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?