Download Overview of Rett Syndrome

Overview of Rett Syndrome
 First described by Dr. Andreas Rett in 1964 but did not receive worldwide
recognition until the first English language publication by Dr. Bengt Hagberg in
1983
 Neurodevelopmental disorder (not a degenerative disorder)
 Onset in early infancy
 Occurs in 1:10,000 to 1:23,000 female births
 Primarily affects girls
 Child appears to be born healthy
 Development appears normal until 6-18 months old
 Often misdiagnosed as autism, cerebral palsy or non-specified developmental
delay
 Occurs in a variety of racial and ethnic groups worldwide
 Several Stages have been identified
Course and Stages of Rett Syndrome
STAGE I: Early Onset
Age: 6 months to 1½ years
Duration: months
 Stage usually overlooked
 Symptoms just emerging and somewhat vague
 May be reduced interest in toys and play activity
 May be decreased eye contact
 Often described as a "good" baby, calm and placid
 May be delays in gross motor milestones
 Non-specific hand wringing
 May be decelerating head growth
STAGE II: Rapid Destructive
Age: 1 to 4 years
Duration: weeks to months
 Rapid onset or more gradual
 Purposeful hand skills and spoken language are lost
 Stereotyped hand movements emerge
o Hand-to-mouth movements as the first expression
o Most often midline hand wringing or hand washing
o Persist while awake but disappear during sleep
o Hand clapping or tapping
o Hands are sometimes clasped behind the back or held at the sides in a
specific pose, with random touching, grasping and releasing.
 Breathing irregularities may emerge
o Breath holding and hyperventilation associated with vacant spells
o Breathing is usually normal during sleep
 Some girls appear autistic-like
o Loss of social interaction and communication
 General irritability and sleep irregularity may be seen
 Periods of tremulousness, especially when excited
 Unsteady gait patterns
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Difficulty initiating motor movements
Slowing of head growth is usually noticed from 3 months - 4 years
STAGE III: Plateau
Age: Pre-school to school years (2-10 years)
Duration: years
 More prominent
o Apraxia
 The inability to perform motor functions
 Perhaps the most severely disabling feature
 Interfering with every body movement, including eye gaze and speech.
o Motor problems
o Severe seizures
 Mental Retardation
 Bruxism (teeth grinding),
 Improvement in behavior
o Less irritability and crying
o Less autistic features
o Show greater interest in surroundings
o Alertness, attention span and communication skills improve
 Many girls with RS remain in Stage III for most of their lifetime
STAGE IV A (Previously ambulant): Late Motor Deterioration
STAGE IV B (Never ambulant): Late Motor Deterioration
Age: When stage III ceases, 5-15-25-? years
Duration: up to decades
 Usually begins after age 10
 Characterized by reduced mobility
o Some stop walking, others have never walked.
o Scoliosis is a prominent feature
o Muscle Wasting
o Rigidity (stiffness)
o Dystonia (increased muscle tone with abnormal extremity or trunk positions)
 no decline in cognition, communication or hand skills
 Repetitive hand movements may decrease.
 Eye gaze/contact usually improves
 Puberty begins at the expected age in most girls
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DSM-IV: Pervasive Developmental Disorder: 299.80 Rett’s Disorder
A. All of the following:
(1) Apparently normal prenatal and perinatal development
(2) Apparently normal psychomotor development through the first 5 months after birth
(3) Normal head circumference at birth
B. Onset of all of the following after the period of normal development:
(1) Decelaration of head growth between ages 5 and 48 months
(2) Loss of previously acquired purposeful hand skills between ages 5 and 30 months
with the subsequent development of stereotyped hand movements (e.g., hand-wringing
or hand washing)
(3) Loss of social engagement early in the course (although often social interaction
develops later)
(4) Appearance of poorly coordinated gait or trunk movements
(5) Severely impaired expressive and receptive language development with severe
psychomotor retardation
Recent Revised diagnostic criteria for Rett Syndrome
Hagberg B, Hanefeld F, Percy A, Skjeldal O. An update on clinically applicable
diagnostic criteria in Rett syndrome. European J of Paediatric Neurology 2002; 6: 293297
 IRSA convened a panel of international experts as part of the European Pediatric
Neurology Society.
 Based on the correlation between genotypes (gene mutations) and phenotypes
(symptoms).
 Includes information on atypical or borderline variants of RS.
 The diagnosis of RS remains a clinical one and is not made solely on the basis of
MECP2 mutations. This means that RS can occur with or without mutations in
MECP2, and MECP2 mutations can occur without the diagnosis of RS.
