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Brain & Development 23 (2001) S202–S205 www.elsevier.com/locate/braindev Original article Rett syndrome: clinical correlates of the newly discovered gene q Alan K. Percy* Department of Pediatrics, Neurology, and Neurobiology, University of Alabama at Birmingham, School of Medicine, Birmingham, AL 35233, USA Abstract The recent identification of mutations in the gene, MECP2, in girls with Rett syndrome (RS) firmly establishes the molecular genetic basis of this X-linked dominant disorder. This discovery, with ramifications far beyond establishing the gene for RS, represents a dramatic conclusion to an intensive, decade-long search. MECP2 encodes a methyl-CpG-binding protein (MeCP2) involved in transcriptional silencing of a yet to be defined number and type of genes. The clinical spectrum of resultant disorders extends well beyond RS. Indeed, the clinical phenotypes for MECP2 mutations range from mild disability in the mother of a girl with RS to rapidly progressive encephalopathy in her brother. Further, the recent identification of MECP2 mutations in boys with phenotypes quite different from RS adds yet another element to the mix. Within the classic RS group, clinical severity varies remarkably, depending at least in part on the degree of non-random X-inactivation. Those with clinical patterns in the border zones of RS remain to be examined fully for less severe mutational events. Further, the pathobiology of RS and the role of transcriptional silencing as a disease-producing mechanism could be a prototype for other disorders of neurodevelopment. Thus, the identification of mutations in MECP2 creates completely new vistas as to fundamental neurobiologic processes, to disease mechanisms in the neurodevelopmental disabilities, and to potential new therapeutic strategies for RS and related disorders. q 2001 Elsevier Science B.V. All rights reserved. Keywords: Rett syndrome; Phenotypic variation; Transcriptional silencing; MECP2 mutations 1. Rett syndrome and its variant forms Rett syndrome (RS), with a prevalence of 1:10,000– 20,000, is a numerically significant cause of neurodevelopmental disability in females, exceeding that of phenylketonuria [1–3]. RS typically has its clinical onset between 6–18 months of age following a period of apparently normal development. The diagnosis of RS requires that certain clinical criteria (Table 1) are met [4]. Variant forms of RS including formes fruste, preserved speech, and congenital onset have been recognized for some time and criteria [5] have been established for these as well (Table 2). Among the population of girls in Sweden [3], more than 80% have classic RS (Table 3). The recent discovery of mutations in the MECP2 gene in girls fulfilling the established criteria for RS culminates a decade long search for a genetic explanation of this very intriguing disorder [6]. This discovery allows the confirmation of clinical diagnoses and the development of genotypephenotype correlations. Further, the border zones of clinical involvement for girls who do not meet all diagnostic criteria q Presented in part at the World Congress on Rett Syndrome 2000, Karuizawa Nagano Japan, July, 2000. * 1600 7th Avenue South, Suite 516. Tel.: 11-205-939-9588; fax: 11205-939-6184. E-mail address: [email protected] (A.K. Percy). for RS can now be examined carefully at the molecular genetic level. At the present time, the majority of girls fulfilling the criteria for RS have mutations in MECP2 [7–11]. The remainder either have mutations in as yet unexplored regions of MECP2 or are explained by alternative genes. One critical element in advancing our understanding of the role of MECP2 in neurodevelopmental disabilities is the establishment of firm criteria that extend over the continuum of clinical involvement for RS and its variant forms. Further, these criteria must be carefully applied. This places the responsibility squarely on the clinician to provide clear and complete descriptions of the clinical presentations for all girls in whom mutations in MECP2 are identified. Furthermore, how far should the net be cast in the evaluation of girls or boys with unexplained neurodevelopmental disabilities? As will be discussed below, the phenotypic spectrum arising from mutations in MECP2 is remarkable. Are we wise enough to determine which individuals and under what circumstances mutational analysis should be requested? The recent data suggest that we are not yet there. 