Rettpedia
	Summary Rettpedia covers Classic Rett Syndrome, Atypical Rett Syndrome, MECP2-Related Severe Neonatal Encephalopathy, and PPM-X Syndrome.  This information is provided with grateful acknowledgements to the University of Washington, Seattle and the authors listed below. Disease characteristics.   MECP2-related disorders include classic Rett syndrome, variant or atypical Rett syndrome, and mild learning disabilities in females and neonatal encephalopathy and mental retardation syndromes in males. Classic Rett syndrome is a progressive neurologic disorder in girls characterized by normal birth and apparently normal psychomotor development during the first six to 18 months of life. The girls then enter a short period of developmental stagnation followed by rapid regression in language and motor skills. The hallmark of the disease is the loss of purposeful hand use and its replacement with repetitive stereotyped hand movements. Screaming fits and inconsolable crying are common by age 18-24 months. Additional characteristics include autistic features, panic-like attacks, bruxism, episodic apnea and/or hyperpnea, gait ataxia and apraxia, tremors, and acquired microcephaly. After this period of rapid deterioration, the disease becomes relatively stable, though girls will likely develop dystonia and foot and hand deformities as they grow older. Seizures occur in up to 90% of affected females; generalized tonic-clonic seizures and partial complex seizures are the most common. Females with classic Rett syndrome typically survive into adulthood, but the incidence of sudden, unexplained death (which may be caused by cardiac arrhythmias) is significantly higher than in controls of similar age. Atypical Rett syndrome is increasingly observed as MECP2 mutations have been identified in individuals previously diagnosed with autism, mild learning disability, clinically suspected but molecularly unconfirmed Angelman syndrome, or mental retardation with spasticity or tremor. Males meeting the clinical criteria for Rett syndrome have been identified in association with a 47,XXY karyotype and post-zygotic MECP2 mutations resulting in somatic mosaicism. Males with a 46,XY karyotype and a MECP2 mutation may have such severe neonatal encephalopathy that they die before their second year. Diagnosis/testing.  The diagnosis of Rett syndrome rests on clinical diagnostic criteria established for the classic syndrome and/or molecular testing of the MECP2 gene. Molecular genetic testing identifies MECP2 mutations in approximately 80% of females with classic Rett syndrome. Such testing is available clinically. Management.  Treatment is mainly symptomatic and multidisciplinary and may include psychosocial support for family members. Genetic counseling.  Rett syndrome is inherited in an X-linked dominant manner. Approximately 99.5% of cases are single occurences in a family, resulting either from a de novo mutation in the child with Rett syndrome or from inheritance of the disease-causing mutation from one parent who has somatic or germline mosaicism. A mother who is a carrier may have favorably skewed X-chromosome inactivation that results in her being unaffected or only slightly affected. When the mother of an affected individual is found to have the MECP2 mutation identified in her affected child, the risk to sibs of the proband of inheriting the mutant MECP2 allele at conception is 50%. If a mutation is not identified in the parent, the risk to sibs of the proband is low; however, germline mosaicism in either parent cannot be excluded. Prenatal testing is available in pregnancies at risk if the MECP2 mutation has been identified in a family member. Of note, because germline mosaicism cannot be excluded, it is appropriate to offer prenatal diagnosis to couples who have had a child with Rett syndrome or mental retardation as a result of a MECP2 mutation regardless of whether the disease-causing mutation has been identified in a parent. Diagnosis Clinical Diagnosis The spectrum of phenotypes in MECP2-related disorders includes: classic Rett syndrome, variant Rett syndrome, and very mild learning disabilities in females and neonatal encephalopathy and syndromic or nonsyndromic mental retardation syndromes in males. Classic Rett syndrome.  In 1988, well before the discovery of the genetic basis of Rett syndrome, clinical diagnostic criteria were developed [Rett Syndrome Diagnostic Criteria Work Group 1988]. The following are limitations to clinical diagnosis using these criteria: Clinical diagnosis may be considered tentative until the affected individual reaches age two to five years, by which point she has likely gone through several stages of the disease. Atypical forms may be either milder or more severe than classic Rett syndrome [Hagberg 1995]: In the more severe variant, no period of grossly normal development occurs, and early manifestations include congenital hypotonia and infantile spasms. In the milder variant, girls have less dramatic regression and milder mental retardation [Hagberg 1989]. Other children experience an even more gradual regression that begins after the third year, lose purposeful hand use, and develop seizures; however, they retain some speech and the ability to walk [Zappella et al 1998]. More recently, the diagnostic criteria have been modified to resolve inconsistencies and ambiguities in the categorization of affected individuals into classic Rett syndrome (Table 1) or variant Rett syndrome (Table 2) [Hagberg et al 2002]. Table 1. Classic Rett Syndrome: Revised Diagnostic Criteria Criteria Necessary Normal prenatal and perinatal history Normal psychomotor development for the first six months Normal head circumference at