Rett syndrome: history1966: Described by Andreas Rett

1983: Described in English by Bengt Hagberg

Andreas Rett, MD1924-1997

RETT SYNDROME IS A DEVELOPMENTALDISORDER

NOT degenerative

Worldwide average of 1:15,000 Female Births

Scotland: 1:15,000Japan: 1:10,000France: 1:18,000USA: 1: 23,000Sweden: 1: 15,000

RETT SYNDROMEWHAT DO WE KNOW?GENETIC DISORDER MAINLY IN FEMALESVARIABLE CLINICAL EXPRESSIONPERVASIVE GROWTH FAILURESIGNIFICANT LONGEVITYCONSISTENT NEUROPATHOLOGY>95% OF FEMALES MEETING CONSENSUS CRITERIA HAVE MECP2 MUTATIONS

CLINICAL AND MOLECULAR DIAGNOSISClinical Relies on a set of diagnostic criteria that are based on the typical pattern of development seen in children with Rett syndromeMolecular - DNA test can confirm it in about 95% of cases

RETT SYNDROME CONSENSUS CRITERIA - 2001Normal at birthApparently normal early development (may be delayed from birth)Postnatal deceleration of head growth in mostLack 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 mouthingGait dysfunction: Impaired (dyspraxic) or failing locomotion

VARIANT EXPRESSIONSDelayed onset or forme frustePreserved speechEarly-onset seizuresDiagnosis by variant consensus criteria Variant forms may account for 15-20%MECP2 mutations in approximately 50%

RETT SYNDROME AND MECP2RETT SYNDROME IS A CLINICAL DIAGNOSISRETT SYNDROME IS NOT SYNONYMOUS WITH MECP2 MUTATIONSRETT SYNDROME MAY BE SEEN WITH MECP2 MUTATIONSRETT SYNDROME MAY BE SEEN WITHOUT MECP2 MUTATIONSMECP2 MUTATIONS MAY BE SEEN WITHOUT RETT SYNDROME

MECP2 AND RETT SYNDROME

8 MUTATIONS ACCOUNT FOR ~ 65% OF THOSE IN RETT SYNDROMESPORADIC RS: MAJORITY APPEAR TO BE OF PATERNAL ORIGINFAMILIAL RS (

MECP2 Mutation Phenotypes in Females Infantile encephalopathyClassic Rett syndromeAngelman syndrome phenotypeMental retardation with seizures AutismMild mental retardationLearning disabilityNormal

Rett SyndromeMale MECP2 PhenotypesFatal Encephalopathy

Rett/Klinefelter Syndrome

X-Linked MR/Progressive Spasticity

Somatic Mosaicism/NDD

MECP2 Duplications and X-linked MR

Q19XD97EP101LP101HP101TR106W (12)R106QR133C (7)S134C (2)411delGY141XP152R (6)F155IF155SD156EF157LT158M (16)R168X (37)Q170XR198X P225R (3)R255X (23)K256X620insT654del4677insA705delG803delG (6)807delCR270X (16)R294X (15)P302AP302RP302LR306C (19)R306H (2)P322AX487C1364insC258delCAsplice (2)407del507+ ins GCTTTTAG1053ins101096del1011098del701116del841120del691141del551147del170ins31152del411152del441156del171157del321157del411157del441158del101159del431162del261163del261163del351165del261182del71189insA1193insT1194insTP322Lmissensetruncating

MUTATION TYPESMissense DNA code changed from one amino acid to another; complete MeCP2 protein made; example R133CNonsense DNA code change does not code for amino acid; incomplete MeCP2 made; example R168XFrameshift insertion or deletion of coding material; incomplete MeCP2 madeLarge scale rearrangements large portion of DNA missing; incomplete MeCP2 is made

MutationsMutations in MeCP2 found in >95% classical Rett syndromeMissense, nonsense, frameshift, large scale rearrangements

Two girls with the same mutation can be very different.

MUTATIONS AND PHENOTYPER294X 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 outcomeLower severity scoresSlower progressionPreserved speech variantsGreater anxiety/fearMissense mutations in C-terminal region associated with XLMR alone

RESEARCH UPDATERare Disease Consortium

Longevity Study

Mouse ModelsReversibility Studies Anxiety and its Implications

Therapeutic HorizonsPTC 124Anxiety studiesAmpakines

Genetic counseling issuesThese 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.

