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For members of the Texas Children's Hospital medical staff
Rett syndrome and the expanding world of MeCP2 disorders
By Huda Y. Zoghbi, M.D.
Over 40 years ago pediatrician Andreas Rett was quick to notice two girls in his waiting room with a similar peculiar behavior: They were both wringing their hands incessantly. After making note of their repetitive movements and neurological deficits, he went on to identify an additional 20 girls with similar features(1). In 1983, Hagberg and colleagues reported on 35 patients who had similar features to those observed by Rett and termed the disorder Rett syndrome(2).
Rett syndrome patients appear normal the first 6-18 months of life; their head size is normal at birth, but head growth decelerates after their first birthday resulting in acquired microcephaly. Affected girls lose acquired language and social skills and engage in stereotyped hand wringing, clapping, or hand mouthing activities. They go on to develop ataxia, apraxia and spasticity. Seizures and respiratory abnormalities (apnea alternating with hyperventilation) occur in the majority of the patients. Additional features include anxiety, scoliosis, decreased gastrointestinal motility, and autonomic dysfunction manifesting as cold hands and feet. Although these features occur gradually over a period of three to five years, the disorder is not degenerative and the vast majority of patients survive into adulthood up to the seventh decade so far.
Rett syndrome is a sporadic disorder in 99 percent of the cases; however, the occurrence of this syndrome in females coupled with a handful of familial cases related through maternal lines suggested that Rett syndrome is an X-linked disorder. In 1999, mutations in MECP2, a gene that encodes methyl CpG-binding protein (MeCP2), proved to cause Rett syndrome(3). The discovery of the Rett syndrome gene allowed earlier diagnosis prior to the development of all the features. To date, mutations in MECP2 account for about 95 percent of classic Rett syndrome cases. Although the genetic defect in the remaining 5 percent has not yet been found, it is likely that MECP2 is the culprit in these cases. Mutations in another X-linked gene, CDKL5 (cyclin-dependant kinase-like 5) account for a neurological disorder that shares some features with Rett syndrome, but differs in that patients do not experience the period of apparently normal early development(4, 5). Patients with CDKL5 mutations typically have neonatal onset of symptoms and present with infantile massive spasms.
The phenotypic spectrum of patients with MECP2 mutations
As clinicians ordered MECP2 analysis on patients with partial features of Rett syndrome, it became clear that a broad spectrum of phenotypes can be caused by mutations in MECP2 (Table 1). It is interesting that some patients who were diagnosed as having Angelman syndrome but did not have the typical genetic defects on chromosome 15q proved to have mutations in MECP2. These phenotypes of MECP2 disorders vary, depending on whether the patient is a female or male. Female patients with partial or milder phenotypes, including autistic spectrum disorder, mild mental retardation with or without seizures, or minimal learning deficits, have been identified. Patterns of X chromosome inactivation underlie the phenotypic variability in such females. Normally, in every female only one of the X chromosomes is active in a particular cell. This process is random; such as in half of the cells the X inherited from a father is active whereas in the other half the X from the mother is active. Therefore, if a Rett patient has a MECP2 mutation, half of her cells will express non-functional MeCP2 whereas the other half will express a functional copy. Deficiency of a functional protein in half of the cells is enough to cause Rett syndrome (Figure 1).
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Figure 1. Patterns of X-inactivation explain the variability of phenotypes in females with MECP2 mutations. Red and Blue cells represent cells expressing either maternal or paternal X chromosome as active. In the example shown, the MECP2 mutation is on maternal X chromosome (Red).
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In some females carrying a mutant copy of MECP2, it appears that during early development the cells with the healthy copy divide faster (or survive better) resulting in a higher ratio of cells expressing a functional MeCP2. Such patients may then only express a couple of features rather than the full-blown syndrome. For example, patients in which 85 percent of the cells express the healthy MECP2 copy and only 15 percent express the mutant copy typically present with mild mental retardation or autism. There are rare cases whereby only cells expressing the healthy allele survive; such patients may not have any symptoms, although they are carriers of the mutant allele. Such asymptomatic carriers may have affected children; hence it is important to identify them.
Because males have only one X chromosome, a mutation that inactivates this protein results in loss of function of the protein in 100 percent of the cells. This proved to be detrimental and causes neonatal encephalopathy and death during infancy. Males carrying mutations that partially compromise the protein function present with a variety of neuropsychiatric symptoms, as outlined in Table 1. Occasionally, males with an inactivating mutation may present with classic Rett syndrome if a mutation occurs in context of 47XXY karyotype (as in Klinefelter syndrome) or if it happens in somatic tissue, such as half of the cells will have a healthy X chromosome(6). More recently, a new type of mutation expanded the list of disorders caused by MeCP2 dysfunction. Duplication of a 450 kilobase pair region of the X chromosome, encompassing MECP2, has been discovered in boys with a progressive neurological disorder characterized by hypotomia, mental retardation, seizures, movement abnormalities, and recurrent respiratory infections(7-9). Some of these males had Rett-like features. Although the duplication encompasses more genes than MECP2, the finding that doubling levels of MeCP2 in transgenic mice reproduces the phenotypes of human patients suggests that most of the features in the duplication cases are due to increased MECP2 levels(10). Altogether, the data point to the critical role of MeCP2 in neuronal function and integrity. Disturbances of either its function or its level cause a broad spectrum of clinical phenotypes and clearly interfere with postnatal neuronal development.
