Retts Disorder Past and Present

1
Retts 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
• Retts Disorder, Autistic Disorder, Childhood
  Disintegrative Disorder, Aspergers 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 Retts 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 Retts 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

• Retts 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 Retts
  Disorder
• Regression occurs later than Retts Disorder
• Aspergers 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 Retts
  Disorder or other PDD

7
Four Stages of Retts 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 Retts 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 Retts 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 Retts 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 Retts 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
• Retts Disorder in males

12
Genetics of Retts Disorder

• X-linked dominant disorder, lethal in 46,XY males
• Proof of genetic basis of Retts 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 Retts 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
  Retts 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
Retts 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 Retts 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 Retts Disorder

• Cardiorespiratory failure
• Status epilepticus leading to sudden death

22
Summary

• Retts 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 Retts Disorder, but no cure at
  present
• Future studies Gene therapy?