Handbook of Genetic Counseling/Rett Syndrome

Rett Syndrome


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Intake and Family HistoryEdit

  • Development during first 6-18 months (should be normal)?
  • Recent development - will see rapid regression in language and motor skills?
  • Loss of purposeful hand use? Repetitive hand movement?
  • Screaming fits and inconsolable crying (18-24 months)?
  • Autistic features?
  • Apnea or hyperpnea?
  • Tremors and acquired microcephaly?
  • Seizures?


  • Progressive neurological disorder characterized by normal birth and normal psychomotor development until 6-18 months when see rapid regression
    • Affects girls
    • Diagnosis based on clinical or molecular basis
  • X-linked dominant inheritance
    • About 99.5% of cases are sporadic
      • Result from de novo mutation or from one parent who has somatic or germline mosaicism
      • Mother may have favorable skewed X-inactivation that results in her being unaffected or only slightly affected
    • Risks to siblings depends on status of parents
      • When mother of affected has MECP2 mutation, risk to inherit mutation is 50%
      • If mutation is not identified in parents, risk to low but germline mosaicism cannot be excluded
      • Healthy sisters of girl with Rett syndrome could be carriers with no symptoms due to skewed X-inactivation
    • Females who reproduce have 50% chance of passing on mutation
      • Daughters who inherit mutation at high risk to develop classic Rett syndrome
      • Skewed X inactivation in girls may result in milder phenotype
      • Sons who inherit mutation may suffer severe neonatal encephalopathy or have severe mental retardation syndrome - usually result in miscarriage
  • Due to mutations in MECP2 gene
    • Located at Xq28
    • Methyl-CpG-binding protein 2 (MeCP2)
      • Expressed in all tissues
      • Thought to be global transcriptional repressor, and mutation disrupts gene expression during development
      • Most active in brain tissue
  • Prevalence is estimated to be 1:10,000 to 1:15,000

Clinical FeaturesEdit

  • Normal course of development but may have mild hypotonia
    • Poor suck or weak cry
    • Generally very placid
  • Stage I (early onset)
    • Generally begins between 6 and 18 months of age
      • Symptoms are vague and often overlooked
      • Lasts for a few months to a year
    • Infants show less eye contact and less interested in toys
    • Delays in gross motor skills such as crawling or sitting
    • Handwringing and decreasing head growth are mild
  • Stage II (rapid destructive stage)
    • Begins between ages 1 and 4 years old
      • Lasts for weeks or months
      • May have rapid or gradual onset
    • Purposeful hand skills and spoken language lost
      • May being wringing, washing, clapping, tapping, or hand-to mouthing
      • Hands sometimes clasped behind back or at sides with random touching, grasping, and releasing
      • Movements persist while awake but disappear during sleep
      • Often screaming fits and inconsolable crying
    • May see breathing irregularities
      • Apnea and hyperventilation
      • Breathing normal during sleep
    • Autistic-like behaviors
      • Loss of social interaction and communication
      • General irritability and sleep irregularities
    • Gait patterns unsteady and difficult to initiate movements
    • Slowing of head growth is noticeable
      • Brain size may eventually be 30% smaller than normal
      • May begin to notice change as early as 3 months
    • Gastrointestinal findings
      • About 85-90% of girls have general growth failure and wasting
      • Oropharyngeal and gastroesophageal incoordination may result in poor food intake
      • Bowel dysmotility, constipation, and functional megacolon common
      • Fecal impaction, volvulus, and intussusception can occur
      • May also involve gallstones
  • Stage III (plateau or pseudostationary stage)
    • Begins between ages 2 and 10
      • Can last for years
      • Many girls remain in this stage for most of their lives
    • Apraxia, motor problems common during this stage
    • Seizures occur in about 50% of girls
      • Tonic-clonic and partial complex are most common
      • Occur more frequently once disease stabilizes
    • Improvement in behavior with less irritability, crying, and autistic-like features
    • May show more interest in her surroundings
      • Alertness and attention span may improve
      • Communication skills may also improve
    • Osteoporosis is problem, possibly due to poor bone formation - results in fractures
  • Stage IV (late motor deterioration stage)
    • Can last for years or decades
    • Characterized by reduced mobility
      • Muscle weakness, rigidity (stiffness), spasticity, dystonia (increased muscle tone with abnormal posturing of extremity or trunk), and scoliosis
      • Girls may stop walking
      • Generally no decline in cognition, communication, or hand skills
      • Repetitive hand movements may decrease
      • Eye gaze usually improves
  • Girls typically survive into adulthood
    • Incidence of sudden, unexplained death significantly higher
    • May be due to reduced heart rate variability and neurological differences
  • Atypical Rett syndrome
    • Females have mild learning disability or a few women with no symptoms and skewed X-inactivation
    • Mutations have been found in those previously diagnosed with autism, mild learning disability, and Angelman syndrome
  • Males
    • Males meeting clinical phenotype have been found with 47,XXY and mosaicism for MECP2 mutations
    • Males with 46,XY can also (rarely) be affected

