Published articles related to dup15q syndrome

September 5, 2018
Autism Spectrum Disorder and Cannabidiol: Have We Seen This Movie Before?

 

Authors: Carlos A. Salgado, MD and Daniel Castellanos, MD

Summary: Recently, the use of marijuana and cannabidiol (CBD) in children with autism spectrum disorder (ASD) has received increasing attention in the media with articles sensationally titled “Marijuana may be a miracle treatment for children with autism.”1,2 An absence of empirical data appears to have resulted in a growing body of anecdotal evidence espousing the benefits of CBD for children with ASD. Some reports describe the effects as miraculous or “unbelievable.”2 Increasingly, parents of children with severe ASD, frustrated with the lack of options, have turned to CBD. Many have heard anecdotal reports of success; others have read of promising results with epileptic children. Parents who frequently felt they had exhausted all other options have turned to CBD as a “last resort.” An increasing number of parents are advocating for their children to be treated with CBD.3 Vocal parents have taken to the internet utilizing social media to distribute their message.4 However, clinical research remains nearly nonexistent.

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September 5, 2018
Neurophysiological Oscillations as Biomarkers of Neurodevelopmental Disorders (PhD Thesis)

 

Authors: Joel Frolich  Advisor: Shafali Jeste, MD

Abstract: Mechanism-based biomarkers are needed to guide clinical trials for neurodevelopmental disorders by indexing disease pathology or a treatment response. In this dissertation, I describe electroencephalogram (EEG) biomarkers in two neurodevelopmental disorders, Dup15q syndrome and Angelman syndrome. Dup15q syndrome is caused by duplications of 15q11.2-q13.1, including UBE3A—a paternally imprinted gene involved in synapse development—and several gamma-aminobutyric acid type-A (GABA-A) receptor subunit genes. In Angelman syndrome, the majority of cases are caused by deletions of 15q11.2-q13.1, though some cases are caused by UBE3A dysfunction alone. Both disorders are characterized by epilepsy, intellectual disability, and phenotypic overlap with autism spectrum disorder (ASD).

In Chapter 1, I introduce biomarkers and neurodevelopmental disorders. In Chapter 2, I infer the emergence of stable oscillations from neural noise in typically developing (TD) preschool age children. In Chapter 3, I describe a beta EEG phenotype of Dup15q syndrome, which distinguishes children with this disorder from TD and nonsyndromic ASD controls. In Chapter 4, I compare this phenotype with beta oscillations induced with midazolam, a GABA-A modulator, in healthy adult participants. Furthermore, two cases of paternal Dup15q syndrome (i.e., duplications of the UBE3A-silenced allele) also show this EEG phenotype, suggesting that it is a marker of GABAergic pathology. In Chapter 5, I describe a delta EEG phenotype of Angelman syndrome (previously described by Sidorov and colleagues in 2017) that is stronger in children with a deletion genotype than those with a non-deletion genotype. Furthermore, I find lower beta power and higher theta power in the deletion genotype. Thus, beta power and theta power appear to reflect GABAergic dysfunction, whereas delta power appears to reflect UBE3A dysfunction but is modulated by GABA-A receptor gene deletion. Chapter 6 summarizes this work and provides a discussion about implications and next steps.

In conclusion, neurophysiological oscillations are likely markers of gene-specific disease pathology in Dup15q syndrome and Angelman syndrome. Clinical trials targeting specific gene products (e.g., GABA-A receptors) may utilize these EEG measures as biomarkers of target engagement or surrogate endpoints.

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September 5, 2018
Quantitative Measures of Motor Function in children with Duplications of 15q11.3–13.1 (Dup15q Syndrome) and Typically Developing (TD) Children

 

Authors: Rujuta BhattAbigail DickinsonCarly HydeSumana RallipalliKatie DahlerbruchCarolyn RochaShafali Jeste

Objective: To compare quantitative measures of gait (QMG), including stride width, cadence (steps/minute), and gait variability index (GVI), in children with Dup15q Syndrome and typically developing (TD) children and to evaluate the relationship between QMG and social communication.

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September 5, 2018
Hyperexcitable phenotypes in iPSC-derived neurons from patients with 15q11-q13 duplication syndrome, a genetic form of autism

 

Authors: James J Fink, Jeremy D Schreiner, Judy E Bloom, Dylan S Baker, Tiwanna M Robinson, Richard Lieberman, Leslie M Loew, Stormy J Chamberlain, Eric Levine

Abstract

Chromosome 15q11-q13 duplication syndrome (Dup15q) is a neurogenetic disorder caused by duplications of the maternal copy of this region. In addition to hypotonia, motor deficits, and language impairments, Dup15q patients commonly meet the criteria for autism spectrum disorder (ASD) and have a high prevalence of seizures. Here, we explored mechanisms of hyperexcitability in neurons derived from induced pluripotent stem cell (iPSC) lines from Dup15q patients. Maturation of resting membrane potential in Dup15q-derived neurons was similar to neurons from unaffected control subjects, but Dup15q neurons had delayed action potential maturation and increased synaptic event frequency and amplitude. Dup15q neurons also showed impairments in activity-dependent synaptic plasticity and homeostatic synaptic scaling. Finally, Dup15q neurons showed an increased frequency of spontaneous action potential firing compared to control neurons, in part due to disruption of KCNQ2 channels. Together these data point to multiple mechanisms underlying hyperexcitability that may provide new targets for the treatment of seizures and other phenotypes associated with Dup15q.

