Rett Syndrome: Clinical Review and Genetic Update
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Downloaded from jmg.bmjjournals.com on 11 April 2005 Rett syndrome: clinical review and genetic update L S Weaving, C J Ellaway, J Gécz and J Christodoulou J. Med. Genet. 2005;42;1-7 doi:10.1136/jmg.2004.027730 Updated information and services can be found at: http://jmg.bmjjournals.com/cgi/content/full/42/1/1 These include: Rapid responses You can respond to this article at: http://jmg.bmjjournals.com/cgi/eletter-submit/42/1/1 Email alerting Receive free email alerts when new articles cite this article - sign up in the box at the service top right corner of the article Topic collections Articles on similar topics can be found in the following collections • Genetics (3254 articles) Notes To order reprints of this article go to: http://www.bmjjournals.com/cgi/reprintform To subscribe to Journal of Medical Genetics go to: http://www.bmjjournals.com/subscriptions/ Downloaded from jmg.bmjjournals.com on 11 April 2005 1 REVIEW Rett syndrome: clinical review and genetic update L S Weaving, C J Ellaway, J Ge´cz, J Christodoulou ............................................................................................................................... J Med Genet 2005;42:1–7. doi: 10.1136/jmg.2004.027730 Rett syndrome (RS) is a severe neurodevelopmental causes RS remains somewhat of an enigma, but recent advances in our knowledge of its precise disorder that contributes significantly to severe intellectual roles in neuronal and other cell types have gone a disability in females worldwide. It is caused by mutations in long way towards clarifying this issue. MECP2 in the majority of cases, but a proportion of Nevertheless, diagnosis of RS remains a clinical one, as a small proportion of clinically well atypical cases may result from mutations in CDKL5, defined RS patients (,5–10%) do not appear to particularly the early onset seizure variant. The relationship have MECP2 mutations. between MECP2 and CDKL5, and whether they cause RS through the same or different mechanisms is unknown, but CLINICAL OVERVIEW is worthy of investigation. Mutations in MECP2 appear to RS is characterised by a specific developmental give a growth disadvantage to both neuronal and profile, with the diagnosis of RS being based on a consistent constellation of clinical features and lymphoblast cells, often resulting in skewing of X the use of established diagnostic criteria.7 More inactivation that may contribute to the large degree of recently, refined diagnostic criteria have been phenotypic variation. MeCP2 was originally thought to be proposed to clarify previous ambiguities in interpretation of clinical features8 (table 1, fig a global transcriptional repressor, but recent evidence 1), and guidelines have been developed to aid suggests that it may have a role in regulating neuronal researchers in being more consistent in their activity dependent expression of specific genes such as reporting of clinical features in RS patients.9 The diagnostic criteria for classical RS include Hairy2a in Xenopus and Bdnf in mouse and rat. a normal prenatal and perinatal period with ........................................................................... normal developmental progress for the first 5–6 months of life. The birth head circumference is normal with subsequent deceleration of ett syndrome (RS) was first described as a head growth, usually leading to microcephaly. clinical entity in the German literature in Between 3 months and 3 years there is reduction R1966.1 Hagberg and colleagues increased or loss of acquired skills such as purposeful hand awareness of the disorder in the English medical function, vocalisation, and communication skills. literature in 1983 with a further description of The hallmark of RS is the intense, sometimes the condition in 35 girls with strikingly similar continuous, stereotypic hand movements, which clinical features of ‘‘progressive autism, loss of develop after the loss of purposeful hand move- purposeful hand movements, ataxia, and ments. Patterns consist of tortuous hand wring- acquired microcephaly’’.2 RS is now recognised ing, hand washing, clapping, patting, or other as a panethnic disorder, and presents an ever more bizarre hand automatisms, during waking 5 widening clinical phenotype.3 The estimated hours. A jerky truncal and or gait ataxia is cumulative incidence of RS in Australia is 10 another prominent feature. Supportive diagnos- per 100 000 females by the age of 12 years4 and it tic criteria include breathing dysfunction, EEG is considered to be the second most common abnormalities, spasticity, peripheral vasomotor cause, after Down’s syndrome, of severe mental disturbance, scoliosis, and growth retardation. It retardation in females.5 RS is a severe