Diagnostic criteria for Rett syndrome [29]
1. Introduction
Defects in epigenetic mechanisms can give rise to several neurological and behavioral phenotypes. Rett syndrome (MIM 312750) is a pervasive neurodevelopmental disorder that is primarily caused by mutations in a gene encoding methyl-CpG-binding protein 2. The functions of the protein are related to DNA methylation, a key epigenetic mechanism that plays a critical role in gene silencing through chromatin remodeling. Rett syndrome was the first human disorder in which a link between epigenetic modification and neuronal dysfunction was discovered. In this chapter, the clinical features and the molecular pathology of Rett syndrome will be discussed.
1.1. History
Rett syndrome was first recognized by the Viennese pediatrician Andreas Rett. In 1965, he observed two girls sitting on their mothers’ laps in his waiting room. Both girls were profoundly intellectually disabled and were continually wringing their hands in the same unusual manner. Dr. Rett recollected seeing such behavior in previous patients and searched for their files with his secretary. They found several girls with a similar developmental history and clinical features. He realized that these symptoms constituted something other than cerebral palsy, which was the usual designation at the time. In 1966, Dr. Rett published the first description of the disorder that now bears his name [1]. His paper, however, remained unnoticed by the medical community until the 1980s, when Swedish child neurologist Bengt Hagberg with colleagues published the same clinical findings and named the disorder Rett syndrome [2]. Later, diagnostic criteria were proposed [3], and Rett syndrome became recognized worldwide by pediatricians, neurologists, geneticists, and neuroscientists. Despite great effort, the genetic cause of the disorder was not determined until more than 30 years after the first clinical account. In 1999, mutations within the methyl-CpG-binding protein 2 gene (
1.2. Occurence
The estimated prevalence of Rett syndrome is 1:10,000 females by the age of 12 years old [6] with no specific ethnic or geographical preference. Rett syndrome is one of the leading genetic causes of profound mental retardation in females, second only to Down syndrome [7]. Male cases are very rare, and their phenotypic manifestations are different from those observed in girls with Rett syndrome.
2. Clinical aspects of Rett syndrome
2.1. Symptoms and stages
Rett syndrome, in its classic form, begins to manifest in early childhood and is characterized by neurodevelopmental regression that severely affects motor, cognitive, and communications skills.
Prenatal and perinatal periods are usually normal. Affected girls appear to develop normally during the first 6 to 18 months of life and seem to achieve appropriate developmental milestones. Nevertheless, retrospective analyses of home videos often show that, even during this period, affected female infants display some suboptimal development. This underdevelopment may include subtle motor and behavioral abnormalities, as well as hypotonia and feeding problems. General mobility and eye-hand coordination may be inadequate, and an excess of repetitive hand patting can be observed even during the first year of life. However, the overall developmental pattern is not obviously disturbed. The child is usually quiet and placid, and the parents often describe the child as “very good” [1, 8-11]. The characteristic clinical features appear successively over several stages, forming a distinctive disease progression pattern (Figure 1).
Females with Rett syndrome often survive into adulthood and older age, but their life expectancy is less than that of the healthy population. The estimated annual death rate from Rett syndrome is 1.2%. Approximately 25% of these deaths are sudden and they may occur due to autonomic nervous system disturbances or cardiac abnormalities [25-27].
Many other features are associated with Rett syndrome, but they are not considered diagnostic. The patients are generally small for their age [28], which may be due to poor self-feeding abilities and problems with chewing and swallowing. They often suffer from gastroesophageal reflux and bloating. Decreased intestinal motility often results in severe constipation. Electroencephalogram results tend to be abnormal but without any clear diagnostic pattern. A prolonged QTc interval is observed in many patients and presents a risk for cardiac arrhythmia [26].
2.2. Rett syndrome variants
At least five atypical variants have been delineated in addition to classic Rett syndrome. These variants do not have all of the diagnostic features, and they are either milder or more severe than the classic form.
The most common atypical variant of Rett syndrome is “forme fruste”. This mild variant is characterized by a protracted clinical course with partially preserved communication skills and gross motor functions. Other neurological abnormalities that are typical for Rett syndrome are more subtle and can be easily overlooked in this variant [30]. The mild forms of Rett syndrome also include the late regression variant, which manifests in patients of preschool or early school age [30], and the preserved speech variant (also called the Zappella variant) in which patients have preserved language skills and normal head sizes [31].
Severe variants include the early-onset seizure variant (the Hanefeld variant) with the onset of seizures before the age of 6 months [32] and the congenital variant, which is rare and lacks the early period of normal psychomotor development [33]. The Hanefeld variant is often caused by mutations in the
2.3. Diagnostic criteria
Despite a known genetic cause, Rett syndrome remains a clinical diagnosis. Its diagnosis is based on several well-defined criteria (Table 1), which were revised several times over the past few decades, most recently in 2010 [29].
