Rett Syndrome: Developmental

and Medical Guidelines

Eileen A. Dolan, M.D.

Institute for Child Development
Joseph M. Sanzari Children’s Hospital
Hackensack University Medical Center
 Objectives
•
• Review the diagnostic criteria and recommended genetic
testing for Rett Syndrome.
• Review the evidence-based care recommendations for
the management of children diagnosed with Rett
Syndrome.
• Discuss recent research studies and directions for future
research.
Rett Syndrome (RTT)
X-linked neurodevelopmental disorder
almost exclusively occurring in girls
Prevalence of one in 10,000 to 23,000
female births
Less than 1 percent of recorded cases
are inherited
Most cases are sporadic/mutation occurs
randomly, mostly during spermatogenesis
• Characterized by a period of typical
development, followed by stagnation in
development and regression, particularly
in the areas of fine motor skills and
communication
• Distinctive pattern of hand movements
• Acquired microcephaly
• Described in 1966 by Andreas Rett
• First described in English by Hagberg in
1983
• 1999 – mutations in MECP2 gene reported
• Most often caused by mutations in the
MECP2 gene, which is found on the X
chromosome
• MECP2 gene contains instructions for the
synthesis of a protein called methyl
cytosine binding protein 2 (MeCP2)
• MeCP2 acts as a biochemical switch that
tells other genes when to turn off and stop
producing their own unique proteins
• MECP2 gene does not function properly in
those with Rett syndrome insufficient
amounts or structurally abnormal forms of
the protein are formed

• The absence or malfunction of the protein

is thought to cause other genes to be
abnormally expressed
• The majority of girls with Rett syndrome have
the MECP2 genetic mutation
• Remaining cases may be caused by partial
gene deletions, by mutations in other parts of
the gene, or by genes that have not yet been
identified
• Mutations in CDKL5 are believed to cause an
atypical form of Rett Syndrome called the
early-onset seizure variant.
• Greater than 95% of cases of classic RTT
are caused by a mutation in the MECP2
gene.
• Therefore, genetic testing is
recommended if RTT is suspected
• However, a MECP2 mutation is not
specific to RTT, and this mutation is not
necessary to make a diagnosis of RTT.
 Diagnostic Criteria
• Apparently normal prenatal and perinatal history
• Apparently normal early development
• Postnatal deceleration of head size for most children
• Loss of achieved purposeful hand skill ( ½ -2 ½ years)
• Regression in social interaction/interest, motor skills,
communication, cognition, and gait dysfunction
• Development of stereotypic hand movements
• Gait disturbance (dyspraxic or failing locomotion)
 Diagnostic Criteria
• Absence of:
– Organomegaly
– Optic atrophy
– Retinal changes
– Intrauterine growth retardation
• Children with RTT typically progress
through four clinical stages:
1. Stage I Early-onset stagnation
2. Stage II Rapid developmental regression
3. Stage III Pseudostationary period
4. Stage IV Late motor deterioration*

*A few patients with early serious neuromotor impairment

never learn to stand and walk, and thus do not enter
stage III, but progress directly from stage II to stage IV
 Stage I
• Onset: 6 months to 1.5 years
• Developmental progress delayed
• Developmental pattern still not significantly
abnormal
• Duration: weeks to months
 Stage II
• Onset: 1 year to 3 or 4 years
• Loss of acquired skills/communication
• Mental deficiency appears
• Duration: weeks to months, possibly one
year
 Stage III
• Onset: after passing stage II
• Some restitution of communication
• Apparently preserved ambulant ability
• Inapparent, slow neuromotor regression
• Duration: years or decades
 Stage IV
• Onset: when stage III ambulation ceases
• Complete wheelchair dependence
• Severe disability; wasting and distal
distortions
• Duration: decades
• Multiple problems occur in individuals with
RTT, involving the cardiovascular,
respiratory, gastrointestinal,
musculoskeletal and neurologic systems,
among others
• Particular developmental and behavioral
patterns are also observed
•
Management Recommendations
by System
 Cardiovascular
Reduced Heart Rate Variability
• Prolonged QTc (9-55%) – increases risk of
developing life threatening arrhythmias
• Poor peripheral circulation
• -Findings may be present at the time of
diagnosis, however, they may also develop with
later stages
 Recommendations
1) Obtain ECG at diagnosis
2) If ECG is normal, repeat periodically (every few
years)
3) If ECG is abnormal, refer to cardiologist
 Cardiologist may monitor, or start medication
(beta blocker) if indicated
3) If abnormal QTc, avoid medications which can lead
to further QTc prolongation: antipsychotics,
tricyclic antidepressants, prokinetic agents,
antiarrhythmics, and some antibiotics
(erythromycin, ketoconazole)
 Dental

