Rett syndrome history 1966 Described by Andreas Rett

  • Slides: 87
Download presentation

Rett syndrome: history • 1966: Described by Andreas Rett • 1983: Described in English

Rett syndrome: history • 1966: Described by Andreas Rett • 1983: Described in English by Bengt Hagberg Andreas Rett, MD 1924 -1997

RETT SYNDROME IS A DEVELOPMENTAL DISORDER NOT degenerative

RETT SYNDROME IS A DEVELOPMENTAL DISORDER NOT degenerative

Worldwide average of 1: 15, 000 Female Births • • • Scotland: 1: 15,

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 SYNDROME WHAT DO WE KNOW? § GENETIC DISORDER MAINLY IN FEMALES § VARIABLE

RETT SYNDROME WHAT 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 MECP 2 MUTATIONS

CLINICAL AND MOLECULAR DIAGNOSIS • Clinical Relies on a set of diagnostic criteria that

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

RETT SYNDROME CONSENSUS CRITERIA - 2001 § Normal at birth § Apparently normal early

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

VARIANT EXPRESSIONS – Delayed onset or forme fruste – Preserved speech – Early-onset seizures Diagnosis by variant consensus criteria Variant forms may account for 15 -20% MECP 2 mutations in approximately 50%

RETT SYNDROME AND MECP 2 § RETT SYNDROME IS A CLINICAL DIAGNOSIS § RETT

RETT SYNDROME AND MECP 2 § RETT SYNDROME IS A CLINICAL DIAGNOSIS § RETT SYNDROME IS NOT SYNONYMOUS WITH MECP 2 MUTATIONS § RETT SYNDROME MAY BE SEEN WITHOUT MECP 2 MUTATIONS § MECP 2 MUTATIONS MAY BE SEEN WITHOUT RETT SYNDROME

MECP 2 AND RETT SYNDROME § 8 MUTATIONS ACCOUNT FOR ~ 65% OF THOSE

MECP 2 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

MECP 2 Mutation Phenotypes in Females • • Infantile encephalopathy Classic Rett syndrome Angelman

MECP 2 Mutation Phenotypes in Females • • Infantile encephalopathy Classic Rett syndrome Angelman syndrome phenotype Mental retardation with seizures Autism Mild mental retardation Learning disability Normal

Rett Syndrome Male MECP 2 Phenotypes • Fatal Encephalopathy • Rett/Klinefelter Syndrome • X-Linked

Rett Syndrome Male MECP 2 Phenotypes • Fatal Encephalopathy • Rett/Klinefelter Syndrome • X-Linked MR/Progressive Spasticity • Somatic Mosaicism/NDD • MECP 2 Duplications and X-linked MR

T 158 M (16) F 157 L missense D 156 E F 155 I

T 158 M (16) F 157 L missense D 156 E F 155 I F 155 S R 106 Q R 106 W (12) P 101 T P 101 H P 101 L P 322 A P 152 R (6) S 134 C (2) R 306 H (2) R 306 C (19) R 133 C (7) P 225 R (3) P 302 L P 302 R P 302 A X 487 C D 97 E splice (2) Q 19 X 258 del. CA 411 del. G Y 141 X R 168 X (37) 1053 ins 10 1141 del 55 1096 del 101 1098 del 70 1182 del 7 1116 del 84 R 255 X (23) 1120 del 69 K 256 X 1147 del 170 ins 3 R 198 X 1152 del 41 803 del. G (6) 1152 del 44 807 del. C 1364 ins. C 1156 del 17 R 270 X (16) 1157 del 32 R 294 X (15) 1157 del 41 1194 ins. T 1157 del 44 1193 ins. T 1158 del 10 407 del 507+ ins GCTTTTAG 1159 del 43 1189 ins. A 1162 del 26 1165 del 26 1163 del 35 Q 170 X truncating 620 ins. T 654 del 4 677 ins. A 705 del. G

MUTATION TYPES • Missense – DNA code changed from one amino acid to another;

MUTATION TYPES • Missense – DNA code changed from one amino acid to another; complete Me. CP 2 protein made; example R 133 C • Nonsense – DNA code change does not code for amino acid; incomplete Me. CP 2 made; example R 168 X • Frameshift – insertion or deletion of coding material; incomplete Me. CP 2 made • Large scale rearrangements – large portion of DNA missing; incomplete Me. CP 2 is made

Mutations • Mutations in Me. CP 2 found in >95% “classical” Rett syndrome •

Mutations • Mutations in Me. CP 2 found in >95% “classical” Rett syndrome • Missense, nonsense, frameshift, large scale rearrangements

Two girls with the same mutation can be very different.

