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Rett's Disorder - Past and Present

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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?

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