birth Postnatal deceleration of head growth in most individuals Loss of purposeful hand skills between age six months and 2.5 years Hand stereotypies Evolving social withdrawal, communication dysfunction, loss of acquired speech, and cognitive impairment Impairment or deterioration of locomotion Supportive Breathing disturbances during waking hours Bruxism Impairment of sleeping pattern from early infancy Abnormal muscle tone associated with muscle wasting and dystonia Peripheral vasomotor disturbances Progressive kyphosis or scoliosis Growth retardation Hypotrophic, small, and cold feet and/or hands Exclusion Evidence of a storage disorder including organomegaly Cataract, retinopathy, or optic atrophy History of perinatal or postnatal brain damage Confirmed inborn error of metabolism or neurodegenerative disorder Acquired neurologic disorder caused by severe head trauma or infection Table 2. Variant Rett Syndrome: Suggested Diagnostic Criteria Criteria Inclusion At least three of the six main criteria At least five of the 11 supportive criteria Main Reduction or absence of hand skills Loss or reduction of speech (including babble) Hand stereotypies Loss or reduction of communication skills Deceleration of head growth from early childhood Regression followed by recovery of interaction Supportive Breathing irregularities Abdominal bloating or air swallowing Bruxism Abnormal locomotion Kyphosis or scoliosis Lower limb amyotrophy Cold, discolored, and usually hypotrophic feet Night-time screaming and other sleep disturbances Inexplicable episodes of screaming or laughing Apparently diminished sensitivity to pain Intense eye contact and/or eye pointing Hagberg et al 2002 Molecular Genetic Testing GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by at least one US CLIA-certified laboratory or a clinical laboratory outside the US. GeneTests does not independently verify information provided by laboratories and does not warrant any aspect of a laboratory's work. Listing in GeneTests does not imply that laboratories are in compliance with accreditation, licensure, or patent laws. Clinicians must communicate directly with the laboratories to verify information. —ED. Gene.   MECP2 is the only gene known to be associated with MECP2-related disorders. Molecular genetic testing: Clinical uses Diagnostic testing in selected individuals with Angelman syndrome or with nonsyndromic or syndromic X-linked intellectual disability and in males with a neonatal encephalopathy phenotype Confirmatory diagnostic testing in individuals with classic Rett syndrome or one of its variants Prenatal diagnosis Molecular genetic testing: Clinical methods Sequence analysis.  Bidirectional sequencing of the entire MECP2 coding region detects disease-causing mutations in approximately 80% of individuals with classic Rett syndrome. Mutation scanning.   MECP2 mutation scanning (DHPLC followed by sequence analysis) identifies mutations in approximately 80% of individuals with classic Rett syndrome. Deletion testing.  Quantitative PCR or multiplex ligation-dependent probe amplification (MLPA) identifies large deletions (spanning kilobases) of MECP2 in some affected individuals previously considered to be mutation negative. These large deletions are more common in individuals with classic Rett syndrome (36%) than atypical (3%) Rett syndrome [Schollen et al 2003; Ariani et al 2004; Laccone et al 2004; Archer et al 2006; Huppke et al 2005; Ravn, Nielsen, Skjeldal et al 2005; Shi et al 2005]. Table 3 summarizes molecular genetic testing for this disorder. Table 3. Molecular Genetic Testing Used in MECP2-Related Disorders Test Methods Mutations Detected Mutation Detection Rate Test Availability Sequence analysis/mutation scanning MECP2 sequence variants 70%-90%  1 Clinical Deletion testing (quantitative PCR or MLPA) Deletions in MECP2 Up to 16%  2 1. In individuals with classic Rett syndrome [Dragich et al 2000, Shahbazian & Zoghbi 2001] 2. In individuals with classic or variant Rett syndrome Genetically Related (Allelic) Disorders No other phenotypes are associated with MECP2 mutations. Natural History Females.  The phenotypes in females range from classic Rett syndrome, defined by strict clinical criteria, to variant Rett syndrome. Rarely, MECP2 mutations have been identified in adult women with mild learning disabilities. Classic Rett syndrome.  Affected girls usually have a normal birth and neonatal course followed by apparently normal psychomotor development during the first six to 18 months of life, although analysis of retrospective data shows that the majority of these children have subtle behavioral abnormalities. They are described as very placid, with poor suck or a weak cry [Burford 2005, Einspieler et al 2005]. Head growth may begin decelerating as early as age three months and brain size may eventually be smaller than normal by 30% or more. Affected girls then enter a short period of developmental stagnation followed by rapid regression in language and motor skills. The hallmark of the disease is the loss of purposeful hand use and its replacement with repetitive stereotyped hand movements. Most parents describe screaming fits and inconsolable crying by age 18-24 months [Coleman et al 1988]. Additional characteristics include autistic features, panic-like attacks, bruxism, episodic apnea and/or hyperpnea, seizures, gait ataxia and apraxia, tremors, and acquired microcephaly. Intermittent esotropia is common, and vasomotor changes are often noted, especially in the lower limbs. After this period of rapid deterioration, the disease becomes relatively stable, although girls will likely develop dystonia and foot and hand deformities as they grow older. Girls