Valproate and risk of fracture in Rett syndrome

Leonard, Helen; Downs, Jenny; Jian, Le; Bebbington, Ami; Jacoby, Peter; Nagarajan, Lakshmi; Ravine, David; Woodhead, Helen

doi:10.1136/adc.2008.148932

Cited by 35 publications

(21 citation statements)

References 24 publications

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“…No specific medications are contraindicated in Rett syndrome; however, the issue of bone health is an important consideration when prescribing anti-seizure drugs. One study found increased risk of fracture in Rett syndrome associated with valproate use, whereas another study demonstrated that low vitamin D levels, common in Rett syndrome, were not associated with anti-seizure drug use (Leonard et al, 2010;Motil et al, 2011). In summary, when seizures are concluded to be epileptic in origin and anti-seizure drugs are initiated, the side effect profiles of medications should be considered carefully, and medications, which can cause behavioural issues (e.g.…”

Section: Discussionmentioning

confidence: 99%

Longitudinal course of epilepsy in Rett syndrome and related disorders

Tarquinio

Hou

Berg

et al. 2016

Brain

100

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Epilepsy is common in Rett syndrome, an X-linked dominant disorder caused by mutations in the MECP2 gene, and in Rett-related disorders, such as MECP2 duplication. However, neither the longitudinal course of epilepsy nor the patterns of seizure onset and remission have been described in Rett syndrome and related conditions. The present study summarizes the findings of the Rett syndrome Natural History study. Participants with clinical Rett syndrome and those with MECP2 mutations without the clinical syndrome were recruited through the Rett Natural History study from 2006 to 2015. Clinical details were collected, and cumulative lifetime prevalence of epilepsy was determined using the Kaplan-Meier estimator. Risk factors for epilepsy were assessed using Cox proportional hazards models. Of 1205 participants enrolled in the study, 922 had classic Rett syndrome, and 778 of these were followed longitudinally for 3939 person-years. The diagnosis of atypical Rett syndrome with a severe clinical phenotype was associated with higher prevalence of epilepsy than those with classic Rett syndrome. While point prevalence of active seizures ranged from 30% to 44%, the estimated cumulative lifetime prevalence of epilepsy using Kaplan-Meier approached 90%. Specific MECP2 mutations were not significantly associated with either seizure prevalence or seizure severity. In contrast, many clinical features were associated with seizure prevalence; frequency of hospitalizations, inability to walk, bradykinesia, scoliosis, gastrostomy feeding, age of seizure onset, and late age of diagnosis were independently associated with higher odds of an individual having epilepsy. Aggressive behaviour was associated with lower odds. Three distinct patterns of seizure prevalence emerged in classic Rett syndrome, including those who did not have seizures throughout the study, those who had frequent relapse and remission, and those who had relentless seizures. Although 248 of those with classic Rett syndrome and a history of seizures were in terminal remission at last contact, only 74 (12% of those with a history of epilepsy) were seizure free and off anti-seizure medication. When studied longitudinally, point prevalence of active seizures is relatively low in Rett syndrome, although lifetime risk of epilepsy is higher than previously reported. While daily seizures are uncommon in Rett syndrome, prolonged remission is less common than in other causes of childhood onset epilepsy. Complete remission off anti-seizure medications is possible, but future efforts should be directed at determining what factors predict when withdrawal of medications in those who are seizure free is propitious.

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Section: Discussionmentioning

confidence: 99%

Longitudinal course of epilepsy in Rett syndrome and related disorders

Tarquinio

Hou

Berg

et al. 2016

Brain

100

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“…To our knowledge, this is the largest study to date to describe this mutation and the sample size has allowed use of appropriate statistical methods including survival analysis. Our case studies also use information collected at multiple time points, 14 and questionnaire data has been supplemented with observed video data of functional abilities that had been collected on two occasions. 19,33,36 Longitudinal data from different perspectives were able to provide depth to the description of our case studies.…”

Section: Discussionmentioning

confidence: 99%

“…Additional questionnaire data have been collected every 2 to 3 years since 2000. 14 InterRett was established in 2003 15 and cases are ascertained through a variety of sources including parent support groups, the listserv Rettnet and also bulk submission of de-identified data provided by clinicians outside Australia from countries such as Spain, France, Israel and Canada. InterRett questionnaires are completed online by families and clinicians at one time point.…”

Section: Methodsmentioning

confidence: 99%

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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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“…Vitamin D status) environmental and genetic risk factors. Risk factors for fractures such as genotype 173 and use of certain anti-epileptic medications 181 did not always correlate exactly with those for low bone density, which also varied by outcome parameter and body site. For example, right femoral neck areal bone mineral density was particularly impaired with increasing age and lack of mobility in comparison to other parameters.…”

Section: Bone Healthmentioning

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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Valproate and risk of fracture in Rett syndrome

Abstract: The effect of valproate on bone health should be considered when managing epilepsy in Rett syndrome. Multiple mechanisms could be contributing to this effect.

Cited by 35 publications

References 24 publications

Longitudinal course of epilepsy in Rett syndrome and related disorders

Longitudinal course of epilepsy in Rett syndrome and related disorders

The phenotype associated with a large deletion on MECP2

Clinical and biological progress over 50 years in Rett syndrome

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