Handbook of Genetic Counseling/Rett Syndrome
Rett Syndrome
Contracting
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Intake and Family History
edit- 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?
Etiology
edit- 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
- About 99.5% of cases are sporadic
- 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
edit- 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
- Generally begins between 6 and 18 months of age
- 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
- Begins between ages 1 and 4 years old
- 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
- Begins between ages 2 and 10
- 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
edit- 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
- Requires following:
- 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
- Prenatal diagnosis offered to women with known MECP2 mutations
Treatment/Management
edit- 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
edit- 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
edit- 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
edit- 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
edit- Pevsner, Jonathon. "Rett Syndrome 101." Rett Syndrome Association Information Packets.
- "Rett Syndrome." www.geneclinics.org
- "Rett Syndrome." National Institutes of Health Brochure
Notes
editThe information in this outline was last updated in Sept 2002.