular orthopedic evaluations evaluations
– Bracing or surgeryBracing or surgeryhttp://www.spine-health.com/http://www.spine-health.com/
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
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
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
Management IssuesManagement IssuesSleep Disturbances• Night waking, screaming,
laughing• Increased daytime sleep with
age; delayed onset of sleep at night
• Treatment: Behavioral modalities
• Sleep Medications
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
Management IssuesManagement 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
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
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
Management IssuesManagement 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?
Causes of PAIN
• Gastroesophageal reflux (GERD)• Constipation• Gall bladder disease• Pancreatitis• H pylori bacteria• Air swallowing• Menstrual cramps• Fractures• Toothache• Dystonia
Management IssuesManagement 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
Adults
• May see resolution of seizures• Loss of motor abilities-?
Parkinsonism• Premature aging? • Fixed joint deformities
(preventable?)• Breathing better• Feeding abilities stable
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
Physical Status
• Affects her communicability– Walking to the bathroom– Walking to the faucet– Reaching objects to touch
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
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
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 you’re asking for what YOU want, not what SHE wants
Making It Easier
• Make the communication motivating and exciting.
• Be alert to her visual cues and body language
• Minimize distractions• Allow for comfortable seating
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
MOUSE MODELS
• Knock-out mouse: Mecp2 deleted
• Knock-in mouse: Insertion of human mutation in Mecp2
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 2007;315:1143-1147
KNOCK-IN MUTANT
• Note humped back and fore-limb claspingYoung and Zoghbi, Am J Hum Genet 2004;74:511-520
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 2006;26:319-327
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
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 2006;103:18267-18272
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
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