Rett’s Disorder - Past and
Present
Lindsay D. de Flesco
Penn State College of Medicine
July 2001
Introduction
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Pervasive Developmental Disorder (PDD)
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Key Features:
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Delay or loss of appropriate social skills, language, and
behavior
Affects many developmental areas, starting early and
persisting throughout life
Examples:
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Rett’s Disorder, Autistic Disorder, Childhood Disintegrative
Disorder, Asperger’s Disorder, Pervasive Developmental
Disorder Not Otherwise Specified
History
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1966 - Dr. Andreas Rett of Austria observed two
females with unusual hand-wringing motions
1983 - Dr. Bengt Hagberg of Sweden published
comprehensive review of Rett’s Disorder in an English
neurology journal
1984 - First International Rett Syndrome Conference
in Vienna
1985 - Dr. Hugo Moser organized first North American
International Rett Syndrome Conference in Baltimore,
MD; International Rett Syndrome Association
established
DSM-IV: Diagnosis of Rett’s Disorder
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A. All of the following:
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(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:
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(1) deceleration 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
Differential Diagnosis
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Rett’s Disorder
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Mostly females
Deterioration in developmental
milestones, head circumference,
overall growth
Loss of purposeful hand
movements
Stereotypic hand movements
(hand-wringing, hand washing,
hand-to-mouth)
Poor coordination, ataxia, apraxia
Loss of verbalization
Respiratory irregularity
Early seizures
Low CSF nerve growth factor
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Autistic Disorder
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Mostly males
Abnormalities present from
birth
Stereotypic hand movements
not always present
Little to no loss in gross motor
function
Aberrant language, but not
complete loss
No respiratory irregularity
Seizures rare; if occur, develop
in adolescence
Normal CSF nerve growth factor
Differential Diagnosis Continued...
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Childhood Disintegrative Disorder
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Asperger’s Disorder
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Lacks the characteristic deficits of Rett’s Disorder
Regression occurs later than Rett’s Disorder
Marked restriction of interests, activities, and behaviors
No significant impairment of language, cognition, or
adaptive behaviors
Pervasive Developmental Disorder Not
Otherwise Specified
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Lacks the characteristic deficits of Rett’s Disorder or other
PDD
Four Stages of Rett’s Disorder
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Stage I: Early-onset stagnation
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Onset: Six months - 1.5 years old
Delayed development, but not significantly
abnormal
Deceleration of head growth
Disinterest in surroundings
Hypotonia
Normal EEG (or minimal slowing)
Duration: Weeks to months
Four Stages of Rett’s Disorder
Continued...
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Stage II: Rapid developmental regression
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Onset: One to 3 or 4 years old
Loss of acquired skills and communication
Mental deficiency appears
Irritability
Loss of purposeful hand movements
Stereotypic hand movements develop (hand-wringing, hand washing,
hand-to-mouth)
Loss of expressive language
Insomnia
Self-abusive behavior
Occasional seizures
EEG: background slowing with loss of normal sleep patterns; screaming
and sleep disturbances
Duration: Weeks up to one year
Four Stages of Rett’s Disorder
Continued...
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Stage III: Pseudostationary period
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Onset: After passing Stage II
Some restitution of communication
Preserved ambulation
Increasing ataxia, hyperreflexia, and rigidity
Hyperventilation when awake, followed by sleep apnea
Bruxism
Weight loss
Scoliosis
EEG: some epileptiform activity
Happy disposition; enjoy close physical contact
Truncal ataxia
Duration: Years to decades
Four Stages of Rett’s Disorder
Continued...
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Stage IV: Late motor deterioration
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Onset: Ceasing of ambulation
Complete wheelchair dependence
Severely disabled and distorted
Progressive muscle wasting, spasticity, and scoliosis
Growth retardation
Cool extremities due to venous stasis
Constipation
Fewer Seizures
Duration: Decades
Variant Forms of Rett’s Disorder
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Atypical, or “Forme fruste”
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Late childhood regression
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Early psychomotor delay; regression later in
childhood
Congenital
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Characteristics first appear in late childhood
Lacks initial period of normal development
Familial
Preserved speech
Rett’s Disorder in males
Genetics of Rett’s Disorder
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X-linked dominant disorder, lethal in 46,XY males
Proof of genetic basis of Rett’s Disorder
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Confirmed only in females and males with an extra X chromosome
Complete concordance in monozygotic twins
1989: First vertical transmission identified
1990: Drs. Zoghbi, Percy, and Schultz discovered nonrandom X
inactivation in the mother of two half-sisters with Rett’s Disorder
1998: Drs. Sirianni, Naidu, and Pereira confirmed X-linked
dominant inheritance, localizing gene to Xq28
1999: Drs. Amir, Van den Veyver, and Wan linked Rett’s Disorder to
mutations in X-linked MECP2 gene, which encodes methyl-CpGbinding protein 2 and usually undergoes inactivation
2000: Missense mutations = milder phenotype
Rett’s Disorder in 47,XXY Male
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Case described by Dr. Schwartzman, et al.
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47,XXY male born in January 1995
Normal prenatal and perinatal periods
Eight months - could sit without support and speak
Eleven months - lost hand function, head growth
deceleration
One year - stereotypical hand movements, bruxism,
constipation
Twenty eight months - global retardation, hypotonia
Thirty seven months - increasingly severe apnea
Conclusion: Two X chromosomes are needed for the
manifestations of Rett’s Disorder
Neurologic Abnormalities and
Treatment
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Seizures in 75%, most severe earlier in life
Abnormal EEG in 100%
Truncal ataxia
Treatment: Carbamazepine for seizures,
ketogenic diet for seizures and motor function
Gastroenterologic Abnormalities and
Treatment
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Weight loss
Constipation
Bruxism
GI reflux
Swallowing, chewing difficulties
Calcium deficiency
Treatment: Nutritionist, therapist to aid in
feeding, multivitamins, gastrostomy tube
Respiratory Abnormalities and
Treatment
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Cyanotic spells while awake due to central
apnea and hyperventilation
Treatment: Acetazolamide for
hyperventilation
Sleep Disturbances and Treatment
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Night waking, screaming, laughing
Increased daytime sleep with age; delayed
onset of sleep at night
Treatment: Behavioral modalities
Orthopedic Abnormalities, Motor
Disturbances, and Treatment
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Early truncal ataxia
Agitation
Legs abducted
Hypotonic early; hyperreflexive and rigid later
Scoliosis (64% prevalence)
Treatment: Brace/surgery for scoliosis,
orthopedic and intensive physical therapy,
special computers and toys
Gynecologic Concerns
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Usually normal onset of puberty, but delayed
menarche possible due to decreased body fat
Monitor for UTIs and Candida infections
Communicative and Cognitive
Concerns and Treatment
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Babbling, single words by 10-12 months; lose
verbalization by 18 months
Impaired cerebral cortex due to language loss
More quiet, improved eye contact with time
Happy disposition
Treatment: Speech/language therapy,
music therapy
End-Stage Rett’s Disorder
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Cardiorespiratory failure
Status epilepticus leading to sudden death
Summary
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Rett’s Disorder is a type of Pervasive Developmental
Disorder with severely impaired social skills,
language, behavior, and motor function
Affects females and males with 47,XXY karyotype
Normal initial development, regression after 6 months
Consists of four stages of progressive deterioration
X-linked dominant inheritance; caused by mutations
in MECP2 gene
Various therapeutic modalities for individual
dysfunctions of Rett’s Disorder, but no cure at present
Future studies: Gene therapy?