with classic Rett syndrome tend to be small; 85%-90% have growth failure and wasting that worsen with age [Motil et al 1998], perhaps in part caused by oropharyngeal and gastroesophageal incoordination that results in poor food intake [Motil et al 1999]. Bowel dysmotility, constipation, and functional megacolon are common; in extreme cases, fecal impaction, volvulus, and intussusception occur [Budden 1997]. The International Rett Syndrome Association has noted that gallbladder dysfunction, including gallstones, is a significant problem. The frequency seems far greater than that in the general population of children [Percy & Lane 2005]. Seizures are reported in up to 90% of females with Rett syndrome; generalized tonic-clonic seizures and partial complex seizures are the most common [Witt-Engerstrom 1992, Steffenburg et al 2001]. Additional manifestations of seizure activity include focal clonic activity, head or eye deviation, and/or apnea [Glaze et al 1998]. Seizures occur more frequently when the disease stabilizes and often decrease during the late motor deterioration stage. Activity described as seizures may not be associated with epileptiform activity on EEG, and clinical events accompanying EEG epileptiform activities are not always recognized as seizures by the parents [Glaze 2005]. Certain EEG findings common to the disorder are not unique to Rett syndrome and thus are not diagnostic. Nonetheless, it may be helpful to know that the EEG shows slowing of the occipital dominant rhythm and background activity with spike or sharp wave discharges during sleep early in the course of the syndrome. During the regression stage, the EEG shows loss of occipital dominant rhythm, further slowing of background activity, and loss of non-rapid eye movement sleep characteristics. Theta and delta activity is markedly slowed, with multifocal spike and wave discharges. Video/EEG monitoring reveals frequent episodes of apnea and hyperventilation, laughing, screaming, and vacant staring spells. Focal electrographic seizures are usually associated with focal clonic activity, head or eye deviation, and sometimes apnea. Generalized electrographic seizures are frequently accompanied by absence episodes or flexor spasms. Osteoporosis occurs frequently in females with Rett syndrome and has been reported in very young girls, perhaps as a result of poor bone formation. This increases the risk for fractures [Budden & Gunness 2001]. Individuals with Rett syndrome have decreased bone mineral density compared to controls. Ambulatory individuals have better bone mineral density than non-ambulatory individuals [Cepollaro et al 2001]. Over 80% of individuals develop some degree of scoliosis by the age of 25 years [Kerr et al 2003]. Females with Rett syndrome typically survive into adulthood, but the incidence of sudden, unexplained death is significantly higher than in controls of similar age [Kerr & Julu 1999]. This sudden death may in part be caused by the higher incidence of longer corrected QT intervals, T-wave abnormalities, and reduced heart rate variability in Rett syndrome [Sekul et al 1994, Guideri et al 1999]. Other.   MECP2 mutations have been identified in females with a Rett syndrome variant, mild learning disability, and even in a few women with no apparent symptoms who demonstrate highly skewed X-chromosome inactivation [Wan et al 1999, Amir et al 2000]. Microcephaly is not an invariant feature of Rett syndrome: Oexle et al (2005) reported an adult woman with a MECP2 mutation mental retardation, seizures, and macrocephaly. In addition, MECP2 mutations may be found in females with mild learning disability [Orrico et al 2000] and clinically suspected but molecularly unconfirmed Angelman syndrome [Watson et al 2001]. Males.  Males with a 46,XY karyotype can have mutations in MECP2 [Villard et al 2000, Orrico et al 2000, Masuyama et al 2005]. Males with MECP2 mutations may have a severe neonatal-onset encephalopathy with microcephaly, a relentless clinical course that follows a metabolic-degenerative type of pattern, abnormal tone, involuntary movements, severe seizures, and prominent breathing abnormalities (including central hypoventilation or respiratory insufficiency) [Wan et al 1999, Villard et al 2000, Zeev et al 2002, Kankirawatana et al 2006]. Often, males with MECP2 mutations have such a severe neonatal encephalopathy that they die before their second year [Schanen et al 1998, Wan et al 1999]. MECP2 mutations have been identified in some individuals with Angelman syndrome [Watson et al 2001, Kleefstra et al 2004]. Males meeting the clinical criteria for classic Rett syndrome have been identified in association with a 47,XXY karyotype [Hoffbuhr et al 2001, Leonard et al 2001, Schwartzman et al 2001] and post-zygotic MECP2 mutations resulting in somatic mosaicism [Clayton-Smith et al 2000, Topcu et al 2002]. X-linked mental retardation.   MECP2 mutations may also be found in families exhibiting X-linked mental retardation, which may range from mild non-progressive mental retardation in females to severe mental retardation in males associated with manic-depressive psychosis, pyramidal signs, parkinsonian features, and macro-orchidism (the so-called PPM-X syndrome) [Dotti et al 2002, Klauck et al 2002, Gomot et al 2003]. Pathogenesis of Rett syndrome.  The principal characteristics of Rett syndrome and their developmental pattern indicate that abnormal development of the cortex in late infancy may result from dysregulation of subcortical regulator systems, brain stem, basal forebrain nuclei, and basal ganglia. Brain stem involvement is apparent based on many of the functional disturbances in Rett syndrome: breathing, cardiac rate, swallowing, peripheral vasomotor disturbances, sleep, bowel motility, salivation, and pain discrimination. These findings suggest dysregulation of autonomic tone with failure to regulate vagal (parasympathetic) tone and respiratory rhythm, suggesting immaturity of the respiratory regulator. Neuropathology of Rett syndrome.  