Rett syndrome: history 1966: Described by Andreas Rett1966: Described by Andreas Rett 1983: Described in English by Bengt Hagberg1983: Described in English.

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

RETT SYNDROME IS A DEVELOPMENTALDISORDER

NOT degenerative

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

Receptive language is always greater than expressive language

Input is greater than output

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

Processing Takes Time

• We give up when she is still trying

• Give her lots of time

Fluctuations

• Attention• Behavior

– Day to Day– Hour to Hour

A Rett Syndrome Truth

• The most consistent aspect of Rett syndrome is inconsistency

Health Status

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

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

Oftentimes, the greatest statements are made insilence

Listen with your heart

MOUSE MODELS

• Knock-out mouse: Mecp2 deleted

• Knock-in mouse: Insertion of human mutation in Mecp2

KNOCK-OUT MUTANT

•Note hind-limb

claspingGuy et al. Nature Genetics 2001;27:322-326

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