MECP 2 disorders : from the clinic to mice and back

2 9 1 4 jci.org Volume 125 Number 8 August 2015 Introduction Austrian pediatrician Andreas Rett first reported in 1966 on young females exhibiting progressive dementia, motor loss, and stereotyped hand movements following normal development in their first 1 to 1.5 years of life (1). He filmed their unique clinical presentation, attempting to raise awareness and find similar cases of what he termed “cerebral atrophy with hyperammonemia.” Unfortunately, increased awareness of the condition occurred slowly due to the relative rarity of the condition, the fact that Dr. Rett published almost exclusively in German, and an equipment error resulting in only apparent hyperammonemia. It was not until 1983, when Swedish neurologist Bengt Hagberg and colleagues synthesized a series of similar cases from Europe in the Annals of Neurology, that the striking regression disorder would truly enter the international medical consciousness (2). In honor of the original observer and the continued dedication of Dr. Andreas Rett to these patients, the disorder would henceforth be known as Rett syndrome. In the years that followed, a clear clinical picture began to crystallize. Rett syndrome occurs in 1 in 10,000 live female births and is sporadic in over 99% of the cases (3). What genetic or environmental insult could result in such an acute defect around the peak of infant synaptogenesis? In 1999, Dr. Ruthie Amir, a postdoctoral fellow, discovered that loss-of-function mutations in methylCpG–binding protein 2 (MECP2) formed the genetic basis of Rett syndrome (4). Less than 6 years later, duplication of the very same gene was implicated in a severe male intellectual disability syndrome associated with premature death, MECP2 duplication syndrome (MDS) (5). In this Review, we will discuss the clinical consequences of MECP2 loss and gain of function, the power and significance of mouse models of these disorders, our molecular knowledge of MeCP2, and the path these models and molecular knowledge have paved for clinical trials. Manifestations of disease MECP2 dosage sensitivity. In their landmark 1983 article, Hagberg and colleagues catalogued 35 patients encountered over the course of 21 years in three different European countries (2). This breadth of clinical experience enabled them to propose four distinct phases of Rett syndrome: (a) stagnation of development after 7 to 18 months, (b) rapid deterioration, (c) a pseudostationary phase, and (d) late motor deterioration (6). Developmental stagnation is typified by a failure to meet major developmental milestones, including word development, social interaction, and motor ability. This developmental stagnation is further evidenced by acquired microcephaly and overall growth delay. Rapid deterioration results in loss of previously acquired abilities, such as walking or pulling to a stand, word use or babbling, affinity for or attention to social interaction, and grasping or gesturing. Purposeful hand movements are replaced by stereotypies, such as hand clasping and wringing. Respiratory abnormalities, such as hyperventilation and apneas, also often emerge at this stage. Mental decline coincides with motor dysfunction characterized by apraxia and often an ataxic gait. In the so-called pseudostationary phase (onset at ~3 to 10 years of age), seizures and scoliosis are common, but social interaction defects subside somewhat. Eventually, many patients lose the ability to ambulate and sometimes develop parkinsonian features in the phase of late motor deterioration (7, 8). These clinical features occur in the absence of any evidence of neuronal degeneration but are accompanied by decreased brain size, most likely resulting from the smaller neurons and reduced dendritic branching (9). The apparent gender specificity of this disorder was just as puzzling as the clinical presentation of regression. To explain this “exclusive involvement of females,” Hagberg proposed early on that Rett syndrome was due to a dominant X-linked mutation that resulted in nonviable hemizygous males (2). Further, he argued that his model predicted the rare occurrence of Klinefelter males (XXY) with Rett symptoms. Indeed, such a male was identified in 1999 (10). Although 99% of Rett cases are sporadic, the genetic basis of the disorder was affirmed by multiple examples of identical twin sisters concordant for Rett syndrome (11, 12). In the Two severe, progressive neurological disorders characterized by intellectual disability, autism, and developmental regression, Rett syndrome and MECP2 duplication syndrome, result from loss and gain of function, respectively, of the same critical gene, methyl-CpG–binding protein 2 (MECP2). Neurons acutely require the appropriate dose of MECP2 to function properly but do not die in its absence or overexpression. Instead, neuronal dysfunction can be reversed in a Rett syndrome mouse model if MeCP2 function is restored. Thus, MECP2 disorders provide a unique window into the delicate balance of neuronal health, the power of mouse models, and the importance of chromatin regulation in mature neurons. In this Review, we will discuss the clinical profiles of MECP2 disorders, the knowledge acquired from mouse models of the syndromes, and how that knowledge is informing current and future clinical studies. MECP2 disorders: from the clinic to mice and back