The brains are small and closely packed with neurons. Decreased dendritic spines and arbors have been noted in brain neuropathology [Armstrong 2005]. Genotype-Phenotype Correlations Genotype-phenotype correlation studies have so far yielded inconsistent results. It is necessary to gain a far better understanding of MECP2 function and to conduct more controlled studies before valid conclusions can be drawn about the effect of mutation type on the phenotype. Amir et al (2000) found a positive correlation between truncating mutations and breathing abnormalities, whereas scoliosis was more common in individuals with missense mutations. Neither the overall severity score nor other parameters (age of onset, mortality, seizures, and somatic growth failure) correlated with the type of mutation. Cheadle et al (2000) found significantly milder disease in individuals with missense mutations than in those with truncating mutations; they also found that late truncating mutations produced milder phenotypes than early truncating mutations. Cheadle et al (2000) and Huppke et al (2000) both reported several individuals with the same mutation but different phenotypes, findings suggesting that factors other than mutation type influence disease severity. One such factor is the pattern of X-chromosome inactivation (XCI); females who have a mutation but have favorably skewed XCI may have mild symptoms or none at all [Wan et al 1999, Amir et al 2000]. Several of the MECP2 mutations found in males with mental retardation are typically missense or late truncating mutations that have not been identified in girls with Rett syndrome. Because some of the missense mutations such as A140V do not totally inactivate the protein, they cause mental retardation in males but very mild cognitive impairment in females [Dotti et al 2002, Klauck et al 2002, Gomot et al 2003]. Weaving et al (2003) showed that clinical severity can in part be predicted based on the type of mutation (missense versus truncation), its location, particularly when positioned within a functional domain, and the presence of skewed X-chromosome inactivation (XCI) [Weaving et al 2003]; similar conclusions were reached by Schanen et al (2004), Chae et al (2004), and Charman et al (2005). Leonard et al (2003) determined that the phenotype of individuals with the p.R133C mutation is less severe than the usual phenotype, which is consistent with in vitro functional studies demonstrating that R133C does not impair binding to DNA. Penetrance Occasionally, rare obligate heterozygotes for a pathogenic MECP2 mutation may have no clinical evidence of Rett syndrome — the result of protective highly skewed X-chromosome inactivation. Nomenclature Females who fulfill all of the diagnostic criteria for Rett syndrome are classified as having typical or classic Rett syndrome. With increasing experience it has become clear that females with Rett syndrome present with a much broader phenotype than originally described. The majority of Rett syndrome variants are milder than classic Rett syndrome, particularly with regard to gross motor disability and degree of fine motor dysfunction. Hagberg described five possible Rett syndrome variant, or atypical forms [Hagberg et al 1993]: A form seen in females with apparently classic Rett syndrome in whom the presentation is dominated by seizures and onset is before age six months Congenital or precocious Rett syndrome, in which regression is never clearly identified but the clinical picture is otherwise classic A form in which regression develops later and more gradually than in classic Rett syndrome 'Forme fruste' Rett syndrome, with a milder, incomplete, and protracted clinical course. Regression occurs later (age 1-3 years) and is not as severe as that in classic Rett syndrome, as hand use may be preserved and stereotypic hand movements may be minimal or atypical. 'Preserved speech' variant Prevalence The prevalence of Rett syndrome in females is estimated to be 1:8,000 by age 15 years [Laurvick et al 2005]. Differential Diagnosis For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED. Angelman syndrome (AS) is characterized by mental retardation, severe speech impairment, gait ataxia and/or tremulousness of the limbs, and a unique behavior with an inappropriate happy demeanor. Microcephaly and seizures are common. Developmental delay is first noted at around age six months; however, the unique clinical features of AS do not become manifest until after age one year. Developmental regression should help distinguish Rett syndrome from Angelman syndrome clinically, and seizures tend to be much more difficult to manage in Angelman syndrome. Analysis of parent-specific DNA methylation imprints in the 15q11.2-q13 chromosome region detects approximately 78% of individuals with AS, including those with a deletion, uniparental disomy, or an imprinting defect; UBE3A sequence analysis detects mutations in an additional approximately 11% of individuals. The remaining 10% of individuals with classic phenotypic features of AS have a presently unidentified genetic mechanism. Watson et al (2001) found MECP2 mutations in four of 25 females and one of 22 males who had a clinical diagnosis of AS, but no molecular abnormality involving 15q11.2-13. Three of the five subsequently demonstrated progressive clinical features more typical of Rett syndrome than AS. Individuals