# 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

## 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.