Published articles related to dup15q syndrome

July 3, 2019
Mechanisms underlying the EEG biomarker in Dup15q syndrome

Authors: Joel Frohlich1,2,3* , Lawrence T. Reiter4 , Vidya Saravanapandian2 , Charlotte DiStefano2 , Scott Huberty2,5, Carly Hyde2 , Stormy Chamberlain6 , Carrie E. Bearden7 , Peyman Golshani8 , Andrei Irimia9 , Richard W. Olsen10, Joerg F. Hipp1† and Shafali S. Jeste2†

Duplications of 15q11.2-q13.1 (Dup15q syndrome), including the paternally imprinted gene UBE3A and three nonimprinted gamma-aminobutyric acid type-A (GABAA) receptor genes, are highly penetrant for neurodevelopmental disorders such as autism spectrum disorder (ASD). To guide targeted treatments of Dup15q syndrome and other forms of ASD, biomarkers are needed that reflect molecular mechanisms of pathology. We recently described a beta EEG phenotype of Dup15q syndrome, but it remains unknown which specific genes drive this phenotype.

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June 26, 2019
Epigenomic Convergence of Neural-Immune Risk Factors in Neurodevelopmental Disorder Cortex

Authors: A Vogel Ciernia B I Laufer H Hwang K W Dunaway C E Mordaunt R L Coulson D H YasuiJ M LaSalle

Neurodevelopmental disorders (NDDs) affect 7–14% of all children in developed countries and are one of the leading causes of lifelong disability. Epigenetic modifications are poised at the interface between genes and environment and are predicted to reveal insight into NDD etiology. 

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June 19, 2019
SUDEP in the North American SUDEP Registry

Authors: Chloe Verducci, BA, Fizza Hussain, MS, Elizabeth Donner, MD FRCP(C), Brian D. Moseley, MD, Jeffrey Buchhalter, MD, Dale Hesdorffer, PhD, Daniel Friedman, MD, MSc, and Orrin Devinsky, MD

There were 237 definite and probable cases of SUDEP among 530 NASR participants. SUDEP decedents had a median age of 26 (range 1–70) years at death, and 38% were female. In 143 with sufficient information, 40% had generalized and 60% had focal epilepsy. SUDEP affected the full spectrum of epilepsies, from benign epilepsy with centrotemporal spikes (n = 3, 1%) to intractable epileptic encephalopathies (n = 27, 11%). Most (93%) SUDEPs were unwitnessed; 70% occurred during apparent sleep; and 69% of patients were prone. Only 37% of cases of SUDEP took their last dose of antiseizure medications (ASMs). Reported lifetime generalized tonic-clonic seizures (GTCS) were <10 in 33% and 0 in 4%.

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May 19, 2019
SUDEP in patients with epilepsy and nonepileptic seizures

Authors: Chloe Verducci | Daniel Friedman | Orrin Devinsky

Abstract: We report 13 SUDEP cases in the North American SUDEP Registry with both psychogenic nonepileptic seizures (PNES) and epileptic seizures (ES) among a consecutive series of 231 cases (excluding epileptic encephalopathies). On average, cases of PNES + ES died at a younger age (23 ± 11 years) than the ES‐only cohort (30 ± 14 years), and died an average of 3 years after PNES diagnosis. We found no statistically significant confounding cardiac, respiratory, or psychiatric comorbidities and equal rates of anti‐seizure medication adherence, although there was a trend for higher rates of psychiatric disorders in the PNES group. Our findings confirm that patients with comorbid ES and PNES can die from SUDEP and that there may be a high‐risk period after the diagnosis of PNES is made in patients with comorbid ES. Such patients should be closely monitored and provided with coordinated care of both their epilepsy and psychiatric disorder(s).

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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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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


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)

  • •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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