with Rett syndrome — especially those who do not have microcephaly, seizures, or kyphoscoliosis — are commonly diagnosed with autism; however, MECP2 mutations are not a significant cause of autism [Lobo-Menendez et al 2003]. See Autism Overview. Cerebral palsy is often suspected in older individuals with Rett syndrome or males with spasticity, severe wasting, and mental retardation. A detailed history of early childhood development in the light of the revised diagnostic criteria [Hagberg et al 2002] and molecular genetic testing of MECP2 should reveal the proper diagnosis. Mutations in CDKL5, the gene encoding cyclin dependent-like kinase 5, have been identified in individuals with a Rett syndrome-like phenotype. Virtually all individuals with CDKL5 mutations reported to date have had an early-onset seizure variant of Rett syndrome, the so-called Hanefield variant [Tao et al 2004; Weaving et al 2004; Evans, Archer, Colley et al 2005; Scala et al 2005]; however, it seems that mutations in this gene account for only a small subset of individuals with a Rett syndrome-like phenotype. MECP2-related disorders should be considered in male infants with neonatal encephalopathy, or severe hypotonia or in families with a history of X-linked mental retardation. Management Evaluations at Initial Diagnosis to Establish the Extent of Disease Formal developmental assessment Assessment of feeding/eating, digestive problems (including constipation and gastro-esophageal reflux), and nutrition using history, growth measurements and, if needed, gastrointestinal investigations History of sleep and/or breathing problems Video/EEG monitoring to obtain definitive information about the occurrence of seizures and the need for antiepileptic drugs ECG to screen for prolonged QTc Assessment of brain stem autonomic dysfunction to identify appropriate therapies [Julu et al 2001, Julu & Witt-Engerstrom 2005] Examination for scoliosis Treatment of Manifestations Management is mainly symptomatic and focuses on optimizing the individual's abilities using a dynamic multidisciplinary approach, with specialist input from dietitians, physiotherapists, and occupational, speech, and music therapists [Lotan et al 2004, Weaving et al 2005]. Psychosocial support for families is an integral part of management. Therapeutic horseback riding, swimming, and music therapy are often beneficial [Budden 1997]. Effective communication strategies, including the use of augmentative communication techniques, need to be explored for these severely disabled individuals [Ryan et al 2004]. Treatment for seizures needs to be individualized with input from a pediatric neurologist. Topiramate may improve seizure control and/or respiratory abnormalities [Goyal et al 2004]. Risperidone (low dose) or selective serotonin uptake inhibitors have been somewhat successful in treating agitation. Melatonin can ameliorate sleep disturbances [Budden 1997, McArthur & Budden 1998]. Chloral hydrate, hydroxyzine, or diphenhydramine may be used along with melatonin. Ample fluid intake and a high fiber diet can help prevent acute intestinal blockage. When diet is ineffective, Miralax (polyethylene glycol) and other stool softeners may be used to control constipation; they are tolerated better than milk of magnesia. Anti-reflux agents, smaller and thickened feedings, and positioning can decrease gastroesophageal reflux. Scoliosis [Kerr et al 2003] and spasticity [Budden 1997] need to be treated to maintain mobility. Surveillance Examination at regular intervals by a multidisciplinary team with particular attention to growth, nutritional intake, dentition, gastrointestinal function, mobility and communication skills, hand function, and orthopedic and neurologic complications Periodic ECG to screen for prolonged QTc Examination at regular intervals for the progression of scoliosis Agents/Circumstances to Avoid Because individuals with Rett syndrome have an increased risk of life-threatening arrhythmias associated with a prolonged QT interval [Sekul et al 1994], avoidance of drugs known to prolong the QT interval, including the following, is recommended: Prokinetic agents (e.g., cisapride) Antipsychotics (e.g., thioridazine), tricyclic antidepressants (e.g., imipramine) Antiarrhythmics (e.g., quinidine, sotolol, amiodarone) Anesthetic agents (e.g., thiopental, succinylcholine) Antibiotics (e.g., erythromycin, ketoconazole) Therapies Under Investigation Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Other L-carnitine was tested in a double-blind trial. Although parents and caregivers reported improvements in the general well-being of affected individuals [Ellaway et al 1999], significant functional improvements were not observed. Carbidopa/levodopa may be tried for rigidity, but its benefit is unsubstantiated. Following the report of reduced CSF folate concentration in four females with Rett syndrome [Ramaekers et al 2003], Neul analyzed CSF from an additional 76 individuals with Rett syndrome, but could not reproduce earlier findings, and found that supplementation with folinic acid did not lead to any noticeable clinical improvements [Neul et al 2005]. It therefore remains to be established whether cerebral folate deficiency contributes to the pathophysiology of Rett syndrome. Because elevated opioids had been observed in the CSF of individuals with Rett syndrome, the oral opiate antagonist, naltrexone, was investigated. Although it decreased breathing dysrhythmias and had some sedating properties, the efficacy of naltrexone is controversial [Percy et al 1994]. Genetic Counseling Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.  