Scott Demarest's research while affiliated with Children's Hospital Colorado and other places

Publications (17)

Article
Objective To compare quality of life (QOL) across diagnoses associated with intellectual disability, construct QOL profiles and evaluate membership by diagnostic group, function and comorbidities. Method Primary caregivers of 526 children with intellectual disability (age 5–18 years) and a diagnosis of cerebral palsy, autism spectrum disorder, Dow...
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Full-text available
This study investigated the influence of factors at birth and in infancy on the likelihood of achieving major motor milestones in CDKL5 Deficiency Disorder (CDD). Data on 350 individuals with a pathogenic CDKL5 variant was sourced from the International CDKL5 Disorder Database. A first model included factors available at birth (e.g., sex, variant g...
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Full-text available
CDKL5 Deficiency Disorder (CDD) is a rare, X-linked dominant condition that causes a developmental and epileptic encephalopathy (DEE). The incidence is between ∼ 1:40,000 and 1:60,000 live births. Pathogenic variants in CDKL5 lead to seizures from infancy and severe neurodevelopmental delay. During infancy and childhood, individuals with CDD suffer...
Article
Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is a developmental and epileptic encephalopathy with infantile-onset epilepsy. Most individuals with CDD develop refractory epilepsy with multiple seizure types. Management of seizures in CDD remains challenging for clinicians given the highly refractory nature of seizures and the lim...
Article
Pathogenic variants in the CDKL5 gene result in CDKL5 deficiency disorder (CDD), which is characterized by early-onset epilepsy, severe developmental delay, and often, cortical visual impairment. Validated clinical outcome measures are needed for future clinical trials to be successful. This study aimed to adapt the Rett Syndrome Hand Function Scal...
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Cyclin‐dependent kinase‐like 5 (CDKL5) gene pathogenic variants result in CDKL5 deficiency disorder (CDD). Early onset intractable epilepsy and severe developmental delays are prominent symptoms of CDD. Comorbid sleep disturbances are a major concerning symptom for families. We aimed to explore the relationship between insomnia, daytime sleepiness,...
Article
CDKL5 deficiency disorder (CDD) was first identified as a cause of human disease in 2004. Although initially considered a variant of Rett syndrome, CDD is now recognised as an independent disorder and classified as a developmental epileptic encephalopathy. It is characterised by early-onset (generally within the first 2 months of life) seizures tha...
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CDKL5 deficiency disorder (CDD), a severe developmental and epileptic encephalopathy, is being diagnosed earlier with improved access to genetic testing, but this may also have unanticipated impacts on parents’ experience receiving the diagnosis. This study explores the lived experience of parents receiving a diagnosis of CDD for their child using...
Article
Objective: The aim of this study was to devise an evidence-based missing data rule for the Quality of Life Inventory-Disability (QI-Disability) questionnaire specifying how many missing items are permissible for domain and total scores to be calculated using simple imputation. We sought a straightforward rule that can be used in both research and...
Article
Aim To identify additional genes associated with infantile spasms using a cohort with defined infantile spasms. Method Whole-exome sequencing (WES) was performed on 21 consented individuals with infantile spasms and their unaffected parents (a trio-based study). Clinical history and imaging were reviewed. Potentially deleterious exonic variants we...
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This review summarizes the pathogenic mechanisms that underpin the monogenic epilepsies and discusses the potential of novel precision therapeutics to treat these disorders. Pathogenic mechanisms of epilepsy include recessive (null alleles), haploinsufficiency, imprinting, gain-of-function, and dominant negative effects. Understanding which pathoge...
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Full-text available
OBJECTIVES/GOALS: Epilepsy with myoclonic-atonic seizures (EMAS) is a childhood onset epilepsy disorder characterized by seizures with sudden loss of posture, or drop seizures. Our objective was to use short-read genome sequencing in 40 EMAS trios to better understand variants contributing to the development of EMAS. METHODS/STUDY POPULATION: Eligi...
Article
Epilepsy with myoclonic-atonic seizures (EMAS) accounts for 1–2% of all childhood-onset epilepsies. EMAS has been shown to have an underlying genetic component, however the genetics of this disorder is not yet well understood. The purpose of this study was to review genetic testing results for a cohort of EMAS patients. A retrospective chart review...
Article
Purpose: Next-generation sequencing panels are particularly useful in identifying genetic diagnoses in patients with nonspecific clinical findings by allowing for analysis of many genes at once. The purpose of this study was to develop a simple, objective system to evaluate the quality of available next-generation sequencing panels. Methods: A l...
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Objective To obtain and assess opinions on EMAS diagnostic criteria, recommended investigations, and therapeutic options, from a large group of physicians who care for children with EMAS. Methods The EMAS focus group of PERC created a survey to assess the opinions of pediatric neurologists who care for children with EMAS regarding diagnosis and tr...

