Natural History Studies and Clinical Trial Readiness for Genetic Developmental and Epileptic Encephalopathies

Palmer, Elizabeth E.; Howell, Katherine; Scheffer, Ingrid E.

doi:10.1007/s13311-021-01133-3

Cited by 31 publications

(23 citation statements)

References 81 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Developmental and epileptic encephalopathies (DEE) are the most severe forms of childhood epilepsy with frequent severe epileptiform activity and developmental slowing (McTague et al, 2016). DEE increases the risk of premature mortality and patients who survive have significant lifelong disabilities (Palmer et al, 2021). Patients are normally treated with one or more anti-epileptic drugs (AEDs) which aim to reduce the frequency of seizures.…”

Section: Introductionmentioning

confidence: 99%

Characterisation and automated quantification of induced seizure-related behaviours in Xenopus laevis tadpoles

Panthi

Chapman

Szyszka

et al. 2022

Preprint

View full text Add to dashboard Cite

Epilepsy, a clinical diagnosis characterized by paroxysmal episodes known as seizures, affects 1% of people worldwide. Safe and patient-specific treatment is vital and can be achieved by the development of rapid pre-clinical models of for identified epilepsy genes. Epilepsy can result from either brain injury or gene mutations, and can also be induced chemically. Xenopus laevis tadpoles could be a useful model for confirmation of variants of unknown significance found in epilepsy patients, and for drug re-purposing screens that could eventually lead to benefits for patients. Here, we characterise and quantify seizure-related behaviours in X. laevis tadpoles arrayed in 24-well plates. To provoke acute seizure behaviours, tadpoles were chemically induced with either pentylenetetrazole (PTZ) or 4-aminopyridine (4-AP). To test the capacity to adapt this method for drug testing, we also exposed induced tadpoles to the anti-seizure drug valproate (VPA). Four induced seizure-like behaviours were described and manually quantified, and two of these (darting, circling) could be accurately detected automatically, using the video analysis software TopScan. Additionally, we recorded swimming trajectories and mean swimming velocity. Automatic detection showed that either PTZ or 4-AP induced darting behaviour and increased mean swimming velocity compared to untreated controls. Both parameters were significantly reduced in the presence of VPA. In particular, darting behaviour was a shown to be a sensitive measure of epileptic seizure activity. While we could not automatically detect the full range of seizure behaviours, this method shows promise for future studies, since X. laevis is a well-characterised and genetically tractable model organism.

show abstract

Section: Introductionmentioning

confidence: 99%

Characterisation and automated quantification of induced seizure-related behaviours in Xenopus laevis tadpoles

Panthi

Chapman

Szyszka

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…This is due to the vast genetic and complex phenotypic heterogeneity amongst the ultra-rare DEEs, with very little known regarding the natural history of each genetic DEE subtype, many of which have only been described in the last 10 years. 11 Variants within the same gene can be linked to diverse pathophysiological impacts and clinical phenotypes. 6,12 Even the same variant can result in very different clinical outcomes in different individuals.…”

Section: A Causal and Diagnostic Odysseymentioning

confidence: 99%

“…Even when there is a ‘diagnosis’, there often remains a lack of clear prognostic or therapeutic guidance. This is due to the vast genetic and complex phenotypic heterogeneity amongst the ultra‐rare DEEs, with very little known regarding the natural history of each genetic DEE subtype, many of which have only been described in the last 10 years 11 . Variants within the same gene can be linked to diverse pathophysiological impacts and clinical phenotypes 6,12 .…”

Section: A Causal and Diagnostic Odysseymentioning

confidence: 99%

Hope in the uncertainties and certainty for parents of children with rare neurological disorders. Part I (of 3): Uncertainty

