History of Rett Syndrome
Rett syndrome is a rare genetic neurodevelopmental disorder that affects about 1 in 10,000 girls in early childhood. After seemingly developing normally, girls in their second year of life begin to regress, losing learned skills like talking, using their hands, and other movements, and develop autistic behaviors. The disease varies widely among patients in its course and severity, but it can progress to severe intellectual and physical disabilities, sometimes including loss of controlled movement and epileptic seizures. After this initial decline, girls with Rett syndrome usually stabilize and live into adulthood. Although there is no cure for Rett syndrome, researchers have recently made major progress in understanding the genetic and molecular basis of this disease largely through work in animal models.
In 1954, when Austrian pediatrician Andreas Rett noticed a peculiar hand-wringing behavior in a number of his young female patients, the era of modern medical research had barely begun, and information moved at a pace that today seems archaic. Rett traveled throughout Europe conducting research about the disease and sharing information with colleagues, but the disease was not widely recognized until 1983 when Swedish physician Bengt Hagberg described the syndrome, naming it for Rett, in the widely read Annals of Neurology. Even then, doctors and researchers had little clue about what caused the disease, but the pattern seen in very rare familial cases suggested a dominant genetic mutation of a gene found on the X chromosome. (Although X-linked mutations often affect boys, Rett syndrome arises from a mutation of a gene so critical that male infants carrying the mutation seldom survive, and girls carrying even just one copy of the mutation develop the disease.)
A major breakthrough in understanding Rett syndrome came in 1999, when researchers at Baylor College of Medicine tracked down the gene that causes Rett syndrome by analyzing the sequences of genes on the X chromosome from individuals with the disease. The long search revealed mutations in a gene called MECP2, which encodes methyl-CpG-binding protein 2. Since then, the pace of research on Rett syndrome has accelerated rapidly. Among the most important developments for understanding Rett syndrome has been the generation of several mouse models of the disease, in which the MECP2 gene is either mutated or “knocked out.” Powered by the ability to genetically engineer mice and other animals, these studies have revealed information not just about Rett syndrome and the function of MECP2, but also about larger questions like gene regulation, neuronal plasticity, and neural function in general.
Although no animal model of disease can exactly recapitulate the human situation, animals genetically engineered to lack or have mutations to MECP2 give researchers the ability to isolate and examine the factors that contribute to the disease. Mice provide a key tool because researchers can manipulate their genes and observe their disease-related behaviors. Largely through work in the mouse models, the protein encoded by MECP2 has emerged as a critical regulator of neural gene expression, preventing other genes from making proteins when they are not needed. The mutations in MECP2 change the regulatory abilities of the protein, thereby altering the expression of many other genes. Nearly 300 different mutations have been reported in girls with Rett syndrome, but most are clustered around eight “hot spots” on the gene. Through animal studies, scientists are elucidating how each of these mutations affects the protein and its function throughout development. Rett syndrome has been called the “Rosetta stone” for understanding neurodevelopmental disorders, since the animal model work is informing scientists' understanding of so many other brain disorders.
In ongoing work in model animals, scientists are manipulating the MECP2 gene in specific subsets of brain cells to learn about their functions — information that could illuminate many other neurological disorders and even healthy behaviors. Rett research provides an elegant example of how a rare human disease, modeled in animals, has revealed a tremendous amount of information about the human nervous system.
Amir R, Van den Veyver IB, Wan M, Tran C, Francke U, et al. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nature Genetics. Oct;23(2):185-8 (1999).
Hagberg B, Aicardi J, Dias K, Ramos O. A progressive syndrome of autism, dementia, ataxia, and loss of purposeful hand use in girls: Rett's syndrome: report of 35 cases. Annals of Neurology. Oct 14:471-479 (1983).
Neul JL. The relationship of Rett syndrome and MECP2 disorders to autism. Dialogues in Clinical Neuroscience. Sep; 14(3): 253-262 (2012).