Reproductive issuesParents who are not carriers, have ~1% risk of a second affected child but if parent is carrier, risk is 50% for each pregnancy.Family planningIndividual decisions about subsequent pregnanciesPrenatal testing optionsPregnancy termination options

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 childYour Sister or brother?Low but not zeroPossibly increased if parents are blood relativesNeed for individual counseling

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

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 testedInsurability issuesBias, understanding the implicationsDevelopmental disorder: possibly, need to discuss with their physician

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

Adult sister: PossiblyLow risk but it is possible to carry it silently.

LifespanFirst 10 years just like other girls95% survive to age 2570% survive to age 35Lower than 98% of all femalesHigher than the 27% survival of others with profound motor and cognitive disabilites

IRSA North American Database85.5% 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 StudyData gathered on 1928 girls and womenCompletion of data gathering and filling in missing dataAnalysis of longevity underwayDatabank very informativeAppears representative

North American Database

North American Database

North American Database

North American Database

North American Database

Causes of Death ReportedUnexpected causes may be related to autonomic nervous system dysfunctionProlonged QT intervalIntestinal volvulusOther, individual causes

Causes related to level of disability:Aspiration pneumoniaNutritional state

LONG TERM CAREPhysical therapy

Occupational therapy

Communication therapy

Nutritional support

Orthopedic support

Seizure management

Self-abusive behaviors

Managment Issues:Respiratory IrregularitiesBreath holding can be dramaticSeveral minutes in durationDesaturation to 45% (normal- 95-100%If they faint, they will breathe.Can induce seizuresTreatment- difficult to stopMagnesium citrate, Prozac, Buspar, Desipramine

AUTONOMIC NERVOUS SYSTEMHands and feet tend to be cool to coldMore likely in lower extremities; not only cold but red or purple discoloration involving much of lower extremityThought to be due to increased threshold of sympathetic nervous systemDoes not appear to cause discomfortNo specific treatment available

Managment Issues:Gastroenterologic ProblemsWeight lossConstipationBruxismGI refluxSwallowing, chewing difficultiesCalcium deficiencyTreatment: Nutritionist, therapist to aid in feeding, multivitamins, gastrostomy tube

Management Issues: SeizuresMore than 80% have EEG abnormalitiesSome have clinical seizures25-50%Distinguishing true seizures from behaviorsVideo EEG monitoring extremely useful

Management Issues: SeizuresTreat the child not the EEGUsual antiepileptic drugsThe seizures often improve with age

What do I do if my child has a seizure?1. Stay calm2. Safe position3. On side to prevent aspiration4. Don't put anything in the mouth5. Note duration of seizure6. What is moving?7. If it lasts > 5 minutes or there is a color change or breathing difficulty, call 9118. Otherwise, call the pediatrician or take them to the ER after

Management Issues: Respiratory irregularitiesHyperventilation, breathholding, or both are common; may notice forced air expulsionOccur while awakeModified by hunger, agitation, other stressTypically reach maximum in school yearsSignificant air swallowing may occurEffective treatment may be elusive

Respiratory irregularitiesBreath holding can be dramaticSeveral minutes in durationDesaturation to 45% (normal- 95-100%)!!!If they faint, they will breathe.Can induce seizuresTreatment- difficult to stopMagnesium citrate, Prozac, other meds

Management Issues: BehaviorsTeeth grinding, air swallowingStereotypies (splinting, restraints)Poor sleep patternsSelf injurious behaviorsScreaming spellsPain? Frustration? Gall bladder?