neuro- has been suggested that the classical RS pheno- developmental disorder characterised by the type can be described as having a four stage progressive loss of intellectual functioning, fine clinical evolution, and this has helped in and gross motor skills and communicative discussing the natural history of the disorder See end of article for 10 abilities, deceleration of head growth, and the with parents. According to the recently revised authors’ affiliations 8 ....................... development of stereotypic hand movements, criteria, the clinical diagnosis of RS is excluded occurring after a period of normal development. if there is evidence of a storage disorder, Correspondence to: retinopathy, cataract, or optic atrophy, an iden- Professor J Christodoulou, Girls with RS often develop seizures, a disturbed Western Sydney Genetics breathing pattern with hyperventilation and tifiable metabolic or neurodegenerative disorder, Program, The Children’s periodic apnoea, scoliosis, growth retardation, an acquired neurological disorder, or evidence of Hospital at Westmead, and gait apraxia.2 perinatal or postnatal brain injury. It must not be Locked Bag 4001, Westmead, 2145, NSW, The association of RS with mutations in the Australia; johnc@ methyl-CpG binding protein 2 gene (MECP2) was chw.edu.au recognised in 1999.6 The MeCP2 protein is Abbreviations: BDNF, brain derived neurotrophic factor; known to bind methylated CpG sequences and CDKL5, cyclin dependent kinase-like 5; ISSX, infantile Received 1 October 2004 spasms syndrome, X linked; MECP2, methyl-CpG binding Revised 1 October 2004 recruit silencing complexes that lead to compac- protein 2; MR, mental retardation; ORF, open reading Accepted 5 October 2004 tion and silencing of surrounding chromatin. The frame; RS, Rett syndrome; STK9, serine threonine kinase ....................... mechanism(s) by which MeCP2 dysfunction 9; XLRS, X linked retinoschisis www.jmedgenet.com Downloaded from jmg.bmjjournals.com on 11 April 2005 2 Weaving, Ellaway, Ge´cz, et al Table 1 Revised diagnostic criteria for classical and variant RS. Derived from tables 3 and 4 in the paper by Hagberg et al.8 Necessary criteria Supportive criteria Exclusion criteria Classical RS Apparently normal prenatal and Breathing disturbances while awake Organomegaly or other evidence of a perinatal history Bruxism storage disorder Psychomotor development normal Impaired sleeping pattern from early Retinopathy, cataract, or optic atrophy during the first 6 months (may be infancy History of perinatal or postnatal delayed from birth) Abnormal muscle tone accompanied brain damage Normal head circumference at birth by muscle wasting and dystonia Identifiable inborn error of metabolism Postnatal deceleration of head Abnormal muscle tone accompanied or neurodegenerative disorder growth (most individuals) by muscle wasting and dystonia Acquired neurological disorder due to Loss of purposeful hand skills Peripheral vasomotor disturbances severe infection or head trauma between 0.5–2.5 years Progressive scoliosis or kyphosis Stereotypic hand movements Growth retardation Evolving social withdrawal, Hypotrophic small and cold feet communication dysfunction, loss of and/or hands acquired speech, cognitive impairment Impaired or deteriorating locomotion Variant RS At least 3 of the 6 main criteria Breathing irregularities At least 5 of the 11 supportive criteria Air swallowing or abdominal bloating Main criteria Bruxism Absence or reduction of hand skills Abnormal locomotion Reduction or loss of speech Scoliosis or kyphosis (including babble) Hand stereotypies Lower limb amyotrophy Reduction or loss of Cold, discoloured feet, usually communication skills hypotrophic Deceleration of head growth Sleep disturbances, including night from early childhood time screaming Regression followed by recovery Inexplicable episodes of laughing or of interaction screaming Apparently diminished pain sensitivity Intense eye contact and/or eye pointing forgotten that RS may occur coincidently with other Management disorders,11 12 potentially delaying the diagnosis. Medical management of RS is essentially symptomatic and With increasing experience it has become clear that supportive. A multidisciplinary team approach is advocated, females with RS may present with a much broader phenotype aimed at maximising each patient’s abilities and facilitating than originally described. A number of variants have been any skills that may be emerging. Management should include described, which may be more or less severe than the clinical psychosocial support for the families, development of an picture seen in classical RS.13 Although initially thought to be appropriate education plan, and assessment of available a disorder exclusively affecting females, males with a Rett- community resources. Parent