Consider Rett syndrome diagnosis when postnatal deceleration of head growth is observed |
1. A period of regression followed by recovery or stabilization 2. All main and all exclusive criteria 3. Supportive criteria are not required, although often present in classic Rett syndrome |
1. A period of regression followed by recovery or stabilization 2. At least 2 of 4 main criteria 3. 5 out 11 supportive criteria |
1. Partial or complete loss of acquired purposeful hand skills 2. Partial of complete loss of acquired spoken language 3. Gait abnormalities: impaired ability (dyspraxia) or absence of ability (apraxia) 4. Stereotypic hand movements such as hand wringing/squeezing, clapping/tapping, mouthing and washing/rubbing automatisms 1. Brain injury secondary to trauma (perinatally or postnatally), neurometabolic disease or severe infection that cause neurological problems 2. Grossly abnormal psychomotor development in the first 6 months of life 1. Breathing disturbances when awake (hyperventilation, breath-holding, forced expulsion of air or saliva, air swallowing) 2. Bruxism when awake (grinding or clenching of the teeth) 3. Impaired sleep pattern 4. Abnormal muscle tone 5. Peripheral vasomotor disturbances 6. Scoliosis/kyphosis 7. Growth retardation 8. Small cold hands and feet 9. Inappropriate laughing/screaming spells 10. Diminished sensitivity to pain 11. Intense eye communication and eye-pointing behavior |
3. The genetics of Rett syndrome
3.1. Mapping of the causative gene
The mode of inheritance of Rett syndrome was difficult to identify because more than 99% of the cases are sporadic, and the patients rarely reproduce. Therefore, the traditional genome-wide linkage analysis was not an applicable method for mapping the disease locus. The lack of males manifesting the classic Rett syndrome phenotype together with the occurrence of families with affected half-sisters suggested an X-linked dominant inheritance with lethality in hemizygous males [2, 36]. Focused exclusion mapping of the X chromosome in available familial cases was used to narrow down the candidate region, and the subsequent analysis of candidate genes in the patients finally revealed disease-causing mutations in the
3.2. MECP2 gene
The
3.3. MECP2 mutations
Mutations in the
According to the Human Gene Mutation Database [47], more than 550 mutations have been identified in the
The majority of point mutations in the
3.4. MECP2 mutations in males and other disorders
Mutations in the
The estimated frequency of
In females,
3.5. MeCP2 protein
The MeCP2 protein is ubiquitously expressed, but it is particularly abundant in the brain [41, 69]. The protein levels are low during embryogenesis, but they progressively increase during postnatal neuronal maturation and synaptogenesis [70-75]. High expression of MeCP2 in mature neurons implies its involvement in postmitotic neuronal functions, such as the modulation of neuronal activity and plasticity [12].
MeCP2 occurs in two isoforms that arise from alternative splicing of exon 2, and they differ only by their N-termini (Figure 2). MeCP2 e1 (498 amino acids), generated by exons 1, 3, and 4, is the dominant MeCP2 isoform in the brain [76-78]. The MeCP2 e2 isoform (486 amino acids) is encoded by exons 2, 3, and 4. Both isoforms were initially assumed to be functionally equivalent, but recent observations imply that additional isoform-specific functions may exist. This idea is strongly supported by the fact that no mutations in exon 2 have been found in Rett syndrome patients, which contrasts with the finding of identified mutations in exon 1. Thus, defects in MeCP2 e2 may lead to non-Rett phenotypes or fatally affect embryo viability [79, 80].
Apart from different N-terminal regions, both isoforms share the same amino acid sequence, including at least three functional domains and two nuclear localization signals (Figure 2). The methyl-CpG-binding domain (MBD) (amino acids 78-162) mediates binding to symmetrically methylated CpG dinucleotides [81, 82], with a preference for CpGs with adjacent A/T-rich motifs [83]. The MBD also binds to unmethylated four-way DNA junctions, which suggests the role of MeCP2 in higher-order chromatin interactions [84]. The transcriptional repression domain (TRD) (amino acids 207-310) interacts with numerous proteins, such as co-repressor factors and histone deacetylases, HDAC1 and HDAC2. The nuclear localization signals (NLS) (amino acids 173-193 and 255-271) mediate transportation of the protein into the nucleus [85]. The C-terminal domain (amino acids 325-486) facilitates binding to DNA [86] and it most likely increases protein stability [87]. This domain also contains conserved poly-proline motifs that can bind to group II WW domain splicing factors [88].
3.6. MeCP2 function
The original model suggested that MeCP2 is a global transcriptional repressor [89], and it was based on
Surprisingly, transcriptional profiling studies did not reveal major gene expression changes caused by the lack of functional MeCP2 protein [98, 99]. These observations, together with additional evidence, implied that MeCP2 regulates the transcription of tissue-specific genes in specific brain regions during certain developmental stages instead of acting as a global repressor [98, 100-102]. However, recent studies suggest that MeCP2 reduces genome-wide transcriptional noise, potentially by repressing spurious transcription of repetitive elements [103, 104]. Surprisingly, MeCP2 also interacts with the transcriptional activator CREB, and its genomic distribution is often associated with actively transcribed genes [105, 106]. MeCP2 apparently has dual roles in transcriptional regulation as a repressor and as an activator, and it performs different downstream responses depending on the context.
