Rett’s Disorder – Past and Present

Rett’s Disorder – Past and Present
Lindsay D. de Flesco
Penn State College of Medicine
2001

Introduction
n     Pervasive Developmental Disorder (PDD)
n    Key Features:
n    Delay or loss of appropriate social skills, language, and behavior
n    Affects many developmental areas, starting early and persisting throughout life
n    Examples:
n    Rett’s Disorder, Autistic Disorder, Childhood Disintegrative Disorder, Asperger’s Disorder, Pervasive Developmental Disorder Not Otherwise Specified

History
n      1966 – Dr. Andreas Rett of Austria observed two females with unusual hand-wringing motions
n      1983 – Dr. Bengt Hagberg of Sweden published comprehensive review of Rett’s Disorder in an English neurology journal
n      1984 – First International Rett Syndrome Conference in Vienna
n      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
n      A.  All of the following:
n      (1) apparently normal prenatal and perinatal development
n      (2) apparently normal psychomotor development through the first 5 months after birth
n      (3) normal head circumference at birth
n      B.  Onset of all of the following after the period of normal development:
n      (1) deceleration of head growth between ages 5 and 48 months
n      (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)
n      (3) loss of social engagement early in the course (although often social interaction develops later)
n      (4) appearance of poorly coordinated gait or trunk movements
n      (5) severely impaired expressive and receptive language development with severe psychomotor retardation

Differential Diagnosis
n      Rett’s Disorder
n      Mostly females
n      Deterioration in developmental milestones, head circumference, overall growth
n      Loss of purposeful hand movements
n      Stereotypic hand movements (hand-wringing, hand washing, hand-to-mouth)
n      Poor coordination, ataxia, apraxia
n      Loss of verbalization
n      Respiratory irregularity
n      Early seizures
n      Low CSF nerve growth factor

n      Autistic Disorder
n      Mostly males
n      Abnormalities present from birth
n      Stereotypic hand movements not always present
n      Little to no loss in gross motor function
n      Aberrant language, but not complete loss
n      No respiratory irregularity
n      Seizures rare; if occur, develop in adolescence
n      Normal CSF nerve growth factor

n      Childhood Disintegrative Disorder
n     Lacks the characteristic deficits of Rett’s Disorder
n     Regression occurs later than Rett’s Disorder

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

n      Pervasive Developmental Disorder Not Otherwise Specified
n     Lacks the characteristic deficits of Rett’s Disorder or other PDD

Four Stages of Rett’s Disorder
n     Stage I:  Early-onset stagnation
n    Onset: Six months – 1.5 years old
n    Delayed development, but not significantly abnormal
n    Deceleration of head growth
n    Disinterest in surroundings
n    Hypotonia
n    Normal EEG (or minimal slowing)
n    Duration: Weeks to months

n     Stage II:  Rapid developmental regression
n     Onset: One to 3 or 4 years old
n     Loss of acquired skills and communication
n     Mental deficiency appears
n     Irritability
n     Loss of purposeful hand movements
n     Stereotypic hand movements develop (hand-wringing, hand washing, hand-to-mouth)
n     Loss of expressive language
n     Insomnia
n     Self-abusive behavior
n     Occasional seizures
n     EEG:  background slowing with loss of normal sleep patterns; screaming and sleep disturbances
n     Duration: Weeks up to one year

n     Stage III:  Pseudostationary period
n     Onset: After passing Stage II
n     Some restitution of communication
n     Preserved ambulation
n     Increasing ataxia, hyperreflexia, and rigidity
n     Hyperventilation when awake, followed by sleep apnea
n     Bruxism
n     Weight loss
n     Scoliosis
n     EEG: some epileptiform activity
n     Happy disposition; enjoy close physical contact
n     Truncal ataxia
n     Duration: Years to decades

n     Stage IV:  Late motor deterioration
n     Onset: Ceasing of ambulation
n     Complete wheelchair dependence
n     Severely disabled and distorted
n     Progressive muscle wasting, spasticity, and scoliosis
n     Growth retardation
n     Cool extremities due to venous stasis
n     Constipation
n     Fewer Seizures
n     Duration: Decades