• Bruxism
• Secondary effects of medication

• Recommendation
– Referral to dentist accustomed to working with
children with delays
 Development/ Behavior

• Limited verbal communication

• Limited fine motor skills
• Loss of ambulation
• Repetitive/stereotypic behaviors
• Anxiety
• Periods of laughter, crying, screaming
• Social withdrawal
 Recommendations
1. Early Intervention programming
2. Evaluation by Speech Pathologist
(communication assistance, feeding
evaluation)
3. Braces have been used to limit hand
movements, with limited evidence on
effectiveness
4. Current trials are investigating the effect
of various medications on behavior, social
responsiveness, and communication
 Gastrointestinal/ Nutrition

• Constipation (81-85%), Reflux (30-40%),

Gall bladder disease(3%), Growth
restriction, Feeding difficulties (oromotor
dysfunction 63%, aspiration ), Low vitamin
D, calcium, iron levels
 Recommendations
1) Monitor growth parameters throughout lifespan
2) Treat constipation/reflux as in general pediatric
population
3) Clinical evaluation of oromotor function at diagnosis,
with development of feeding plan
4) Assessment of swallowing function by video-
fluoroscopy at onset of clinic signs
5) Consider alternate methods of feeding if unable to
safely achieve an adequate nutritional intake
6) Consider calcium supplementation
 Growth
• http://www.rettsyndrome.org/understandin
g-rett-syndrome/living-with-rett-
syndrome/symptom-management/health-
matters/growth-references
 Musculoskeletal

• Scoliosis
• Hip dysplasia
• Contractures
• Osteopenia
• Fractures
 Recommendations
1) Monitor for scoliosis every 6 months, X-
ray if evidence of a curve
2) Orthopedic care as indicated
3) Proper positioning and bracing can help
minimize complications
 Neurologic
• Seizures (86% by 20 years of age)
• Vacant spells
• Increased sensitivity to pain
 Recommendations
Medication choice for seizure management
should be determined by seizure type
– most commonly used medications are
carbamazepine, lamotrigine, and
levetiracetam
– Small studies and case reports have shown
positive responses to multiple medications,
including carbamazepine, lamotrigine,
levetiracetam, and topiramate
 Respiratory
• Breath holding spells
• Hyperventilation
• Air swallowing
• Pneumonia
 Recommendations
1) No treatment indicated for breath holding
spells
2) Swallow study if frequent respiratory
infections (possible aspiration)
 Sleep
• Irregular sleep cycle
 Recommendations
1) Monitor for sleep problems and refer for
sleep study as indicated by history
2) Melatonin may be beneficial for sleep
onset (limited good quality evidence)
 Life Expectancy

• Normal survival until age 10

• > 50% survival to age 50 (versus > 95% in

all females and 27% in persons with
profound motor and cognitive
impairments)
• Rett Syndrome Natural History Study
• Rett Syndrome Clinical Trials
• Animal Models
• A Phase 2A Randomized, Placebo Controlled Trial of
EPI-743 in Children with Rett Syndrome
• Safety Study of NNZ-2566 in Patients with Rett
Syndrome
• Treatment of Rett Syndrome With Recombinant Human
IGF-1 (Mecasermin [rDNA]Injection)
• Placebo-controlled Trial of Detromethorphan in Rett
Syndrome
• Autonomic Dysfunction and Seizures in Rett Syndrome
• The Natural History of Osteopenia in Rett Syndrome
• Biliary Tract Disease in Rett Syndrome
 Research
• Dr. Adrian Bird: introducing appropriate
levels of MeCP2 to mice that are severely
compromised by disease will reverse the
symptoms
 Resources
• www.rettsyndrome.org
• www.rett.com
• THE RETT SYNDROME HANDBOOK: Second Edition
•
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