Management Issues: Anxiety

Recently recognizedPronounced in mouse modelsClinical trials in miceStress hormone elevatedCortisolMedications in developmentAntidepressants

Managment Issues:StereotypiesInterfere with purposeful hand useWorse when stressedCan and do injure themselvesWhat can you do?Restrain the dominant hand for abuseRestrain the non-dominant hand for usewrist or elbow restraintweightsVelcro

Management Issues:BruxismCan interfere with nutritionDental damage Tends to diminish or disappear after school ageOccurs in almost all girls or womenVaries in frequency and intensityMay increase with anxiety or excitement

Bruxism

Intervention??Separate the teethbite guard chew towel or toyDeter the behaviorElectric toothbrush

Management Issues:NutritionPoor weight gainSupplementsGastrostomy tubesMany have GE refluxConstipation: Probably neurologic in originCan be severe, judicious use of stimulant laxativesMiralax powder (Glycolax)

What is Reflux?When stomach contents move up into the esophaguscan lead to pain, irritability, poor feeding, vomiting, ulcers in esophagus, problems with weight gainDiagnosis: pH probe, swallow studyTreatment: medical, surgicalhttp://www.gerd.com

OSTEOPENIAOccurs in almost all girls or womenWorse with poor calorie-protein intake Fractures much more common; may be unrecognizedUnexplained immobility of limb a red flagRegardless of age, use of oral calcium supplementation should be considered

Management IssuesScoliosis

May progress rapidlyMore risk if non-ambulatory What can you do??Encourage weight bearing: standers, walkers, assisted walkingRegular orthopedic evaluations Bracing or surgeryhttp://www.spine-health.com/

The Autonomic Nervous SystemAutomatic control of things like breathing, heart rate, intestinal function, blood pressureDoes not function properly in RettBrainstem nerve cells involvedPossible imbalance of signals

CARDIAC CONDUCTION SYSTEMCardiac conduction may be immatureProlonged QT interval may be observedAt diagnosis, an electrocardiogram (EKG) should be obtained; likely to be normalIf abnormal, a cardiologist should be seen; medical treatment should be effectiveIf abnormal, other family members should be checked

The Heart: EKG ChangesThe heart is structurally normalProlonged QTc interval, increases with age (50% in Late Motor Stage)Loss of normal heart rate variabilityProposed as cause of sudden, unexpected death

Management IssuesSleep DisturbancesNight waking, screaming, laughingIncreased daytime sleep with age; delayed onset of sleep at nightTreatment: Behavioral modalities Sleep Medications

SLEEP AIDSAntihistamines: limited effectivenessMelatonin may induce sleep, but not prevent arousalsTrazodone and zolpidem may promote full night of sleepChloral hydrate effective but unpalatablePrivate pharmacy may formulate as suppository or capsule

Management IssuesOrthopedic AbnormalitiesEarly truncal ataxiaLegs abductedHypotonic early; hyperreflexive and rigid laterScoliosis (64% prevalence)10% require surgeryTreatment: Brace/surgery for scoliosis, orthopedic and intensive physical therapy, special computers and toys

AMBULATION80% learn to walkAbout 25% lose this ability with regressionOverall, ~ 60% remain ambulatoryOrthotic devices may be needed for toe walkingGreat effort should be exerted to maintain ambulationStanding frames, walkers, or parallel bars should be used at home and school for those who do not walk

OTHER MOTOR SYSTEMSHypotonia the rule during infancyStrength typically normalAfter puberty, motor activities may slow and muscle tone is often increasedIn addition to hand stereotypies, other movements may be seenTremor, myoclonus, or choreiformDystonia may be prominent with ageDrug Treatment available to relieve pain

Management IssuesPathologic FracturesReported to occur in 40% by 15 yrsMore common in children who have never walked, who take AEDsBone loss or lack or normal bone growth?Interleukin 1 from brain needed for normal bone density?

Causes of PAINGastroesophageal reflux (GERD)ConstipationGall bladder diseasePancreatitisH pylori bacteriaAir swallowingMenstrual crampsFracturesToothacheDystonia

Management IssuesGynecologic ConcernsUsually normal onset of puberty, but delayed menarche possible due to decreased body fatMonitor for UTIs and Candida infections Management of periodsDepo ProveraBirth control pillsHysterectomyEndometrial ablation

AdultsMay see resolution of seizuresLoss of motor abilities-?ParkinsonismPremature aging? Fixed joint deformities (preventable?)Breathing betterFeeding abilities stable

Severe Dyspraxia - Motor Planning DifficultyLimits her ability to coordinate speech Limits her ability to gestureMay interfere with the ability to eye gaze touch a switch

