Review articleRett syndrome: Current status and new vistas☆
Section snippets
Clinical characteristics
RS (Fig. 1) is characterized by profound cognitive impairment, communication dysfunction, stereotypic movements, and pervasive growth failure, which follow a period of apparently normal development for the first 6 to 18 months of life [9]. All attempts to find a biologic marker were unsuccessful until the recent identification of a gene for RS [10]. The diagnosis of RS, however, is based on clinical criteria (Table 2) [11], [12], because not all girls with the RS phenotype have mutations in
Clinical staging
RS has been characterized in four clinical stages [14], providing a format for plotting clinical progression. The transition from one stage to the next is generally along a continuum rather than an abrupt change. The first stage is the early-onset stagnation period, which occurs from the age of 6 to 18 months. Usually, this stage lasts weeks to months and consists of delay in developmental progress but no clear evidence of regression. The second stage is that of rapid developmental regression
Variant phenotypic expression
Variant phenotypic expressions of RS are well described. The so-called forme fruste is the most common, consisting of delay in onset until the age of 8 to 10 years [15]. Other atypical forms include a preserved speech variant [16], a congenital form in which no period of developmental progress is noted, and an early-onset seizure form [17]. The relatively severe epileptic encephalopathy of the early-onset seizure form results in little or no normal early development.
Hagberg and Skjeldal [18]
Rett syndrome in boys and men
Convincing descriptions of boys and men with RS are limited. RS has been described in boys with more than one X chromosome (Klinefelter syndrome [XXY]) [19], [20], [21], [22]. Alternatively, mutations in MECP2 have been identified in male patients with features quite different from those of RS. These include individuals with a rapidly progressive encephalopathy [19], [23], [24], [25], severe developmental delay [26], [27], [28], spastic paraparesis [29], and nonspecific mental retardation [30],
Specific clinical issues
Several specific clinical issues should be noted. These include longevity, cognitive impairment, seizures, breathing irregularities, scoliosis, ambulation, growth failure, gastrointestinal function, and self-abuse. In general, survival is quite prolonged, and growth failure is pervasive.
Long-term management
Presently, long-term management of girls with RS involves appropriate physical and occupational therapy, speech therapy, nutritional support, orthopedic intervention, and seizure control [9], [32]. As noted previously, the potential longevity of women with RS requires long-term planning, because the parents may not be able to manage these needs as they age.
Neuropathology
The characteristic neuropathologic findings in RS consist of reduced brain weight, reduced volume of frontal cortex and deep gray nuclei, reduced melanin deposition in the substantia nigra, smaller neurons, reduced dendritic arborizations, and the absence of any recognizable disease process, particularly a progressive neurodegenerative disorder [54], [55], [56], [57], [58]. As such, the fundamental neurobiologic mechanism seems to be an arrest in normal neuronal maturation, giving RS the
Genetic basis of Rett syndrome
RS is a genetic disorder predominantly affecting girls and women and is transmitted in an X-linked dominant fashion with presumed lethality in boys and men. RS is sporadic in more than 99% of affected girls and women; that is, recurrence within families is less than 1%. Thus, for the most part, RS represents new mutations.
Despite the small number of familial cases, linkage studies were able to focus attention to Xq28, a gene-rich region [64], [65]. As a result, mutations were identified in the
MeCP2 function in developmental neurobiology
MeCP2 plays an important role in transcriptional silencing, yet its precise relation to developmental neurobiology is largely unknown [90]. The association of the gene encoding MeCP2 with RS has provided new impetus for such studies. MeCP2 functions in transcriptional silencing by binding to methylated CpG dinucleotides in gene promoter regions. In the mammalian genome, 60% to 90% of the cytosine residues in CpG dinucleotides are methylated, a process established during early embryonic
Summary
RS, the most common cause of profound cognitive impairment in girls and women, is composed of characteristic clinical features, including communication dysfunction, stereotypic movements, and pervasive growth failure. Neuropathologic findings indicate a failure of neuronal maturation with too small neurons and too few dendritic arbors and no evidence of a progressive neurodegenerative process. The combination of clinical and neuropathologic characteristics presents the profile of a
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Supported in part by the International Rett Syndrome Association.