Abstract
Rett syndrome (RTT) is a neurological disorder caused by mutations in the X-linked gene methyl-CpG-binding protein 2 (MECP2), a ubiquitously expressed transcriptional regulator. Despite remarkable scientific progress since its discovery, the mechanism by which MECP2 mutations cause RTT symptoms is largely unknown. Consequently, treatment options for patients are currently limited and centred on symptom relief. Thought to be an entirely neurological disorder, RTT research has focused on the role of MECP2 in the central nervous system. However, the variety of phenotypes identified in Mecp2 mutant mouse models and RTT patients implicate important roles for MeCP2 in peripheral systems. Here, we review the history of RTT, highlighting breakthroughs in the field that have led us to present day. We explore the current evidence supporting metabolic dysfunction as a component of RTT, presenting recent studies that have revealed perturbed lipid metabolism in the brain and peripheral tissues of mouse models and patients. Such findings may have an impact on the quality of life of RTT patients as both dietary and drug intervention can alter lipid metabolism. Ultimately, we conclude that a thorough knowledge of MeCP2's varied functional targets in the brain and body will be required to treat this complex syndrome.
Highlights
Rett syndrome (RTT) is a neurological disorder caused by mutations in the X-linked gene methyl-CpG-binding protein 2 (MECP2), a ubiquitously expressed transcriptional regulator
Thought to be an entirely neurological disorder, RTT research has focused on the role of MECP2 in the central nervous system
We explore the current evidence supporting metabolic dysfunction as a component of RTT, presenting recent studies that have revealed perturbed lipid metabolism in the brain and peripheral tissues of mouse models and patients
Summary
Rett syndrome (RTT, OMIM #312750) was first described by Andreas Rett, an Austrian paediatric neurologist, after observing two female patients with identical hand-wringing stereotypies in his clinic waiting room Upon examination, he found that both patients had the same history: normal early development, followed by a period of regression and loss of purposeful hand movements. Wringing, clapping, washing) stereotypic, repetitive hand movements breathing irregularities appear microcephaly worsens seizures may occur duration: weeks to months, up to 1 year stage III: pseudo-stationary/plateau period prominent hand apraxia/dyspraxia may show more interest in surroundings, increased alterness and eye-pointing seizures are common duration: years to decades stage IV: motor deterioration severe physical disability wasting, dystonia and bradykinesia scoliosis wheelchair dependency (in some) not all girls progress to this stage duration: decades. Patients have a sudden and unexpected death rate of 26%, much higher than healthy individuals of a similar age, and typically die due to respiratory infection, cardiac instability and respiratory failure [32,33,34]
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