Epilepsy and the natural history of Rett syndrome

Glaze, Daniel G.; Percy, Alan K.; Skinner, Steven A.; Motil, Kathleen J.; Neul, Jeffrey L.; Barrish, James P.; Lane, Jane; Geerts, Suzanne; Annese, Fran; Graham, Joy; McNair, Lauren; Lee, H. S.

doi:10.1212/wnl.0b013e3181d6b852

Cited by 187 publications

(229 citation statements)

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“…26 However, in the present study of 51 individuals, those with a large deletion were at greater odds than those with another pathogenic mutation of having epilepsy of earlier onset and greater severity. Similarly, in the Italian study seizures had occurred in 9/10 of those with large deletions while in the US study 28 the p.T158M mutation was the mutation where seizures were reported most frequently.…”

Section: Discussionmentioning

confidence: 80%

“…In another Australian study using data collected in 2000, the seizure rate in those with a C-terminal deletions and in those with a p.R294X mutation was significantly lower than in those with no identified mutation. 26 In a more recent Italian 27 but not in a US study, 28 this result was replicated for C-terminal deletions but not for pR294X mutations. In the 2000 Australian study we were not able to demonstrate an increased seizure rate in those with large deletions, but only five individuals with a large deletion were included.…”

Section: Discussionmentioning

confidence: 85%

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The phenotype associated with a large deletion on MECP2

et al. 2012

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Multiplex ligation-dependent Probe Amplification (MLPA) has become available for the detection of a large deletion on the MECP2 gene allowing genetic confirmation of previously unconfirmed cases of clinical Rett syndrome. This study describes the phenotype of those with a large deletion and compares with those with other pathogenic MECP2 mutations. Individuals were ascertained from the Australian Rett Syndrome and InterRett databases with data sourced from family and clinician questionnaires, and two case studies were constructed from the longitudinal Australian data. Regression and survival analysis were used to compare severity and age of onset of symptoms in those with and without a large deletion. Data were available for 974 individuals including 51 with a large deletion and ages ranged from 1 year 4 months to 49 years (median 9 years). Those with a large deletion were more severely affected than those with other mutation types. Specifically, individuals with large deletions were less likely to have learned to walk (OR 0.42, 95% CI: 0.22-0.79, P¼0.007) and to be currently walking (OR 0.53, 95% CI: 0.26-1.10, P¼0.089), and were at higher odds of being in the most severe category of gross motor function (OR 1.84, 95% CI: 0.98-3.48, P¼0.057) and epilepsy (OR 2.72, 95% CI: 1.38-5.37, P¼0.004). They also developed epilepsy, scoliosis, hand stereotypies and abnormal breathing patterns at an earlier age. We have described the disorder profile associated with a large deletion from the largest sample to date and have found that the phenotype is severe with motor skills particularly affected.

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Section: Discussionmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 85%

The phenotype associated with a large deletion on MECP2

et al. 2012

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“…Although not examined in our study, this could be significant given the high prevalence of epilepsy in RTT patients (53). Additionally, clenbuterol has been shown to block sodium channels (31), whose overactivity is hypothesized to result in the lethal cardiac arrhythmias present in RTT (54).…”

Section: Discussionmentioning

confidence: 94%

β2-Adrenergic receptor agonist ameliorates phenotypes and corrects microRNA-mediated IGF1 deficits in a mouse model of Rett syndrome

Mellios

Woodson

Garcia

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Rett syndrome is a severe childhood onset neurodevelopmental disorder caused by mutations in methyl-CpG-binding protein 2 (MECP2), with known disturbances in catecholamine synthesis. Here, we show that treatment with the β2-adrenergic receptor agonist clenbuterol increases survival, rescues abnormalities in respiratory function and social recognition, and improves motor coordination in young male Mecp2-null (Mecp2 −/y ) mice. Importantly, we demonstrate that short-term treatment with clenbuterol in older symptomatic female heterozygous (Mecp2 −/+ ) mice rescues respiratory, cognitive, and motor coordination deficits, and induces an anxiolytic effect. In addition, we reveal abnormalities in a microRNA-mediated pathway, downstream of brain-derived neurotrophic factor that affects insulin-like growth factor 1 (IGF1) expression in Mecp2 −/y mice, and show that treatment with clenbuterol restores the observed molecular alterations. Finally, cotreatment with clenbuterol and recombinant human IGF1 results in additional increases in survival in male null mice. Collectively, our data support a role for IGF1 and other growth factor deficits as an underlying mechanism of Rett syndrome and introduce β2-adrenergic receptor agonists as potential therapeutic agents for the treatment of the disorder.let-7f | LIN28A

