Handbook of Genetic Counseling/Rett Syndrome

Rett Syndrome

Contracting

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Intake and Family History

• 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 miccrocephaly?
• Seizures?

Etiology

• 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 Features

• 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, vovulus, 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 Options

• 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

Treatment/Management

• 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 Diagnosis

• 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 Issues

• 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 Resources

• International Rett Syndrome Association

(800) 818-7388

www.rettsyndrome.org

• Rett Syndrome Research Foundation

4600 Devitt Drive

Cincinnati, OH 45246

(513) 874-3020

www.rsrf.org

• Easter Seals

(800) 221-6827

www.easter-seals.org

References

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

Notes

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