Mode of Inheritance MECP2-related disorders are inherited in an X-linked dominant manner. Risk to Family Members Parents of a female proband Approximately 99.5% of cases are single occurrences in a family, resulting either from a de novo mutation in the child with a MECP2-related disorder or from inheritance of the disease-causing mutation from one parent who has germline mosaicism. If the disease-causing MECP2 mutation has been identified in the proband, it is appropriate to offer molecular genetic testing to both parents. A mother who has a MECP2 mutation may have favorably skewed X-chromosome inactivation that results in her being unaffected or mildly affected. Parents of a male proband The father of an affected male will not have the disease or be a carrier of the mutation. If the disease-causing MECP2 mutation has been identified in the proband, it is appropriate to offer molecular genetic testing to the mother. A mother who has a MECP2 mutation may have favorably skewed X-chromosome inactivation that results in her being unaffected or mildly affected. Sibs of a proband The risk to sibs depends upon the genetic status of the parents. When the mother of an affected individual is found to have the MECP2 mutation identified in her affected child, the risk to sibs of inheriting the mutant MECP2 allele at conception is 50%. If a mutation is not identified in a parent, the risk to sibs is low. However, germline mosaicism in either parent cannot be excluded even if the disease-causing MECP2 mutation present in the proband has not been identified in DNA extracted from the leukocytes of either parent. Germline mosaicism has been reported [Amir et al 1999, Zeev et al 2002, Mari et al 2005]. Offspring of a female proband Each child of an individual with a MECP2-related disorder has a 50% chance of inheriting the mutation. One woman with classic Rett syndrome gave birth to a girl who developed classic Rett syndrome. Mildly affected females have reproduced. Females who inherit the mutation are at high risk of developing classic Rett syndrome, although skewed X-chromosome inactivation may result in a milder phenotype. Males who inherit the mutation may have a severe neonatal encephalopathy, or, if they survive the first year, will have a severe mental retardation syndrome. Offspring of a male proband.  No male with a MECP2 mutation has been known to reproduce. Other family members of a proband.  The risk to other family members depends upon the genetic status of the proband's mother. If the mother is found to be affected or to have a MECP2 mutation, her family members may be at risk. Related Genetic Counseling Issues As with many other genetic conditions, the diagnosis of a MECP2-related disorder in a family member may result in evaluation and diagnosis of the mother and other family members who were previously unaware of the presence of a genetic disorder in the family. This discovery can be difficult for the family because of its implications for their own health and because of a sense of "responsibility" for illness in their children. Efforts should be made to anticipate these issues. Apparently unaffected sisters of a girl with classic Rett syndrome could have the MECP2 mutation that is present in their sister but have few to no symptoms because of skewed X-chromosome inactivation. Genetic counseling needs to address this possibility, as the unaffected sisters may be at risk of transmitting the disease-causing MECP2 mutation to their children. Family planning.  The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy. DNA banking.  DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. DNA banking is particularly relevant in situations in which the sensitivity of currently available testing is less than 100%. See DNA Banking for a list of laboratories offering this service. Prenatal Testing Pregnancies of women with a known MECP2 mutation.  Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at about 15-18 weeks' gestation or chorionic villus sampling (CVS) at about 10-12 weeks' gestation. The disease-causing allele of an affected family member must be identified before prenatal testing can be performed. Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements. Male fetuses with a MECP2 mutation who survive infancy will most likely have severe mental retardation. The phenotype in a female with a MECP2 mutation is difficult to predict; it can range from apparently normal to severely affected. Pregnancies of a couple who have a child with a MECP2-related disorder.  Germline mosaicism cannot be excluded in either parent even when the disease-causing MECP2 mutation present in the proband is not identified in DNA extracted from parental leukocytes; thus, it is appropriate to offer prenatal diagnosis to such couples whether or not the disease-causing mutation has been identified in a parent [Armstrong et al 2002]. One of nine pregnancies of women who did not have evidence of the MECP2 mutation identified in their daughters with classic Rett syndrome resulted in the birth of a daughter with the same MECP2 mutation as the proband [Mari et al 2005]. Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation has been identified in an affected family member. For laboratories offering PGD, see . Molecular Genetics Information in the Molecular Genetics tables may differ from that in the text; tables may contain more recent information.  