Rett’s Disorder - Past and Present

Lindsay D. de FlescoPenn State College of

MedicineJuly 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

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

Autistic Disorder 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...

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?