Rett’s Disorder - Past and Present

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

2. 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

3. 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

4. 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

5. 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

6. 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

7. 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

8. 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

9. 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

10. 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

11. 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

12. 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

13. 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

14. 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

15. 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

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

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

18. 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

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

20. 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

21. End-Stage Rett’s Disorder • Cardiorespiratory failure • Status epilepticus leading to sudden death

22. 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?