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. 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

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?