Molecular Genetics of MECP2-Related Disorders Gene Symbol Chromosomal Locus Protein Name MECP2 Xq28 Methyl-CpG-binding protein 2 Data are compiled from the following standard references: Gene symbol from HUGO; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from Swiss-Prot. OMIM Entries for MECP2-Related Disorders  300005  METHYL-CpG-BINDING PROTEIN 2; MECP2ENCEPHALOPATHY, NONPROGRESSIVE, NEONATAL-ONSET, INCLUDED  312750  RETT SYNDROME; RTT Genomic Databases for MECP2-Related Disorders Gene Symbol Locus Specific Entrez Gene HGMD GeneCards GDB GenAtlas MECP2 MECP2 300005 MECP2 MECP2 3851454 MECP2 For a description of the genomic databases listed, click here. Molecular Genetic Pathogenesis The abundantly expressed nuclear protein MeCP2 is thought to mediate transcriptional silencing and epigenetic regulation of methylated DNA through its association with 5-methylcytosine (5-mC)-rich heterochromatin [Nan et al 1998, Tate et al 1996]. The methyl CpG-binding domain (MBD) of MeCP2 binds to symmetrically methylated CpG dinucleotides; the transcriptional repression domain (TRD) interacts with the co-repressor Sin3A, and together they recruit histone deacetylases [Jones et al 1998, Nan et al 1998, Ng & Bird 1999]. When lysine residues of the core histones H3 and H4 become deacetylated, the chromatin structure changes and renders the DNA inaccessible to the transcriptional machinery. DNA methylation-dependent repression is important for X-chromosome inactivation (XCI) and genomic imprinting. MeCP2 is expressed in all tissues and is hypothesized to act as a global transcriptional repressor [D'Esposito et al 1996, Nan et al 1998, Coy et al 1999]. Most MECP2 mutations occur de novo. The leading hypothesis holds that MeCP2 dysfunction resulting from mutations in the TRD or MBD disrupts the delicate precision of gene expression during development. Some mutations affect residues that are important for DNA binding, whereas others may disrupt the native structure of the protein and/or its interactions with other proteins. The documented nonsense, frameshift, and splicing mutations, most of which are distal to the MBD, likely result in premature termination of the protein. Truncated proteins may still bind methylated DNA but be unable to interact with the corepressor Sin3A; it is also possible that mutations in the carboxy terminus of the protein disable DNA binding [Chandler et al 1999]. In either case, the silencing complex would not be properly assembled, and the target genes could not be properly silenced. It is puzzling that a ubiquitously expressed gene should give rise to a predominantly neurologic phenotype. Brain tissues may be more vulnerable to compromises in MeCP2 function, or tissue-specific differences in MeCP2 expression levels may occur. (There are, in fact, alternate transcripts that are differentially expressed in the brain during development [Kriaucionis & Bird 2004, Mnatzakanian et al 2004].) Alternatively, the post-mitotic nature of neurons may make them more susceptible to the ill effects of MeCP2 dysfunction. To understand the pathogenesis of Rett syndrome, it will first be necessary to identify the genes normally targeted by MeCP2 activity. MeCP2 has been known to silence specific genes, such as brain-derived neurotrophic factor [Chen et al 2003, Martinowich et al 2003], Hairy2a [Stancheva et al 2003], Dlx5 [Horike et al 2005], and sgk [Nuber et al 2005]. The constellation and consistency of features among individuals with classic Rett syndrome suggest that the disorder may be attributable to the dysfunction of a select group of genes. Functional studies of the various mutations and analysis of animal models for Rett syndrome should illuminate the pathogenesis of the disorder and establish how DNA methylation-dependent processes are disrupted. Three groups have generated mice lacking functional MeCP2; male mice that are null are born alive and develop tremors, hypoactivity, and small brains. They typically die between age eight and 12 weeks [Chen et al 2001, Guy et al 2001]. Deletion of the mouse Mecp2 gene in neurons produces a phenotype very similar to that seen with deletion of Mecp2 in all cells [Chen et al 2001], indicating that despite its purported role as a global transcriptional repressor, MeCP2 function — or one of its functions — may be most critical in neurons. Male mice carrying a mutation that truncates the protein past amino acid 308 (Mecp2308/y) appear normal for six weeks, then develop tremor, seizures, hypoactivity, forepaw, stereotypies, and kyphosis [Shahbazian et al 2002]. A fourth group has generated a targeted deletion of the MBD coding region and disruption of mRNA splicing was introduced in the mouse, resulting in a complete loss of Mecp2 transcripts and protein [Pelka et al 2006]. Postnatal comparison of XO and XY mutant Mecp2 allele-containing null mice revealed similar effects on mouse growth and viability, suggesting that phenotypic manifestations are not modulated by the Y chromosome. Further assessment of Mecp2-null XY mice highlighted cerebellar and hippocampal/amygdala-based learning deficits in addition to reduced motor dexterity and decreased anxiety levels. Brain tissues containing the hippocampal formation of XY Mecp2-null mice also displayed significant changes in genetic activity, related to the severity of the mutant phenotype. In addition, studies by Horike et al (2005), Kaufmann et al (2005), and Makedonski et al (2005) showing that Mecp2 deficiency leads to epigenetic aberrations of chromatin suggest that Mecp2 deficiency could lead to loss of imprinting, thereby contributing to the pathogenesis of Rett syndrome. Finally, evidence suggests that over expression of MeCP2 protein could have detrimental effects on brain development and function as shown in mouse models [Collins et al 2004] and in the human [Shi et al 2005, Van Esch et al 2005]. Normal allelic variants: The MECP2 gene contains four exons, transcribed from telomere to centromere. Exons 2, 3, and 4 were thought to contain the coding sequence; the first exon was identified through sequence