Physical StatusAffects her communicabilityWalking to the bathroomWalking to the faucetReaching 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 languageInput is greater than output

Arm, Hand or Elbow SplintsNon- dominant handCan make a big differenceability to use the dominant hand operate a switch choose a picture, object or word by touch

Processing Takes TimeWe give up when she is still trying

Give her lots of time

FluctuationsAttentionBehaviorDay to DayHour to Hour

A Rett Syndrome TruthThe most consistent aspect of Rett syndrome is inconsistency

Health StatusConcentration may be difficult Reflux SeizuresScoliosis Breathing

Making It EasierBe alert to her body languageBe sensitive about what you say in front of herExplore different kinds of communication strategiesShe may not comply because youre 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 languageMinimize distractionsAllow for comfortable seating

Do Not Underestimate HerShe has not lost the will to speak, only the way to speak

Understanding and responding are two different thingsKnowing It and Showing It are Different

Oftentimes, the greatest statements are made insilenceListen with your heart

MOUSE MODELSKnock-out mouse: Mecp2 deleted

Knock-in mouse: Insertion of human mutation in Mecp2

KNOCK-OUT MUTANTNote hind-limb claspingGuy et al. Nature Genetics 2001;27:322-326

Reversibility Studies Knock-out MutantIs 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, tamoxifenRapid re-expression in immature males resulted in death in 50%Guy et al. Science 2007;315:1143-1147

KNOCK-IN MUTANTNote humped back and fore-limb claspingYoung and Zoghbi, Am J Hum Genet 2004;74:511-520

KNOCK-IN MUTANTImpaired hippocampus-dependent social, spatial, and contextual fear memory Impaired long-term potentiation and depressionReduced post-synaptic densitiesNo change in BDNF expressionMoretti 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 MUTANTEnhanced 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 regionMcGill et al. PNAS 2006;103:18267-18272

KNOCK-IN MUTANTImplications 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 HorizonsPTC 124: Small molecule capable of reading through stop codons (nonsense mutations) to produce full length proteinsCurrently in clinical trials for cystic fibrosis and Duchenne muscular dystrophyPre-clinical studies on-going in cell systems and in near future in R168X knock-in mouse model Anxiety studies

We need to be there for one anotherI think this higher survival rate is probably associated with preserved walking and preserved eating in more women with RTT than in most people considered profoundly disabled. The ability to eat and move gives women with RTT a significant protection against being malnourished and getting pneumonias. Most girls with RTT survive into adulthood, but it is the sudden, unexpected death that understandably causes the most anxiety in parents.

Most children with RTT survive into adulthood, so we have to plan for this likelihood. We need to make sure that our county, state and federal governments develop appropriate supports for our children, that there continue to be nonprofit agencies that provide the direct services, and that there is a future for them that is caring and keeps them involved in life. The autonomic nervous system, which controls all the involuntary processes in our bodies, like intestinal movement, breathing, heart rate, blood pressure, does not function normally in Rett syndrome. There is a normal balance between sympathetic and parasympathetic systems. The sympathetic NS is our fight or flight system. This is overactive in Retts or is not adequately balanced out by the parasympathetic (eat and sleep) system. This sympathetic overactivity leads to the cold hands and feet by overconstricting the blood vessels. It may lead to the loss of heart rate variability.Anticonvulsant use was associated with decreased bone density, and there is no evidence to date that calcium supplementation makes up for this. Best study so far from Helen Leonard, DMCN 1999.

There was also an interesting study on the effect of folate and B12 on hip fractures in patients with stroke. These patients had elevated homocystine levels and low levels of folate and B12. Supplementing them with folate and b12 reduced their risk of fracture. Given the persisting fringe interest in folic acid and Rett, I wonder whether we should be measuring homocytine levels in girls with reduced bone density, and if thats elevated, supplementing them. It also shows that keeping an eye on nonpediatric literature can lead to at least ideas that might be useful.Although some adults with Retts continue to live at home, some communities provide community-based living opportunities and even some supported work experiences. These are no longer organized as group homes or sheltered workshops, but as places in the community, like 3 bedroom apartments with live-in staff and two roommates. It is important to try to keep mobility by vigilant attention to joint contractures and strength. However, some of this may just not be preventable.