Diagnostic Criteria: Typical
A. Necessary criteria
1.apparently normal prenatal and perinatal history
2.psychomotor development largely normal through the first six months or may be
delayed from birth
3.normal head circumference at birth
4.postnatal deceleration of head growth in the majority
5.loss of achieved purposeful hand skill between ages ½ - 2½ years
6.stereotypic hand movements such as hand wringing/squeezing, clapping/tapping,
mouthing and washing/rubbing automatisms
7.emerging social withdrawal, communication dysfunction, loss of learned words, and
cognitive impairment
8.impaired (dyspraxic) or failing locomotion
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B. Supportive criteria
1.awake disturbances of breathing (hyperventilation, breath-holding, forced expulsion of
air or saliva, air swallowing
2.bruxism
3.impaired sleep pattern from early infancy
4.abnormal muscle tone successively associated with muscle wasting and dystonia
5.peripheral vasomotor disturbances
6.scoliosis/kyphosis progressing through childhood
7.growth retardation
8.hypotrophic small and cold feet; small, thin hands
C. Exclusion criteria
1.organomegaly or other signs of storage disease
2.retinopathy, optic atrophy, or cataract
3.evidence of perinatal or postnatal brain damage
4.existence of identifiable metabolic or other progressive neurological disorder
5.acquired neurological disorder resulting from severe infections or head trauma
Revised delineation of variant phenotypes: Atypical or Borderline
-15% of total number of diagnosed cases
A. Inclusion criteria
1.meet at least 3 of 6 main criteria
2.meet at least 5 of 11 supportive criteria
B. Six main criteria
1.absence or reduction of hand skills
2.reduction or loss of babble speech
3.monotonous pattern to hand stereotypies
4.reduction or loss of communication skills
5.deceleraton of head growth from first years of life
6.RS disease profile: a regression stage followed by a recovery of interaction
contrasting with slow neuromotor regression
C. Eleven supportive criteria
1.breathing irregularities
2.bloating/air swallowing
3.teeth grinding, harsh sounding type
4.abnormal locomotion
5.scoliosis/kyphosis
6.lower limb amyotrophy
7.cold, purplish feet, usually growth impaired
8.sleep disturbances including night screaming outbursts
9.laughing/screaming spells
10.diminished response to pain
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11.intense eye contact/eye pointing
Pathogenesis
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Genetic Disorder
o Caused by a mutations or a defective regulatory MECP2 gene
o X chromosome
o Usually Sporadic Mutation, (most often on father’s sperm)
 Not inherited: less than 1 percent of recorded cases are inherited or
passed from one generation to the next.
o MECP2 is believed to control the functions of several other genes
 contains instructions for the synthesis of a protein called methyl
cytosine binding protein 2 (MeCP2), which acts as one of the many
biochemical switches that tell other genes when to turn off and stop
producing their own unique proteins.
 In RS, insufficient amounts of the protein are formed.
 The absence of the protein causes other genes to be switched on
and stay on at inappropriate stages, forming excessive amounts of
proteins, causing the neurodevelopmental problems that are
characteristic of the disorder.
o Not all children with Rett’s have mutations of the MECP2 gene
 70-90% with “classical” RS
 0-30% with atypical RS
Why Rett’s is seen almost exclusively in females
o Since males have an X and a Y chromosome, they lack a "backup" copy
of the X chromosome that can compensate for a defective one
o mutations in MECP2 are typically lethal to the male fetus
Central Nervous System
 Reduced Brain Weight
 Reductions in Volume
o Frontal Cortex: Most Vulnerable
o Caudate Nucleus
 Reduced Melanin in Substantia Nigra
 Smaller Neurons
Treatment
 No cure for Rett syndrome
 Treatment is symptomatic — focusing on the management of symptoms
 Medication may be needed for breathing irregularities and motor difficulties, and
antiepileptic drugs may be used to control seizures.
 There should be regular monitoring for scoliosis and possible heart abnormalities
 Occupational therapy
 Physiotherapy
 Hydrotherapy may prolong mobility
 Nutritionists to help them maintain adequate
 Special academic, social, vocational, and support services
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Future: Stem Cell and Gene Therapy
Long-Term Prognosis
 Little is known
 Females have a 95% chance of surviving to 25 years old
 Morbidity often related to seizure disorder or swallowing difficulties
More information
International Rett Syndrome Association (IRSA)
9121 Piscataway Road
Suite 2B
Clinton, MD 20735
[email protected]
http://www.rettsyndrome.org
Tel: 301-856-3334 800-818-RETT (7388)
Fax: 301-856-3336
Rett Syndrome Research Foundation (RSRF)
4600 Devitt Drive
Cincinnati, OH 45246
[email protected]
http://www.rsrf.org
Tel: 513-874-3020
Fax: 513-874-2520
Easter Seals
230 West Monroe Street
Suite 1800
Chicago, IL 60606-4802
[email protected]
http://www.easter-seals.org
Tel: 312-726-6200 800-221-6827
Fax: 312-726-1494
National Institute of Child Health and Human Development (NICHD)
National Institutes of Health
Bldg. 31, Rm. 2A32
Bethesda, MD 20892-2425
[email protected]
http://www.nichd.nih.gov
Tel: 301-496-5133 800-370-2943
http://www.ninds.nih.gov/health_and_medical/pubs/rett.htm
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