Variant Forms of Rett’s Disorder
n     Atypical, or “Forme fruste”
n    Characteristics first appear in late childhood
n     Late childhood regression
n    Early psychomotor delay; regression later in childhood
n     Congenital
n    Lacks initial period of normal development
n     Familial
n     Preserved speech
n     Rett’s Disorder in males

Genetics of Rett’s Disorder
n      X-linked dominant disorder, lethal in 46,XY males
n      Proof of genetic basis of Rett’s Disorder
n     Confirmed only in females and males with an extra X chromosome
n     Complete concordance in monozygotic twins
n     1989:  First vertical transmission identified
n     1990:  Drs. Zoghbi, Percy, and Schultz discovered nonrandom X inactivation in the mother of two half-sisters with Rett’s Disorder
n     1998:  Drs. Sirianni, Naidu, and Pereira confirmed X-linked dominant inheritance, localizing gene to Xq28
n     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
n     2000:  Missense mutations = milder phenotype

Rett’s Disorder in 47,XXY Male
n     Case described by Dr. Schwartzman, et al.
n     47,XXY male born in January 1995
n     Normal prenatal and perinatal periods
n     Eight months – could sit without support and speak
n     Eleven months – lost hand function, head growth deceleration
n     One year – stereotypical hand movements, bruxism, constipation
n     Twenty eight months – global retardation, hypotonia
n     Thirty seven months – increasingly severe apnea
n     Conclusion:  Two X chromosomes are needed for the manifestations of Rett’s Disorder

Neurologic Abnormalities and Treatment
n     Seizures in 75%, most severe earlier in life
n     Abnormal EEG in 100%
n     Truncal ataxia
n     Treatment:  Carbamazepine for seizures, ketogenic diet for seizures and motor function

Gastroenterologic Abnormalities and Treatment
n     Weight loss
n     Constipation
n     Bruxism
n     GI reflux
n     Swallowing, chewing difficulties
n     Calcium deficiency
n     Treatment:  Nutritionist, therapist to aid in feeding, multivitamins, gastrostomy tube

Respiratory Abnormalities and Treatment
n     Cyanotic spells while awake due to central apnea and hyperventilation
n     Treatment:  Acetazolamide for hyperventilation

Sleep Disturbances and Treatment
n     Night waking, screaming, laughing
n     Increased daytime sleep with age; delayed onset of sleep at night
n     Treatment:  Behavioral modalities

Orthopedic Abnormalities, Motor Disturbances, and Treatment
n     Early truncal ataxia
n     Agitation
n     Legs abducted
n     Hypotonic early; hyperreflexive and rigid later
n     Scoliosis (64% prevalence)
n     Treatment:  Brace/surgery for scoliosis, orthopedic and intensive physical therapy, special computers and toys

Gynecologic Concerns
n     Usually normal onset of puberty, but delayed menarche possible due to decreased body fat
n     Monitor for UTIs and Candida infections

Communicative and Cognitive Concerns and Treatment
n     Babbling, single words by 10-12 months; lose verbalization by 18 months
n     Impaired cerebral cortex due to language loss
n     More quiet, improved eye contact with time
n     Happy disposition
n     Treatment:  Speech/language therapy, music therapy

End-Stage Rett’s Disorder
n     Cardiorespiratory failure
n     Status epilepticus leading to sudden death

Summary
n      Rett’s Disorder is a type of Pervasive Developmental Disorder with severely impaired social skills, language, behavior, and motor function
n      Affects females and males with 47,XXY karyotype
n      Normal initial development, regression after 6 months
n      Consists of four stages of progressive deterioration
n      X-linked dominant inheritance; caused by mutations in MECP2 gene
n      Various therapeutic modalities for individual dysfunctions of Rett’s Disorder, but no cure at present
n      Future studies: Gene therapy?