2. Phenotype–genotype correlations Attempts at providing phenotype-genotype correlations with respect to RS and mutations in MECP2 have led to 0387-7604/01/$ - see front matter q 2001 Elsevier Science B.V. All rights reserved. PII: S03 87- 7604(01)0035 0-3 A.K. Percy / Brain & Development 23 (2001) S202–S205 S203 Table 1 Rett syndrome. Obligate criteria for diagnosis a Table 3 Rett syndrome. Phenotypic distribution in Sweden a Criteria Onset Phenotype Number Per cent Normal at birth Apparently normal early development Postnatal deceleration of head growth Loss of purposeful hand skills Psychomotor regression Communication dysfunction Autistic features Stereotypic movements Hand washing/wringing Hand clapping/patting Hand mouthing Gait dysfunction Gait apraxia Truncal ataxia Absence of Organomegaly Optic atrophy Retinal changes Intrauterine growth retardation – 6–8 months 3 months–4 years 9 months–2 1/2 years 9 months–2 1/2 years Classical Formes frustes 9 > Late regression = Preserved speech > ; Congenital 106 15 81.5 11.5 9 7.0 a a 1–3 years 1–4 years Adapted from Refs. [3,4]. mixed results [7,9,10]. This may be due in part to the multiplicity of mutations associated with RS and the fact that different studies are deriving their comparisons from a different set of mutations. The factor which appears to have the greatest influence on phenotype is the degree of non-random X-chromosome inactivation (XCI) [7]. Systematic study of XCI has not been performed. Further, XCI may vary remarkably between tissues. Thus, correlations based on sampling peripheral tissues such as lymphocytes may be misleading. One lesson to be learned is that comparisons among girls with RS must be based on carefully conducted clinical evaluations using agreed upon clinical criteria and clinical severity scales. For example, the clinical criteria for RS and the clinical severity scales differed between the studies of Table 2 Rett syndrome. Delineation of phenotypic variants a Inclusion criteria: 1. Female 2. At least 10 years old 3. Meet at least three of six main criteria 4. Meet at least five of 11 supportive criteria Eleven supportive criteria: 1. Breathing irregularities 2. Teeth grinding 3. Scoliosis/kyphosis 4. Lower limb amyotrophy 5. Cold, purplish feet a Adapted from Hagberg and Witt-Engerström as contained in Ref. [3]. Six main criteria: 1. Loss of finger skills 2. Loss of babble/speech 3. Loss of communication skills 4. Deceleration of head growth 5. Hand stereotypies 6. RS disease profile 6. Bloating 7. Gait apraxia 8. RS EEG pattern 9. RS eye pointing 10. Pain indifference 11. Laughing/screaming spells Adapted from Hagberg and Skjeldal, Ref. [5]. Amir et al. [7] and Cheadle et al. [9]. As such, direct comparisons between the two studies is not possible. In future, it will be important to base phenotype-genotype correlations on a common clinical severity scale among girls who fulfill the classic criteria or whose deviation from these criteria is clearly indicated. 3. MECP2 mutations extending beyond the boundaries of Rett syndrome The second major outcome from identification of mutations in MECP2 is the broad spectrum of clinical phenotypes associated with such mutations [8,12–16]. This finding should, however, not be surprising. Similar results have been obtained for a number of inherited disorders. Disease processes associated with mutations in the hexosaminidase A gene (HEXA), which is responsible for TaySachs disease, represent the most striking example. The phenotypes arising from mutations in HEXA range from Tay-Sachs disease to the distinct clinical pictures of dystonia, spinocerebellar degeneration, amyotrophic lateral sclerosis, spinal muscular atrophy, or psychotic depression. Thus, it is hardly surprising that similar variability in clinical presentation should emerge from mutations in MECP2. As such, it is necessary to consider how wide to cast the net over other neurodevelopmental disorders with respect to mutations in this gene. If recent experience is a guide, the span will be broad. The range of disorders associated with MECP2 mutations now involves both females and males (Table 4). Among females, mutations have been identified in association with RS and Table 4 Rett syndrome. Phenotypes associated with MECP2 mutations Females Rett syndrome Formes fruste Preserved speech variant Delayed onset variant Mild learning disability Normal carriers Males Fatal encephalopathy Rett/Klinefelter syndrome X-linked mental