Pathogenesis studies
Several mouse models have been generated to investigate the pathogenesis of Rett syndrome and related disorders(11). Some of these mice totally lack MeCP2, others express a portion of the protein, and some express extra copies of the gene thus modeling the MECP2 duplication disorder. The mouse models reproduce all the features of the human disease, including neuropsychiatric phenotypes, cognitive deficits and abnormal motor function and movements. Because MeCP2 is believed to silence gene expression in neurons, several of the studies focused on identifying genes whose expression is altered when the protein is not functioning properly. To date, a handful of such genes have been identified. Among these genes, brain-derived neurotrophic factor (BDNF) has gained attention given its critical role for proper neuronal function and maintenance(12, 13). Recently, another molecule critical for normal neuronal function and homeostasis, corticotropin releasing hormone (Crh) has been identified as a misregulated target of MeCP2(14). Increased levels of Crh led to enhanced stress response and anxiety, features seen in Rett patients and the mouse model. Efforts are now focusing on testing therapeutic options that might target such molecules. Restoring BDNF levels genetically in the mouse improved the activity level and life span in a mouse model of Rett syndrome(15). Thus, it would be interesting to determine if pharmacologic approaches could restore BDNF levels. In the case of Crh, antagonists for the receptor have been shown to decrease anxiety in rodents and humans(16, 17), thus pre-clinical studies in the Rett mouse model are indicated to see if such therapy will subdue the anxiety and the exaggerated stress response.
Clinical implications
The findings that mutations in MECP2 cause Rett syndrome and a broad class of neurodevelopmental disorders, allow the practicing pediatrician to identify such cases early. Although a pharmacologic intervention to treat Rett syndrome is not available yet, targeted management of the various symptoms is clearly improving the quality of life and general health of these patients. Early physical therapy will keep the patients ambulatory, decrease incidence of scoliosis, and prevent secondary complications. Nutritional support is combating the somatic growth retardation seen in most of these patients. Other therapies include treatment of seizures, management of gastrointestinal symptoms and behavioral interventions that capitalize on the retained skills. The hope is that in the coming few years, therapies targeting the specific symptoms of Rett and related disorders can be developed. The apparently normal period of development provides a window of opportunity to intervene. Even if symptoms have developed, it is likely that when proper therapeutic interventions are developed, the course of the disease in symptomatic individuals will be altered given the plasticity of neurons and the promising data emerging from animal studies(18).
| Table 1. Spectrum of phenotypes seen in patients with MECP2 mutations |
Females |
Classic Rett syndrome |
Mental retardation with seizures |
Angelman-like |
Autism spectrum disorders |
Mild mental retardation |
Males |
Encephalopathy and infantile death |
Classic Rett syndrome (47 XXY or somatic mosaic) |
Mental retardation, seizures, ataxia, tremors |
Mental retardation, autism, tremors, and hyperactivity |
Mental retardation, bipolar disease or juvenile onset schizophrenia, and tremor |
| Table 2. Phenotypes of MECP2 duplication syndrome |
Deceleration of head growth |
Facial and axial hypotonia |
Progressive motor delay |
Spasticity and hypoactivity |
Seizures (absence or tonic-clonic) |
Profound mental retardation with limited or absent speech |
Ataxia |
Autistic features |
Rett-like phenotypes |
Recurrent infections and premature death |
Useful Links:
The Blue Bird Circle - http://www.thebluebirdcircle.com
International Rett Syndrome Association - http://www.rettsyndrome.org
Rett Syndrome Research Foundation - http://www.rsrf.org
Huda Y. Zoghbi, M.D., is the Marvin Fishman chair in pediatric neurology research; professor, departments of Pediatrics, Molecular and Human Genetics, Neurology, and Neuroscience at Baylor College of Medicine; and an investigator with the Howard Hughes Medical Institute.
References:
A. Rett, Wien Med Wochenschr 116, 723 (1966). B. Hagberg, J. Aicardi, K. Dias, O. Ramos, Ann Neurol 14, 471 (1983). R. E. Amir et al., Nat Genet 23, 185 (1999). L. S. Weaving et al., Am J Hum Genet 75, 1079 (Dec, 2004). J. Tao et al., Am J Hum Genet 75, 1149 (Dec, 2004). J. L. Neul, H. Y. Zoghbi, Neuroscientist 10, 118 (Apr, 2004). H. Van Esch et al., Am J Hum Genet 77, 442 (Sep, 2005). M. J. Friez et al., Pediatrics 118, e1687 (Dec, 2006). D. Del Gaudio et al., Genet Med 8, 784 (Dec, 2006). A. L. Collins et al., Hum Mol Genet 13, 2676 (Sep 6, 2004). T. Bienvenu, J. Chelly, Nat Rev Genet 7, 415 (Jun, 2006). Z. Zhou et al., Neuron 52, 255 (Oct 19, 2006). H. Wang et al., J Neurosci 26, 10911 (Oct 18, 2006). B. E. McGill et al., Proc Natl Acad Sci U S A 103, 18267 (Nov 28, 2006). Q. Chang, G. Khare, V. Dani, S. Nelson, R. Jaenisch, Neuron 49, 341 (Feb 2, 2006). D. A. Gutman, M. J. Owens, K. H. Skelton, K. V. Thrivikraman, C. B. Nemeroff, J Pharmacol Exp Ther 304, 874 (Feb, 2003). M. Lancel, P. Muller-Preuss, A. Wigger, R. Landgraf, F. Holsboer, J Psychiatr Res 36, 197 (Jul-Aug, 2002). G. Miller, Science 314, 1536 (Dec 8, 2006).
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