MeCP2 additionally acts as an architectural chromatin protein that is involved in chromatin remodeling and nucleosome clustering, which is consistent with the fact that the majority of MeCP2-binding sites are located outside of genes [105, 107]. MeCP2 can bind
For further complexity, MeCP2 may also be involved in RNA splicing. Its interaction with the RNA-binding protein Y box-binding protein 1 (YB-1) has been observed, and MeCP2-deficient mice showed aberrant alternative splicing patterns [110].
MeCP2 functions are undeniably much more complex than initially anticipated (Figure 3), although the precise mechanisms of their regulation remain unknown.
3.7. MeCP2 target genes
A comprehensive knowledge of the target genes that are controlled by MeCP2 is essential for understanding the pathomechanisms of Rett syndrome and subsequently developing effective therapeutic strategies. Multiple studies have attempted to identify genes with altered expression in neuronal and nonneuronal tissues from Rett syndrome patients and mouse models, but these studies have often yielded conflicting results [102, 106, 112, 113]. Nevertheless, several candidate target genes have been proposed (Table 2). One of the most extensively studied target genes is the brain-derived neurotrophic factor gene (
|
|
|
|
member of ubiquitin proteasome pathway, transcriptional co-activator | [118] |
|
neurotransmission (GABA-A receptor) | [118] |
|
cell adhesion | [119] |
|
cell adhesion | [119] |
|
neuronal development and survival, neuronal plasticity, learning and memory (brain derived neurotropic factor) | [113, 114] |
|
neuronal transcription factor (probably involved in control of GABAergic differentiation) | [116] |
|
hormone signaling (regulation of renal functions and blood pressure) | [120] |
|
hormone signaling (regulation of glucocorticoid receptor sensitivity) | [120] |
|
member of mitochondrial respiratory chain | [121] |
|
transcription factors (involved in cell differentiation and neural development) | [122] |
|
ion channel regulator | [123] |
|
hormone signaling (regulation of cell proliferation and apoptosis) | [124] |
|
regulation of GDP/GTP exchange | [112] |
|
enhancer of neuronal apoptosis | [112] |
|
Extracellular molecular chaperone | [112] |
|
neuropeptide (regulation of neuroendocrine stress response) | [125] |
3.8. The effect of MECP2 mutations on MeCP2 function
Mutations in the
3.9. Genotype-phenotype correlation
The severity of the clinical manifestations in Rett syndrome patients is widely variable and is relevant beyond the context of classic vs. atypical variants. Therefore, much effort has been devoted to uncovering the relationships between various
The general genotype-phenotype correlations were confirmed by numerous studies. As expected, patients with early truncating mutations (specifically p.R168X, p.R270X, p.R255X), large deletions of several exons, or the entire
Despite some overall trends, considerable variability in clinical severity is often observed among patients with the same
3.10. Genetic counseling
A negative result from the
4. Management of Rett syndrome
Currently, there is no effective cure for Rett syndrome. However, hopes for developing a targeted therapy have risen following the announcement of a study that rescued the pathological phenotype in a mouse model after postnatal reactivation of
Rehabilitation programs and physical therapy help to control and improve balance and movement, maintain flexibility and strengthen muscles. These programs should be adapted to the patient’s individual state and needs. Proper physical therapy is also important for preventing joint contractures and other deformities, such as scoliosis. Occupational therapy is recommended for improving purposeful hand use and to attenuate stereotypic hand movements. Particular care should be taken to preserve and maintain alternative communication (eye contact, eye pointing, facial expressions, signs, etc.) and thereby improving social interactions. Receiving necessary nutrients and maintaining an adequate weight may result in improved growth. To ensure appropriate caloric and nutritional intake, a high-fat, high-calorie diet or gastrostomy feeding may be required. Sufficient intake of fluid and high-fiber food is necessary to prevent constipation. The patients with cardiac conduction defects (such as prolonged QTc intervals) should avoid certain medications, which may worsen the condition. These medications include several antipsychotics (thioridazine, tricyclic antidepressants), certain antiarrhythmics (quinidine, sotalol, amiodarone), and antibiotics (erythromycin) [147].
Early diagnosis and intervention, together with life-long management focused on each patient’s specific needs, can significantly improve the health, quality of life, and longevity of patients with Rett syndrome.
5. Conclusion
Much progress has been made in the identification of the multiple roles of the MeCP2 protein in the brain since its discovery. Nevertheless, many mysteries still remain in understanding the precise mechanisms of how
Acknowledgments
I would like to thank prof. Pavel Martasek, MD, Ph.D. for helpful discussions and critical reading of the manuscript. The author was supported by grants NT 13120-4/2012, MZCR RVO-VFN64165/2012, P24/LF1/3, and UNCE 204011/2012.References
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