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“…Participants with classic RTT and atypical RTT and MECP2-positive participants without clinical RTT (non-RTT) were recruited from 2006 to 2011 through the multicenter RTT Natural History Study (RNHS) at 1 of 7 sites and evaluated every 6Ϫ12 months as described previously. 18 Diagnosis of classic and atypical RTT was based on consensus criteria 19,20 and was confirmed by an RNHS neurologist or geneticist (D.G.G., J.L.N., A.K.P., S.A.S.). All participants had MECP2 testing; participants with clinical RTT were included despite absence of a mutation.…”

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confidence: 99%

Growth failure and outcome in Rett syndrome

Tarquinio¹,

Motil²,

Hou³

et al. 2012

Neurology

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108

110

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Objectives: Prominent growth failure typifies Rett syndrome (RTT). Our aims were to 1) develop RTT growth charts for clinical and research settings, 2) compare growth in children with RTT with that of unaffected children, and 3) compare growth patterns among RTT genotypes and phenotypes.Methods: A cohort of the RTT Rare Diseases Clinical Research Network observational study participants was recruited, and cross-sectional and longitudinal growth data and comprehensive clinical information were collected. A reliability study confirmed interobserver consistency. Reference curves for height, weight, head circumference, and body mass index (BMI), generated using a semiparametric model with goodness-of-fit tests, were compared with normative values using Student's t test adjusted for multiple comparisons. Genotype and phenotype subgroups were compared using analysis of variance and linear regression.Results: Growth charts for classic and atypical RTT were created from 9,749 observations of 816 female participants. Mean growth in classic RTT decreased below that for the normative population at 1 month for head circumference, 6 months for weight, and 17 months for length. Mean BMI was similar in those with RTT and the normative population. Pubertal increases in height and weight were absent in classic RTT. Classic RTT was associated with more growth failure than atypical RTT. In classic RTT, poor growth was associated with worse development, higher disease severity, and certain MECP2 mutations (pre-C-terminal truncation, large deletion, T158M, R168X, R255X, and R270X). Conclusions:RTT-specific growth references will allow effective screening for disease and treatment monitoring. Growth failure occurs less frequently in girls with RTT with better development, less morbidity typically associated with RTT, and late truncation mutations. Neurology ® 2012;79:1653-1661 GLOSSARY ANOVA ϭ analysis of variance; BMI ϭ body mass index; CSS ϭ Clinical Severity Score; EDF ϭ equivalent degrees of freedom; FDR ϭ false discovery rate; FOC ϭ fronto-occipital head circumference; MBA ϭ Motor Behavioral Assessment; non-RTT ϭ participants possessing MECP2 mutation but without Rett syndrome; RNHS ϭ Rett Natural History Study; RTT ϭ Rett syndrome.Growth failure is a prominent feature in Rett syndrome (RTT); however, no RTT-specific growth charts exist. Many comorbid disorders have an impact on growth in RTT, such as oropharyngeal and gastrointestinal dysfunction, scoliosis, seizures, and osteopenia. The pattern of growth in female patients with RTT trends well below the lowest centile on standard growth references, 1 which fail to differentiate a normal RTT growth pattern from one caused by malnutrition or illness.Disease-specific standards screen for disease [2][3][4][5][6][7][8][9][10][11][12][13] and measure the effect of therapeutic interventions designed to improve nutrition and neurologic function.14,15 With more than 200 mutation sites identified in the methyl-CpG-binding protein 2 gene (MECP2), the clinical severity in RTT var...

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Epilepsy and the natural history of Rett syndrome

Abstract: Background: Rett syndrome (RTT) is a neurodevelopmental disorder primarily seen in females,

Cited by 187 publications

References 8 publications

The phenotype associated with a large deletion on MECP2

The phenotype associated with a large deletion on MECP2

β2-Adrenergic receptor agonist ameliorates phenotypes and corrects microRNA-mediated IGF1 deficits in a mouse model of Rett syndrome

Growth failure and outcome in Rett syndrome

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