homology between species and was thought to contain a non-coding 5' untranslated region (UTR) [Reichwald et al 2000]. However, it has been more recently shown that a transcript containing exon 1 is the predominant isoform in the brain [Kriaucionis & Bird 2004, Mnatzakanian et al 2004]. Most of exon 4 encodes the unusually long (8.5-kb) 3'UTR; alternate polyadenylation sites here result in differentially expressed transcripts of various sizes, all encoding for the same size protein. The significance of the mRNA features with regard to stability, regulation, and function is currently not well understood [Coy et al 1999, Reichwald et al 2000], but may point to a potential tissue-specific function of the 3'UTR in the regulation of MeCP2 protein synthesis in response to the age-specific requirement of MeCP2 function, at least in the mouse [Pelka et al 2005]. The C-terminal domain shares homology with neuronal-specific transcription factors containing forkhead domains, suggesting that the protein may have additional, more complex, possibly neuronal-specific functions [Vacca et al 2001]. This region also contains evolutionarily conserved polyhistidine and polyproline regions that may play a role in the interaction of MECP2 with the nucleosome core [Chandler et al 1999]. Pathologic allelic variants: To date, over 200 individual nucleotide changes that cause pathogenic mutations have been described [Christodoulou et al 2003]; the eight most commonly occurring missense and nonsense mutations account for almost 50% of all mutations and small deletions associated with a deletion hotspot in the C-terminal region of the MeCP2 protein account for an additional 9% of pathogenic mutations [RettBASE]. Although these deletions tend to affect the same region, completely identical deletions are rare. Mutations are dispersed throughout the gene; however, a clustering of missense mutations occurs 5' of the transcriptional repression domain (TRD), mostly in the methyl binding domain (MBD); another clustering of nonsense and frameshift mutations appears beyond the MBD. More recently, large deletions (kilobases in size) that delete whole exons have been identified in a proportion of affected individuals who were previously considered to be mutation negative. These large deletions are more commonly found in females with classic Rett syndrome (36%; 46/128) than atypical Rett syndrome (3%; 7/229) [Ariani et al 2004; Laccone et al 2004; Amir et al 2005; Huppke et al 2005; Ravn, Nielsen, Skjeldal et al 2005; Shi et al 2005; Archer et al 2006]. On the other hand, pathogenic mutations involving exon 1 appear to be only rarely associated with Rett syndrome [Amir et al 2005; Evans, Archer, Whatley et al 2005; Poirier et al 2005; Ravn, Nielsen, Skjeldal et al 2005; Saxena et al 2006]. In almost all cases the mutations are de novo, and some evidence suggests that in the majority of cases the mutation has arisen on the paternal X chromosome [Girard et al 2001, Trappe et al 2001]. Normal gene product: The proteins resulting from the two MECP2 isoforms, created by alternative splicing of exon 2 and use of two alternative start codons, are almost identical but have alternative N-termini. The MeCP2 protein has two major functional domains: the methyl binding domain (MBD), which binds specifically to DNA at methylated CpG's, and a transcription repression domain (TRD) that is responsible for recruiting other proteins that mediate transcription repression [Jones et al 1998, Nan et al 1998, Kokura et al 2001, Stancheva et al 2003, Harikrishnan et al 2005]. In addition, the MeCP2 protein has a WW domain at its C-terminus [Buschdorf & Stratling 2004]. Evidence suggests that MeCP2 may play a role in mediating splicing [Young et al 2005]. Abnormal gene product: Functional studies have shown that MECP2 mutations affect the methyl binding or transcription repression properties of the mutant protein, depending on the location of the mutation [Kudo et al 2001, Kudo et al 2002, Kudo et al 2003]. MeCP2 binds specifically to certain DNA sequences [Klose et al 2005]. Several studies have identified specific MeCP2 targets, suggesting that downstream alterations in the expression of specific MeCP2 targets may contribute to the neurodevelopmental abnormalities seen in Rett syndrome and other MECP2-related disorders [Chen et al 2003, Horike et al 2005, Martinowich et al 2003, Nuber et al 2005, Stancheva et al 2003]. Literature Cited Amir RE, Fang P, Yu Z, et al (2005) Mutations in exon 1 of MECP2 are a rare cause of Rett syndrome. 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Eur J Hum Genet 14:896-903 [Medline] Author Information John Christodoulou, MBBS, PhD, FRACP, ARCPA Professor, Pediatrics and Biochemical, Molecular, and Human Genetics Director, Western Sydney Genetics Program Children's Hospital at Westmead Sydney Author History Vicky L Brandt; Baylor College of Medicine (2000-2004) John Christodoulou, MBBS, PhD, FRACP, RCPA (2006-present) Huda Y Zoghbi, MD; Baylor College of Medicine (2004-2006) Last Updated: 15 August 2006 Funding Support: United States National Institute of Health, National Library of eMedicine, National Human Genome Project Source: www.genetests.org) Copyright © 1993-2007, All Rights Reserved University of Washington, Seattle Terms of Use <	Enter your search terms Web www.rettsyndrome.info Submit search form More Rett Syndrome Sites RSRF: The Rett Syndrome Research Foundation. www.RSRF.org IRSA: The Internatonal Rett Syndrome Association. www.RettSyndrome.org Rett Syndrome Bookstore: The official online bookstore of the Rett Syndrome Community. www.RettBooks.com Rett Syndrome Videos: Share your special videos with the Rett Syndrome Community. www.Rett.tv