retardation/progressive spasticity Somatic mosaicism/neurodevelopmental delay S204 A.K. Percy / Brain & Development 23 (2001) S202–S205 Fig. 1. These overlapping circles depict the relationship between Rett syndrome (RS) and mutations in the MECP2 gene. Mutations have been defined in some but not all girls with RS. Conversely, mutations have been defined in individuals lacking some or all of the features of RS including normal carrier females. MECP2, designation for the methyl-CpG-binding protein 2 gene; C, female; F, male. its variants and in normal women as well as those with mild learning disability. In males, typical RS profiles have been identified in at least two boys with Klinefelter syndrome [12,13]. Other males have also been described. These include (1) severe X-linked mental retardation and progressive spasticity in two boys in one family [16], (2) a Rett-like phenotype in another boy [14], and (3) progressive encephalopathy in at least two others [17]. In the first family, both mothers and the two boys share a common mutation in MECP2 [16]. One mother was normal, but the other had borderline intelligence. Both boys had non-syndromic mental retardation and progressive spasticity. The boy with a Rett-like phenotype lacked stereotypic hand movements and evidence was not presented regarding the presence or absence of deceleration in the rate of head growth. His phenotype is explained by somatic mosaicism for the MECP2 gene, that is, some of his cells express a mutation in MECP2, the remainder have a normal copy of this gene [14]. More recent observations of this boy suggest that he now has hand stereotypies and may well fit the criteria for classic RS (personal communication, Kathy Hunter, International Rett Syndrome Association). One of the boys with progressive encephalopathy shared a common MECP2 mutation with his mother, who has a mild learning disability, and his sister and aunt, who have classic RS [8]. This array of phenotypes associated with RS is displayed in the Fig. 1 as overlapping circles depicting the close relationship between this disorder and individuals with mutations in MECP2. Currently, mutations in this gene have not been identified in some girls with RS. Conversely, mutations in MECP2 have been described in males and females who display features either in common with RS or completely disparate. The overlap region includes girls with classic and variant forms of RS. This pattern is likely to expand as new associations with MECP2 mutations are defined. As stated above, it seems unlikely that we are wise enough or have sufficient information at this time to predict which neurodevelopmental disabilities are likely to be explained by such mutations. Certainly, girls fulfilling some or all criteria for RS should be tested. Mutational analysis should also be considered carefully in children with non-syndromic cognitive impairment, autism with progressive features, and X-linked neurodevelopmental disabilities. 4. Role of MECP2 in developmental neurobiology The role of MECP2 in transcriptional silencing and of its subsequent effects on developmental neurobiology is largely unexplored. The identification of mutations in this A.K. Percy / Brain & Development 23 (2001) S202–S205 gene in girls with RS has sparked new interest in this area. From our understanding of the neuropathology of RS, MECP2 would appear to impact fundamental mechanisms in synaptic development [18,19]. As proposed by Michael Johnston at this meeting, the hallmark of cellular dysfunction in RS may be the ‘sick’ synapse. This fits well with the known involvement of multiple neurotransmitter systems and abnormalities in dendrite formation and places the timing of cellular dysfunction in the last third of gestation or very early infancy. Evidence that proliferation and migration of neurons proceed appropriately during the first 25 weeks of gestation and that deceleration in the rate of head growth is present already by three months of life suggests this temporal boundary [20]. The specific neurobiologic events and the downstream genes underlying RS on the one hand and normal neurodevelopment on the other remain to be determined. The unfolding panorama of ongoing investigations will certainly provide important new insights for both. [8] [9] [10] [11] [12] [13] [14] References [15] [1] Rett A. Über ein eigenartiges hirnatrophisches Syndrom bei Hyperammonamie im Kindesalter [German]. 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