Handbook of Genetic Counseling/Rett Syndrome

Rett Syndrome Contracting What were you told about why you were referred to genetics? What would you like to learn today? Do you have any questions that you would like us to be sure to address? 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.