The common
            <i>BDNF</i>
            polymorphism may be a modifier of disease severity in Rett syndrome

Zeev, Bruria Ben; Bebbington, Ami; Ho, Gladys; Leonard, Helen; Klerk, Nicholas de; Gak, Eva; Vecksler, M.; Christodoulou, John

doi:10.1212/01.wnl.0000345664.72220.6a

Cited by 67 publications

(42 citation statements)

References 40 publications

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“…Additionally, increasing BDNF in KO animals via administration of fingolimod resulted in total rescue of motor dysfunction, as measured by the ability to stay on the rotating rod, and a 3-to 4-week extension of median lifespan (124). Importantly, the BDNF V66M polymorphism in patients with Rett syndrome appears to modulate the severity of symptoms in humans (125). Thus, two small clinical trials are currently underway to explore the effects of FDA-approved copaxone (glatiramer acetate), which has been shown to increase the number of BDNF-expressing cells in KO animals (126), on outcomes in patients with Rett syndrome.…”

Section: From Patient To Protein: the Molecular Function Of Mecp2mentioning

confidence: 98%

MECP2 disorders: from the clinic to mice and back

Lombardi¹,

Baker²,

Zoghbi³

2015

J. Clin. Invest.

191

166

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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.

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Section: From Patient To Protein: the Molecular Function Of Mecp2mentioning

confidence: 98%

MECP2 disorders: from the clinic to mice and back

Lombardi¹,

Baker²,

Zoghbi³

2015

J. Clin. Invest.

191

166

View full text Add to dashboard Cite

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“…Of interest also were their better growth parameters and increased likelihood of kyphosis. 120 Information from these 120,126,127,129 and other studies 20 is enormously useful when considering prognosis although it is clear that genotype is but one factor and other factors such as X-inactivation, 130 genetic modifiers, 131 and possibly environmental factors 132 also have a role to play (see Box 2).…”

Section: Overall Severity and Relationship With Genotypementioning

confidence: 99%

Clinical and biological progress over 50 years in Rett syndrome

2016

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It is fifty years since Andreas Rett first described Rett syndrome, a disorder now known to be caused by a mutation in the MECP2 gene. A compelling blend of astute clinical observations, clinical and laboratory research has already built our understanding of Rett syndrome and its biological underpinnings. We document the contributions of the early pioneers and describe the evolution of knowledge in terms of diagnostic criteria, clinical variation and the interplay with other Rett-related disorders. We provide a synthesis of what is known about the neurobiology of MeCP2, the lessons from both cell and animal models and how they may inform future clinical trials. With a focus on the core criteria, we examine the relationships that have been demonstrated between genotype and clinical severity. We review what is known about the many comorbidities that occur in this disorder and how genotype may also modify their presentation. We acknowledge the important drivers that are accelerating this research program including the roles of research infrastructure, international collaboration and advocacy groups. Finally, we conclude by highlighting the major milestones since 1966 and what they mean for the day-to-day lives of those with Rett syndrome and their families. Key pointsThere has been an explosion of knowledge about Rett syndrome in relation to its genetic basis, clinical characteristics and their relationships during the fifty years since the disorder was first described by Andreas Rett.Whilst initially the diagnosis of Rett syndrome was based only on clinical criteria, identifying its genetic cause has had a major positive impact on how clinicians diagnose the disorder but also provides new challenges as we enter the era of next generation sequencing.

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“…It not surprising therefore that it has been associated with a number of disorders of the brain, including Alzheimer’s disease, Huntington's disease [98], depression [99] schizophrenia [100] and Rett syndrome [101]; with changes in BDNF levels being associated with each of these conditions. …”

Section: Bdnf and Synaptic Plasticitymentioning

confidence: 99%

The Neurotrophins and Their Role in Alzheimers Disease

Allen

Watson²,

Dawbarn³

2011

141

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Besides being essential for correct development of the vertebrate nervous system the neurotrophins also play a vital role in adult neuron survival, maintenance and regeneration. In addition they are implicated in the pathogenesis of certain neurodegenerative diseases, and may even provide a therapeutic solution for some. In particular there have been a number of studies on the involvement of nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF) in the development of Alzheimer’s disease. This disease is of growing concern as longevity increases worldwide, with little treatment available at the moment to alleviate the condition. Memory loss is one of the earliest symptoms associated with Alzheimer’s disease. The brain regions first affected by pathology include the hippocampus, and also the entorhinal cortex and basal cholinergic nuclei which project to the hippocampus; importantly, all these areas are required for memory formation. Both NGF and BDNF are affected early in the disease and this is thought to initiate a cascade of events which exacerbates pathology and leads to the symptoms of dementia. This review briefly describes the pathology, symptoms and molecular processes associated with Alzheimer’s disease; it discusses the involvement of the neurotrophins, particularly NGF and BDNF, and their receptors, with changes in BDNF considered particularly in the light of its importance in synaptic plasticity. In addition, the possibilities of neurotrophin-based therapeutics are evaluated.

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The common BDNF polymorphism may be a modifier of disease severity in Rett syndrome

Abstract: Background: Rett syndrome (RTT) is caused by mutations in the transcriptional repressor methyl

Cited by 67 publications

References 40 publications

MECP2 disorders: from the clinic to mice and back

MECP2 disorders: from the clinic to mice and back

Clinical and biological progress over 50 years in Rett syndrome

The Neurotrophins and Their Role in Alzheimers Disease

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