Two girls with the same mutation can be very different.

MUTATIONS AND PHENOTYPE • R 294 X Abnormalities of mood • R 225 X

MUTATIONS AND PHENOTYPE • R 294 X Abnormalities of mood • R 225 X and R 270 X Stereotypies of hand/face • R 133 C and R 306 C Milder overall involvement and heightened anxiety and fear • R 168 X more severe

DOES MUTATION PREDICT OUTCOME? • R 133 C, R 294 X, and R 306

DOES MUTATION PREDICT OUTCOME? • R 133 C, R 294 X, and R 306 C mutations and Cterm truncations are associated with “better outcome” – Lower severity scores – Slower progression – Preserved speech variants – Greater anxiety/fear

RESEARCH UPDATE ● Rare Disease Consortium ● Longevity Study ● Mouse Models ● Reversibility

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

Genetic counseling issues • These are general guidelines, individual cases should always be done

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.

Reproductive issues • Parents who are not carriers, have ~1% risk of a second

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

My (child, sister, brother) has Rett syndrome, but the MECP 2 test was negative,

My (child, sister, brother) has Rett syndrome, but the MECP 2 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

My sister has Rett syndrome and an MECP 2 mutation, should I be tested?

My sister has Rett syndrome and an MECP 2 mutation, should I be tested? Adult brother: not really, your risk of having a child with Rett is population riskwould arise by new mutation

My daughter with Rett syndrome has a MECP 2 mutation. Should I test my

My daughter with Rett syndrome has a MECP 2 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

My sister has Rett syndrome and an MECP 2 mutation, should I be tested?

My sister has Rett syndrome and an MECP 2 mutation, should I be tested? Adult sister: Possibly Low risk but it is possible to carry it silently.

Lifespan • First 10 years just like other girls • 95% survive to age

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

IRSA North American Database • 85. 5% were typical • 13. 4% were atypical • 1. 1% had MECP 2 mutations but did not have RS

N AMERICAN DATABASE 1, 928 PATIENTS Lived to AGE 30+ 40+ 50+ 60+ 70+

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

Longevity Study ● Data gathered on 1928 girls and women ● Completion of data

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.

North American Database Total enrolled 1928 Typical 1648 (85. 5 %) Atypical 259 (13. 4 %) Not RS (MECP 2 positive) 21 (1. 1 %)

North American Database Group Total Mutation No mutation Unknown Typical 1648 791 (91%) 79

North American Database Group Total Mutation No mutation Unknown Typical 1648 791 (91%) 79 (9%) 778 Atypical 259 94 (58%) 68 (42%) 97 Not RS 21 21 (100%) 0 0

North American Database Mutation T 158 M R 168 X R 255 X R

North American Database Mutation T 158 M R 168 X R 255 X R 270 X R 306 C R 133 C R 294 X R 106 W N 109 86 83 66 62 59 57 40 % 11. 9 9. 4 9. 0 7. 2 6. 8 6. 4 6. 2 4. 4 Rett. Base % 9. 1 8. 8 7. 9 6. 9 4. 6 4. 4 5. 6 3. 4

North American Database Mutation N % Large deletions 59 6. 4 C-terminal del 81

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 Database Mutation Type N % Missense 356 38. 8 % France (Philippe

North American Database Mutation Type N % Missense 356 38. 8 % France (Philippe et al. ) 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

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

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

Managment Issues: Respiratory Irregularities • Breath holding can be dramatic • Several minutes in

Managment Issues: 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, Buspar, Desipramine

AUTONOMIC NERVOUS SYSTEM • Hands and feet tend to be cool to cold •

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: Gastroenterologic Problems • • Weight loss Constipation Bruxism GI reflux Swallowing, chewing

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: Seizures • • More than 80% have EEG abnormalities Some have clinical

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

Management Issues: Seizures • • • Treat the child not the EEG ‘Usual’ antiepileptic

Management Issues: Seizures • • • Treat the child not the EEG ‘Usual’ antiepileptic drugs The seizures often improve with age

What do I do if my child has a seizure? 1. Stay calm 6.