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September 5, 2018
Open-label use of highly purified CBD (Epidiolex®) in patients with CDKL5 deficiency disorder and Aicardi, Dup15q, and Doose syndromes

 

Authors: Orrin Devinsky (a), ChloeVerducci (a), Elizabeth A.Thiele (b), Linda C.Laux (c), Anup D.Patel (d), Francis Filloux (e), Jerzy P.Szaflarski (f), Angus Wilfongg (h), Gary D.Clark (i,j,k), Yong D.Park (l,m), Laurie E.Seltzer (n), E. Martina Bebin (o), RobertFlamini (p), Robert T.Wechsler (q,r), DanielFriedman (a)

Highlights
  • •CBD is a favorable adjuvant to antiseizure medication in patients with intractable genetic epilepsy.
  • •Safety profile is tolerable; common adverse events are diarrhea, somnolence, and fatigue.
  • •CBD reduced the median number of seizures by half at 12 and 48 weeks of follow-up.
  • •Randomized, controlled trials of CBD are warranted given maintained efficacy and safety.
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September 5, 2018
What's missing in autism spectrum disorder motor assessments?

Authors: Rujuta B. Wilson, James T. McCracken, Nicole J. Rinehart and Shafali S. Jeste

 

Background

Motor delays and impairments in autism spectrum disorders (ASD) are extremely common and often herald the emergence of pervasive atypical development. Clinical accounts of ASD and standardized measures of motor function have identified deficits in multiple motor domains. However, literature describing frequently used standardized motor assessments in children with ASD, their test properties, and their limitations are sparse.

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September 5, 2018
Inaugural annual special section of the intellectual and developmental disabilities research centers: developmental cognitive neuroscience and neurodevelopmental disorders

 

Authors: Shafali S Jeste and Charles A Nelson III

Intro: As a child neurologist (SSJ) and developmental cognitive neuroscientist (CAN), we care for and study individuals across a wide developmental, age, and ability spectrum. Over the years, as we have engaged with and learned from families of individuals with a variety of neurodevelopmental disorders, including intellectual and developmental disabilities (IDDs), we have been struck by the impact of the rapid advances that have been made in the field over the last several decades. Parents of adults with IDD often report that years ago, when they were first concerned about their child’s development (i.e., due to motor delays, early seizures, or failure to gain language) few, if any educational, medical, or therapeutic resources were available for their children. Many were told by their health care provider not to worry because their child would “eventually catch up,” while others were instructed to just “watch and wait, because [boys] develop more slowly.” Those who eventually received a genetic diagnosis, usually in late childhood, received little to no concrete information about the functional significance (including treatment options) of the genetic variant or mutation, thus perpetuating continued uncertainty and fear about their child’s future. In contrast, parents with recently diagnosed infants and children often share stories of hope and empowerment, with early detection of developmental delays facilitating prompt intervention and genetic testing which, in turn, leads to improved clinical monitoring and prognostication, engagement with patient advocacy groups, and new opportunities for entry into patient registries, natural history studies, and clinical trials.

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September 5, 2018
Cerebrospinal fluid and the early brain development of autism

 

Authors: Mark D ShenEmail authorView ORCID ID profile

Background

There is currently a renaissance of interest in the many functions of cerebrospinal fluid (CSF). Altered flow of CSF, for example, has been shown to impair the clearance of pathogenic inflammatory proteins involved in neurodegenerative diseases, such as amyloid-β. In addition, the role of CSF in the newly discovered lymphatic system of the brain has become a prominently researched area in clinical neuroscience, as CSF serves as a conduit between the central nervous system and immune system.

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September 5, 2018
Sudden unexpected death in epilepsy: The neuro-cardio-respiratory connection

Authors: Theodora A.Manolis, Antonis A.Manolis, HelenMelita, and Antonis S.Manolis

Sudden unexpected death in epilepsy (SUDEP) is the major cause of epilepsy-related premature mortality which targets preferentially younger people. Its etiology remains unknown. Several risk factors have been identified with generalized tonic-clonic seizures as the most important one; seizure control remains the most effective measure of prevention. Although some cases may be attributable to cardiac causes, mainly undiagnosed cardiac channelopathies, the majority appear linked to epilepsy-related disruption of the functional connectivity of certain brain structures associated with the central autonomic control of cardio-respiratory function (neuro-cardio-respiratory connection). Obtaining further data on its pathophysiologic mechanisms is a cardinal step towards preventing and reducing the incidence of SUDEP. Neuroimaging and molecular genetic studies may provide insights into the causes of SUDEP and identify potential biomarkers for risk stratification of patients susceptible to SUDEP. These issues are herein reviewed with emphasis placed on the neuro-cardio-respiratory functions affected by epilepsy and their genetic control and influences.

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September 5, 2018
Comorbidities of Rare Epilepsies: Results from the Rare Epilepsy Network

 

Authors: Nhan Thi Ho, MD, PhD, Barbara Kroner, MPH, PhD, Zachary Grinspan, MPH, MD, Brandy Fureman, PhD, Kathleen Farrell, MB, BCh, BAO, Jingzhou Zhang, MPH, MD, Janice Buelow, RN, PhD, Dale C. Hesdorffer, MPH, PhD Correspondence information about the author MPH, PhD Dale C. Hesdorffer  Email the author MPH, PhD Dale C. Hesdorffer and the Rare Epilepsy Network Steering Committee.

Summary: Persons with rare epilepsies and caregivers of those affected were recruited through the Epilepsy Foundation and more than 30 rare epilepsy advocacy organizations affiliated with the Rare Epilepsy Network (REN). A web-based survey was conducted using a questionnaire consisting of core sections to collect data from affected persons on various aspects, including comorbidities. Comorbidity information was grouped into 15 classes, 12 of which had a stem question followed by detailed branch questions and 3 that were created from a combination of related questions.

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