Palmer

Sachdev

Beavis

et al. 2022

J Paediatrics Child Health

View full text Add to dashboard Cite

This is the first of three articles exploring the aspects of clinical care for children with rare neurological disorders including uncertainties old and new. The disruptive technologies of genomic sequencing and advanced therapeutics such as gene‐based therapies offer parents of children with severe but rare neurological conditions for the first‐time unprecedented opportunities for ‘precision medicine’. At the same time, the realities of limited genomic diagnostic yields and not infrequent detection of variants of uncertain significance, lack of natural history study data and management guidelines for individually rare neurogenetic conditions, means that high pre‐genomic test expectations are all too often replaced by an accumulation of new uncertainties. This can add to the chronic traumatic stress experienced by many families but may also have under‐recognised impacts for their clinicians, contributing to ‘burn‐out’ and attendant negative psychosocial impacts. This first article aims to address how clinicians might manage the accumulation of uncertainties to be more helpful to patients and their families. Moreover, it seeks to address how clinicians can move forward providing compassionate care to their patients and a little more consideration for themselves.

show abstract

“…This is because DEEs are genetically heterogeneous with over 400 monogenic causes 7. Many genetic causes have only recently been identified due to significant advancements in genomic sequencing 7 8. Even when a genetic cause is identified, this can have a vast range of comorbidities and phenotypes.…”

Section: Introductionmentioning

confidence: 99%

“…These factors mean that there is very little information regarding natural history, prognosis and comorbidities, and limited dedicated patient advocacy or support services for DEE,9 a common theme across rare disease care 3 8 10. Of the limited information about DEE, the frequently generic nature of this information often limits relevance to the unique situation of each child 11…”

Section: Introductionmentioning

confidence: 99%

Acceptability and feasibility of an online information linker service for caregivers who have a child with genetic epilepsy: a mixed-method pilot study protocol

et al. 2022

View full text Add to dashboard Cite

IntroductionDevelopmental and epileptic encephalopathies (DEEs) are rare epilepsy conditions that collectively impact 1 in 2000 children. They are highly genetically heterogeneous, resulting in significant barriers to accurate and adequate information for caregivers. This can lead to increased distress and dissatisfaction with the healthcare system. To address this gap, we developed ‘GenE Compass’ to provide caregivers with the highest-quality possible, understandable and relevant information in response to specific questions about their child’s DEE. Using a mixed-method design, we will now pilot GenE Compass to evaluate the acceptability to caregivers and clinicians, feasibility and impact to caregivers.Methods and analysisWe will recruit 88 caregivers (estimated final sample of 50 at follow-up) who have a child under 18 years of age with a suspected or confirmed DEE diagnosis. Following consent and a baseline questionnaire (questionnaire 1 (Q1)), participants will be able to submit questions to GenE Compass over a 3-month period. After 3 months, participants will complete a follow-up questionnaire (Q2) and an optional telephone interview to answer the research questions. Primary outcomes are acceptability of GenE Compass and feasibility of delivering the intervention (eg, cost of the intervention, number of questions submitted and time taken to respond to questions). Secondary outcomes include the impact of GenE Compass on caregivers’ quality of life, information searching behaviours, perceptions of their child’s illness and activation.Ethics and discussionThe study protocol (V.2, dated 16 September 2021) has been approved by the Sydney Children’s Hospitals Network Human Research Ethics Committee (ETH11277). The results will be disseminated in peer-reviewed journals and at scientific conferences. A lay summary will be disseminated to all participants.Trial registration numberACTRN12621001544864.

show abstract

Natural History Studies and Clinical Trial Readiness for Genetic Developmental and Epileptic Encephalopathies

Cited by 31 publications

References 81 publications

Characterisation and automated quantification of induced seizure-related behaviours in Xenopus laevis tadpoles

Characterisation and automated quantification of induced seizure-related behaviours in Xenopus laevis tadpoles

Hope in the uncertainties and certainty for parents of children with rare neurological disorders. Part I (of 3): Uncertainty

Acceptability and feasibility of an online information linker service for caregivers who have a child with genetic epilepsy: a mixed-method pilot study protocol

Contact Info

Product

Resources

About