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Rett syndrome: history

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. Worldwide average of 1:15,000 Female Births. Scotland: 1:15,000 Japan: 1:10,000 France: 1:18,000

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Rett syndrome: history

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  1. Rett syndrome: history • 1966: Described by Andreas Rett • 1983: Described in English by Bengt Hagberg Andreas Rett, MD1924-1997

  2. RETT SYNDROME IS A DEVELOPMENTAL • DISORDER • NOT degenerative

  3. 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

  4. 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

  5. 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

  6. 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

  7. 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%

  8. RETT SYNDROME AND MECP2 • RETT SYNDROME IS A CLINICAL DIAGNOSIS • RETT SYNDROME IS NOT SYNONYMOUS WITH MECP2 MUTATIONS • RETT SYNDROME MAY BE SEEN WITHMECP2 MUTATIONS • RETT SYNDROME MAY BE SEEN WITHOUTMECP2 MUTATIONS • MECP2 MUTATIONS MAY BE SEEN WITHOUT RETT SYNDROME

  9. 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

  10. MECP2 Mutation Phenotypes in Females • Infantile encephalopathy • Classic Rett syndrome • Angelman syndrome phenotype • Mental retardation with seizures • Autism • Mild mental retardation • Learning disability • Normal

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

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

  13. 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

  14. Mutations • Mutations in MeCP2 found in >95% “classical” Rett syndrome • Missense, nonsense, frameshift, large scale rearrangements

  15. Two girls with the same mutation can be very different.

  16. 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

  17. DOES MUTATION PREDICT OUTCOME? • R133C, R294X, and R306C mutations and C-termtruncations 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

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

  19. 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.

  20. 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

  21. My (child, sister, brother) has Rett syndrome, but the MECP2 test was negative, what is the chance that I will have a(nother) child with Rett syndrome? • Your Child? • Difficult to say- risk may be somewhat higher than 1% for another child • Your Sister or brother? • Low but not zero • Possibly increased if parents are blood relatives • Need for individual counseling

  22. 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

  23. My daughter with Rett syndrome has a MECP2 mutation. Should I test my other kids? Typically developing: No, not until they are adults and can decide on their own whether they want to be tested • Insurability issues • Bias, understanding the implications Developmental disorder: possibly, need to discuss with their physician

  24. My sister has Rett syndrome and an MECP2 mutation, should I be tested? Adult sister: Possibly Low risk but it is possible to carry it silently.

  25. 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

  26. IRSA North American Database • 85.5% were typical • 13.4% were atypical • 1.1% had MECP2 mutations but did not have RS

  27. N AMERICAN DATABASE 1,928 PATIENTS Lived to AGETOTALLIVING 30+    254         187 40+    82            48 50+    17            11 60+   5             1 70+    1               0

  28. 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

  29. North American Database

  30. North American Database

  31. North American Database

  32. North American Database

  33. North American Database

  34. 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

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

  36. Managment Issues:Respiratory Irregularities • Breath holding can be dramatic • Several minutesin duration • Desaturation to45% (normal- 95-100% • If they faint, they will breathe. • Can induce seizures • Treatment- difficult to stop • Magnesium citrate, Prozac, Buspar, Desipramine

  37. 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

  38. 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

  39. 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

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

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

  42. 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

  43. Respiratory irregularities • Breath holding can be dramatic • Several minutesin duration • Desaturation to45% (normal- 95-100%)!!! • If they faint, they will breathe. • Can induce seizures • Treatment- difficult to stop • Magnesium citrate, Prozac, other meds

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

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

  46. 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 • Velcro

  47. 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

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

  49. 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)

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