Citations

... Cases of individuals with MDS have been ascertained alongside individuals with a MECP2 mutation in the InterRett [19], thus forming an important platform for our development of the international MECP2 Duplication Database (MDBase) in 2020. Following the success of InterRett and the ICDD [15,20,21], and informed by ongoing stakeholder engagement, our group created the MDBase in their likeness [9]. In this methodological paper, we illustrate the development of an international registry for MDS. ...
... As such, the relatively limited nature of our knowledge regarding the etiology of epilepsy indicates that much progress is still needed. Firstly, around the identification and mechanistic understanding of new genetic causes, where multiple mutations in the same gene may provide novel genotype:phenotype correlations [8]. Secondly, regarding the underlying dynamics of neurotransmission and its mechanisms that are pivotal for disease management; indeed, many of the known genetic causes already cluster around fundamental aspects of neuronal cell communication [9]. ...
... Здесь отражено, что различие между четырьмя синдромами IGE не всегда четкие, поскольку имеет место схожесть клинических проявлений. Кроме того, существует пересечение между IGE и не-IGE GGE, о чем свидетельствует более высокая частота синдромов IGE у родственников больных эпилепсией с миоклонией век, эпилепсией с миоклоническими абсансами, миоклонической эпилепсией младенчества, эпилепсией с миоклоническими атоническими приступами и генетической эпилепсией с фебрильными судорогами плюс (GEFS+) [23,35,42,43]. ...
... The group reviewed existing gene-disease validity evaluation frameworks [19][20][21][22] to determine whether one could be adopted to serve the needs of the clinical community for documentation of genes relevant to ASD. As the purpose is to define an ASD-relevant gene list for use in a clinical setting, criteria for inclusion will be more stringent than they would be for a discovery-driven agenda 23,24 . The Clinical Genome (ClinGen) Gene-Disease Validity curation framework was selected as a starting point. ...
... 7 Similarly, a recent survey of diagnosis and treatment of EMAS showed only 50% to 79% of respondents felt developmental delay prior to seizure onset was an exclusionary criterion for the diagnosis of EMAS. 10 Initial seizure types included myoclonic, atonic-astatic, myoclonic-astatic (now known as myoclonic atonic), absence, absence or nonconvulsive status epilepticus, and generalized tonic clonic seizures. Nocturnal tonic seizures, as well as rare focal seizures, were also seen. 1 The ILAE now reports a history of epileptic spasms or focal seizures as being exclusionary for a diagnosis of EMAS (EpilepsyDiagnosis.org). ...
... Hypsarrhythmia is the typical feature of EEG during the interictal period and is an important diagnostic criterion and index for therapeutic evaluation in IS. However, many variant forms of hypsarrhythmia in IS exist, with an occurrence rate of up to 69%) (Demarest et al., 2017;Nenadovic et al., 2018). It has been shown that different EEG evaluators have poor inter-rater reliability (IRR) in the assessment of typical hypsarrhythmia and other atypical EEG features of IS (Hussain et al., 2015). ...