What do I do if my child has a seizure? 1. Stay calm 6. What is moving? 2. Safe position 3. On side to prevent aspiration 4. Don't put anything in the mouth 5. Note duration of seizure 7. If it lasts > 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

Management Issues: Respiratory irregularities • Hyperventilation, breathholding, or both are common; may notice forced

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

Respiratory irregularities • Breath holding can be dramatic • Several minutes in duration •

Respiratory irregularities • Breath holding can be dramatic • Several minutes in duration • Desaturation to 45% (normal- 95100%)!!! – If they faint, they will breathe. • Can induce seizures • Treatment- difficult to stop • Magnesium citrate, Prozac, other meds

Management Issues: Behaviors • • • Teeth grinding, air swallowing Stereotypies (splinting, restraints) Poor

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

Management Issues: Anxiety • • • Recently recognized Pronounced in mouse models Clinical trials

Management Issues: Anxiety • • • Recently recognized Pronounced in mouse models Clinical trials in mice – Stress hormone elevated – Cortisol • Medications in development – Antidepressants

Managment Issues: Stereotypies • • Interfere with purposeful hand use Worse when stressed Can

Managment Issues: Stereotypies • • 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

Management Issues: Bruxism • • • Can interfere with nutrition Dental damage Tends to

Management Issues: Bruxism • • • 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

Bruxism Intervention? ? Separate the teeth bite guard “chew towel” or toy Deter the

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

Management Issues: Nutrition • Poor weight gain • Supplements • Gastrostomy tubes • Many

Management Issues: Nutrition • 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)

What is Reflux? • When stomach contents move up into the esophagus – can

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: p. H probe, swallow study • Treatment: medical, surgical http: //www. gerd. com

OSTEOPENIA • Occurs in almost all girls or women • Worse with poor calorie-protein

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 Issues Scoliosis • May progress rapidly • More risk if non-ambulatory • What

Management Issues Scoliosis • 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/

The Autonomic Nervous System • Automatic control of things like breathing, heart rate, intestinal

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

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,

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 Issues Sleep Disturbances • Night waking, screaming, laughing • Increased daytime sleep with

Management Issues Sleep 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

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 Issues Orthopedic Abnormalities • • • Early truncal ataxia Legs abducted Hypotonic early;

Management Issues Orthopedic 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

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 •

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 Issues Pathologic Fractures • Reported to occur in 40% by 15 yrs •

Management Issues Pathologic 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

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

Management Issues Gynecologic Concerns • Usually normal onset of puberty, but delayed menarche possible

Management Issues Gynecologic 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

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 •

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

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

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

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

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

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

Fluctuations • Attention • Behavior – Day to Day – Hour to Hour

A Rett Syndrome Truth • The most consistent aspect of Rett syndrome is inconsistency

A Rett Syndrome Truth • The most consistent aspect of Rett syndrome is inconsistency

Health Status • Concentration may be difficult – Reflux – Seizures – Scoliosis –

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

Making It Easier • Be alert to her body language • Be sensitive about

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

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

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 in silence Listen with your heart

Oftentimes, the greatest statements are made in silence Listen with your heart

MOUSE MODELS • Knock-out mouse: Mecp 2 deleted • Knock-in mouse: Insertion of human

MOUSE MODELS • Knock-out mouse: Mecp 2 deleted • Knock-in mouse: Insertion of human mutation in Mecp 2

KNOCK-OUT MUTANT • Note hind-limb clasping Guy et al. Nature Genetics 2001; 27: 322326

KNOCK-OUT MUTANT • Note hind-limb clasping Guy et al. Nature Genetics 2001; 27: 322326

Reversibility Studies Knock-out Mutant ● Is Mecp 2 knock-out reversible? ● Using estrogen receptor

Reversibility Studies Knock-out Mutant ● Is Mecp 2 knock-out reversible? ● Using estrogen receptor controlled Mecp 2 promoter: – Mecp 2 knock-out phenotype reversed in both immature 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 clasping Young and Zoghbi, Am J

KNOCK-IN MUTANT • Note humped back and fore-limb clasping Young 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

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

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

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 – Me. CP 2 binds to Crh promoter methylated region » Mc. Gill et al. PNAS 2006; 103: 18267 -18272

KNOCK-IN MUTANT • Implications of Crh over-expression: – Anxiety plays central role in clinical

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

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 R 168 X knockin mouse model ● Anxiety studies