A therapeutic trial of pro‐methylation dietary supplements in Angelman syndrome

Bird, Lynne M.; Tan, Wen‐Hann; Bacino, Carlos A.; Peters, Sarika U.; Skinner, Steven A.; Anselm, Irina; Barbieri-Welge, Rene; Bauer-Carlin, Astrid; Gentile, Jennifer; Glaze, Daniel G.; Horowitz, Lucia; Mohan, Kriti; Nespeca, Mark; Sahoo, Trilochan; Sarco, Dean; Waisbren, Susan E.; Beaudet, Arthur L.

doi:10.1002/ajmg.a.34297

Cited by 46 publications

(37 citation statements)

References 28 publications

(33 reference statements)

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“…DNA methylation was recently shown to be a dynamic process that is altered in somatic adult cells in response to environmental factors such as exercise (31). Also, recent investigations have shown that dietary supplements containing betaine, metafoline, creatine, and vitamin B 12 could alter DNA methylation (32). Future studies will aim at examining the effects of these types of dietary supplements on DNA methylation of the NPC1L1 gene and its expression in the intestine and liver.…”

Section: Discussionmentioning

confidence: 99%

Epigenetic Modulation of Intestinal Cholesterol Transporter Niemann-Pick C1-like 1 (NPC1L1) Gene Expression by DNA Methylation

Malhotra

Soni

Kumar

et al. 2014

Journal of Biological Chemistry

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Background: Cholesterol transporter NPC1L1 is expressed in small intestine but not in colon. Results: DNA in the mouse NPC1L1 gene is hypermethylated in colon as compared with small intestine. DNA methylation decreases the promoter activity of NPC1L1. Conclusion: DNA hypermethylation may be responsible for silencing NPC1L1 expression in the colon. Significance: Altering DNA methylation may represent a novel mechanism to modulate NPC1L1 expression and cholesterol absorption.

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Section: Discussionmentioning

confidence: 99%

Epigenetic Modulation of Intestinal Cholesterol Transporter Niemann-Pick C1-like 1 (NPC1L1) Gene Expression by DNA Methylation

Malhotra

Soni

Kumar

et al. 2014

Journal of Biological Chemistry

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“…Attempts to increase transcription from the paternal allele through the use of pro-methylation vitamin supplements did not result in any noticeable improvement 128,129. There is an ongoing randomized, placebo-controlled trial using levodopa/carbidopa to treat AS 130.…”

Section: Status Of Clinical Researchmentioning

confidence: 99%

Angelman syndrome: review of clinical and molecular aspects

Bird

2014

TACG

182

155

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“Angelman syndrome” (AS) is a neurodevelopmental disorder whose main features are intellectual disability, lack of speech, seizures, and a characteristic behavioral profile. The behavioral features of AS include a happy demeanor, easily provoked laughter, short attention span, hypermotoric behavior, mouthing of objects, sleep disturbance, and an affinity for water. Microcephaly and subtle dysmorphic features, as well as ataxia and other movement disturbances, are additional features seen in most affected individuals. AS is due to deficient expression of the ubiquitin protein ligase E3A (UBE3A) gene, which displays paternal imprinting. There are four molecular classes of AS, and some genotype–phenotype correlations have emerged. Much remains to be understood regarding how insufficiency of E6-AP, the protein product of UBE3A, results in the observed neurodevelopmental deficits. Studies of mouse models of AS have implicated UBE3A in experience-dependent synaptic remodeling.

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“…Attempts to alter methylation of UBE3A using promethylation vitamin supplements to increase transcription from the paternal allele did not alter the phenotype of AS [68,69]. Data analysis is in progress for a randomized, placebocontrolled trial using levodopa/carbidopa to treat AS (ClinicalTrials.gov identifier: NCT01281475).…”

Section: Research and Developmentmentioning

confidence: 99%

Angelman Syndrome

et al. 2015

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In this review we summarize the clinical and genetic aspects of Angelman syndrome (AS), its molecular and cellular underpinnings, and current treatment strategies. AS is a neurodevelopmental disorder characterized by severe cognitive disability, motor dysfunction, speech impairment, hyperactivity, and frequent seizures. AS is caused by disruption of the maternally expressed and paternally imprinted UBE3A, which encodes an E3 ubiquitin ligase. Four mechanisms that render the maternally inherited UBE3A nonfunctional are recognized, the most common of which is deletion of the maternal chromosomal region 15q11-q13. Remarkably, duplication of the same chromosomal region is one of the few characterized persistent genetic abnormalities associated with autistic spectrum disorder, occurring in >1-2 % of all cases of autism spectrum disorder. While the overall morphology of the brain and connectivity of neural projections appear largely normal in AS mouse models, major functional defects are detected at the level of context-dependent learning, as well as impaired maturation of hippocampal and neocortical circuits. While these findings demonstrate a crucial role for ubiquitin protein ligase E3A in synaptic development, the mechanisms by which deficiency of ubiquitin protein ligase E3A leads to AS pathophysiology in humans remain poorly understood. However, recent efforts have shown promise in restoring functions disrupted in AS mice, renewing hope that an effective treatment strategy can be found.Key Words Angelman syndrome . neurodevelopmental disorders . autism . ubiquitin ligase . Ube3a . Imprinting. Clinical OverviewIn 1965, the English physician Harry Angelman described 3 patients who presented with a stiff, jerky gait, absence of speech, excessive laughter, and seizures. The disorder that came to bear his name [Angelman syndrome (AS)] is now recognized to affect approximately 1 in 15,000 individuals and is characterized by motor dysfunction, severe intellectual disability, speech impairment, seizures, hyperactivity, and autism spectrum disorder (ASD) as a common comorbidity [1].Developmental delay in individuals with AS is usually observed within the first year of life. Though most individuals lack speech entirely, some who are mildly affected can acquire a few words. Receptive language is less impaired. Seizures occur in >80 % of patients, and onset is usually before the age of 3 years. Movement disorders include tremors, jerkiness, and ataxia. The characteristic behaviors of AS include mouthing of objects, happy demeanor with easily provoked laughter, attraction to water, hyperactivity, short attention span, and decreased sleeping (see recent reviews for more detailed description of the clinical phenotype [2][3][4]). These features of AS can be seen in other neurodevelopmental disorders, leading to a broad differential diagnosis [5], which has recently been reviewed (Table 1) [6]. Overlapping clinical features may indicate common neurophysiological pathways,

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A therapeutic trial of pro‐methylation dietary supplements in Angelman syndrome

Cited by 46 publications

References 28 publications

Epigenetic Modulation of Intestinal Cholesterol Transporter Niemann-Pick C1-like 1 (NPC1L1) Gene Expression by DNA Methylation

Epigenetic Modulation of Intestinal Cholesterol Transporter Niemann-Pick C1-like 1 (NPC1L1) Gene Expression by DNA Methylation

Angelman syndrome: review of clinical and molecular aspects

Angelman Syndrome

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