Diagnosis/Testing OptionsEdit

  • Clinical diagnosis
    • Requires following:
      • Apparently normal prenatal and perinatal period
      • Normal head circumference at birth
      • Apparently normal development through age six months
      • Deceleration of head growth occurring anytime between ages three and 48 months
      • Loss of acquired hand skills and purposeful hand use between ages five and 30 months, with subsequent development of stereotyped hand movements
      • Severe impairment of expressive and receptive language together with severe psychomotor retardation
      • Development of gait apraxia and truncal ataxia between ages 12 and 48 months
    • Limitations
      • May be considered tentative until patient is 2-5 years old
      • Broad clinical variability
        • Some girls do lose purposeful hand motion and have seizures but can walk and retain some speech
        • Some girls severe with no period of normal development
        • Some girls have less dramatic regression and milder mental retardation
  • Biochemical laboratory studies not helpful
  • Mutation analysis
    • Used to confirm diagnosis in patients or family members of patients
    • Bi-directional sequencing
      • Detects mutations in about 80% of patients
      • Can also do PCR based DHPLC or combination of both
    • Must be sure mutation is disease-causing and not polymorphism (truncating or previously reported)
    • Baylor College of Medicine
      • MECP2 testing using PCR amplification of 3 exons
      • 14cc for adults or 6cc for child in purple top EDTA tube
      • CPT codes 83891, 83898x5, 83904x5, 83912 for index case; 83891, 83898x1, 83904x1, and 83912 (for other family members)
  • X-chromosome inactivation
    • Useful in family with several children having various MECP2 mutation phenotypes but asymptomatic mother
    • Mother may have mutation but XCI pattern causes her to have no clinical signs
    • Not used for diagnosis in at-risk family members
  • Prenatal testing
    • Prenatal diagnosis offered to women with known MECP2 mutations
      • Male fetus will at best survive with severe mental retardation
      • Phenotype in female difficult to predict since depends on X-inactivation
    • Also offered whether or not disease-causing mutation is identified in parent because of germline mosaicism


  • No treatment known to improve neurologic outcome
    • Several trials have had questionable efficacy and outcomes
    • Tried naltrexone (oral opiate agonist) and L-carnitine
  • Management is supportive and symptomatic therapy
    • Low dose risperidone for agitation or other selective seratonin uptake inhibitors
    • May also try chloral hydrate, hydroxyzine, or diphenhydramine with melatonin
    • Carbidopa/levodopa for rigidity but benefit not proven
    • Melatonin may help sleep disturbances
    • Try controlling diet to help with constipation
      • Ample fluid intake and high fiber diet can help prevent crisis
      • May use stool softeners
    • Anti-reflux agents, smaller and thickened feedings, and positioning can help with reflux
  • Video/EEG studies can give definitive information about seizures and need for antiepileptic
  • Occupational and physical therapy to maintain function and prevent scoliosis
  • Music therapy may be beneficial to girls to improve receptive and expressive language
  • Mental function is not impaired!

Differential DiagnosisEdit

  • Infantile neuronal ceroid lipofuscinosis
    • Loss of motorskills and seizures, dementia, and spasticit
    • Have retinal dystrophy with blindness not seen in Rett syndrome
    • Relies on electron microscopic findings on tissue biopsy, analysis of PPT-1 enzyme, or mutation analysis of CLN1 gene
  • Autism
    • Common diagnosis of girls with Rett syndrome without microcephaly, seizures, kyphoscoliosis
    • No clinical criteria can distinguish between them
  • Angelman syndrome
    • Mental deficiency, seizures, ataxia, hand stereotypes, and microcephaly
    • Developmental regression should distinguish Rett syndrome
    • Seizures more difficult to manage in Angelman Syndrome
    • Molecular genetic testing identifies about 90% of Angelman mutations
  • Older patients may have been diagnosed with cerebral palsy

Psychosocial IssuesEdit

  • Lifelong care for a child who may never be able to take care of herself
  • Feelings of guilt, anger, fear, sadness, sense of loss surrounding new diagnosis
  • Concern about risk for future children
  • Worry, frustration about what future holds since may not be able to predict
  • One child that requires extra care and attention, detracting from other children or family relationships

Support ResourcesEdit

  • International Rett Syndrome Association
(800) 818-7388
  • Rett Syndrome Research Foundation
4600 Devitt Drive
Cincinnati, OH 45246
(513) 874-3020
  • Easter Seals
(800) 221-6827


  • Pevsner, Jonathon. "Rett Syndrome 101." Rett Syndrome Association Information Packets.
  • "Rett Syndrome." www.geneclinics.org
  • "Rett Syndrome." National Institutes of Health Brochure


The information in this outline was last updated in Sept 2002.