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 microcephaly?
 * 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, 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 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