Rett Syndrome Pervasive Developmental Disorder

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Rett Syndrome Pervasive Developmental Disorder Powered By Docstoc
					Rett’s Disorder - Past and
Present

      Lindsay D. de Flesco
  Penn State College of Medicine
            July 2001
    Introduction
   Pervasive Developmental Disorder (PDD)
       Key Features:
            Delay or loss of appropriate social skills, language, and
             behavior
            Affects many developmental areas, starting early and
             persisting throughout life
       Examples:
            Rett’s Disorder, Autistic Disorder, Childhood
             Disintegrative Disorder, Asperger’s Disorder, Pervasive
             Developmental Disorder Not Otherwise Specified
    History
   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
   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) 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
   Rett’s Disorder                             Autistic Disorder
       Mostly females                              Mostly males
       Deterioration in developmental              Abnormalities present from
        milestones, head circumference,              birth
        overall growth
       Loss of purposeful hand
        movements                                   Stereotypic hand movements
       Stereotypic hand movements                   not always present
        (hand-wringing, hand washing,               Little to no loss in gross motor
        hand-to-mouth)                               function
       Poor coordination, ataxia, apraxia          Aberrant language, but not
       Loss of verbalization                        complete loss
       Respiratory irregularity                    No respiratory irregularity
       Early seizures                              Seizures rare; if occur, develop
       Low CSF nerve growth factor                  in adolescence
                                                    Normal CSF nerve growth
                                                     factor
    Differential Diagnosis Continued...
   Childhood Disintegrative Disorder
       Lacks the characteristic deficits of Rett’s Disorder
       Regression occurs later than Rett’s Disorder

   Asperger’s Disorder
       Marked restriction of interests, activities, and behaviors
       No significant impairment of language, cognition, or
        adaptive behaviors

   Pervasive Developmental Disorder Not
    Otherwise Specified
       Lacks the characteristic deficits of Rett’s Disorder or other
        PDD
Four Stages of Rett’s Disorder
   Stage I: Early-onset stagnation
       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...
   Stage II: Rapid developmental regression
       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...
   Stage III: Pseudostationary period
       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...
   Stage IV: Late motor deterioration
       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
   Atypical, or “Forme fruste”
       Characteristics first appear in late childhood
   Late childhood regression
       Early psychomotor delay; regression later in
        childhood
   Congenital
       Lacks initial period of normal development
   Familial
   Preserved speech
   Rett’s Disorder in males
    Genetics of Rett’s Disorder
   X-linked dominant disorder, lethal in 46,XY males
   Proof of genetic basis of Rett’s Disorder
        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-CpG-
         binding protein 2 and usually undergoes inactivation
        2000: Missense mutations = milder phenotype
    Rett’s Disorder in 47,XXY Male

   Case described by Dr. Schwartzman, et al.
       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
   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
   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
   Cyanotic spells while awake due to central
    apnea and hyperventilation
   Treatment: Acetazolamide for
    hyperventilation
Sleep Disturbances and Treatment
   Night waking, screaming, laughing
   Increased daytime sleep with age; delayed
    onset of sleep at night
   Treatment: Behavioral modalities
Orthopedic Abnormalities, Motor
Disturbances, and Treatment
   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
   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
   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
   Cardiorespiratory failure
   Status epilepticus leading to sudden death
    Summary
   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?