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Bi-allelic variants in NAE1 cause intellectual disability, ischiopubic hypoplasia, stress-mediated lymphopenia and neurodegeneration

Muffels, Irena J J; Schene, Imre F; Rehmann, Holger; Massink, Maarten P G; van der Wal, Maria M; Bauder, Corinna; Labeur, Martha; Armando, Natalia G; Lequin, Maarten H; Houben, Michiel L; Giltay, Jaques C; Haitjema, Saskia; Huisman, Albert; Vansenne, Fleur; Bluvstein, Judith; Pappas, John; Shailee, Lala V; Zarate, Yuri A; Mokry, Michal; van Haaften, Gijs W; Nieuwenhuis, Edward E S; Refojo, Damian; van Wijk, Femke; Fuchs, Sabine A; van Hasselt, Peter M
Neddylation has been implicated in various cellular pathways and in the pathophysiology of numerous diseases. We identified four individuals with bi-allelic variants in NAE1, which encodes the neddylation E1 enzyme. Pathogenicity was supported by decreased NAE1 abundance and overlapping clinical and cellular phenotypes. To delineate how cellular consequences of NAE1 deficiency would lead to the clinical phenotype, we focused primarily on the rarest phenotypic features, based on the assumption that these would best reflect the pathophysiology at stake. Two of the rarest features, neuronal loss and lymphopenia worsening during infections, suggest that NAE1 is required during cellular stress caused by infections to protect against cell death. In support, we found that stressing the proteasome system with MG132-requiring upregulation of neddylation to restore proteasomal function and proteasomal stress-led to increased cell death in fibroblasts of individuals with NAE1 genetic variants. Additionally, we found decreased lymphocyte counts after CD3/CD28 stimulation and decreased NF-κB translocation in individuals with NAE1 variants. The rarest phenotypic feature-delayed closure of the ischiopubic rami-correlated with significant downregulation of RUN2X and SOX9 expression in transcriptomic data of fibroblasts. Both genes are involved in the pathophysiology of ischiopubic hypoplasia. Thus, we show that NAE1 plays a major role in (skeletal) development and cellular homeostasis during stress. Our approach suggests that a focus on rare phenotypic features is able to provide significant pathophysiological insights in diseases caused by mutations in genes with pleiotropic effects.
PMID: 36608681
ISSN: 1537-6605
CID: 5400362

CSNK2B: A broad spectrum of neurodevelopmental disability and epilepsy severity

Ernst, Michelle E; Baugh, Evan H; Thomas, Amanda; Bier, Louise; Lippa, Natalie; Stong, Nicholas; Mulhern, Maureen S; Kushary, Sulagna; Akman, Cigdem I; Heinzen, Erin L; Yeh, Raymond; Bi, Weimin; Hanchard, Neil A; Burrage, Lindsay C; Leduc, Magalie S; Chong, Josephine S C; Bend, Renee; Lyons, Michael J; Lee, Jennifer A; Suwannarat, Pim; Brilstra, Eva; Simon, Marleen; Koopmans, Marije; van Binsbergen, Ellen; Groepper, Daniel; Fleischer, Julie; Nava, Caroline; Keren, Boris; Mignot, Cyril; Mathieu, Sophie; Mancini, Grazia M S; Madan-Khetarpal, Suneeta; Infante, Elena M; Bluvstein, Judith; Seeley, Andrea; Bachman, Kristine; Klee, Eric W; Schultz-Rogers, Laura E; Hasadsri, Linda; Barnett, Sarah; Ellingson, Marissa S; Ferber, Matthew J; Narayanan, Vinodh; Ramsey, Keri; Rauch, Anita; Joset, Pascal; Steindl, Katharina; Sheehan, Theodore; Poduri, Annapurna; Vasquez, Alejandra; Ruivenkamp, Claudia; White, Susan M; Pais, Lynn; Monaghan, Kristin G; Goldstein, David B; Sands, Tristan T; Aggarwal, Vimla
CSNK2B has recently been implicated as a disease gene for neurodevelopmental disability (NDD) and epilepsy. Information about developmental outcomes has been limited by the young age and short follow-up for many of the previously reported cases, and further delineation of the spectrum of associated phenotypes is needed. We present 25 new patients with variants in CSNK2B and refine the associated NDD and epilepsy phenotypes. CSNK2B variants were identified by research or clinical exome sequencing, and investigators from different centers were connected via GeneMatcher. Most individuals had developmental delay and generalized epilepsy with onset in the first 2 years. However, we found a broad spectrum of phenotypic severity, ranging from early normal development with pharmacoresponsive seizures to profound intellectual disability with intractable epilepsy and recurrent refractory status epilepticus. These findings suggest that CSNK2B should be considered in the diagnostic evaluation of patients with a broad range of NDD with treatable or intractable seizures.
PMID: 34041744
ISSN: 1528-1167
CID: 4894992

Diverse genetic causes of polymicrogyria with epilepsy

Allen, A S; Aggarwal, V; Cossette, P; Delanty, N; Eichler, E E; Epstein, M P; Goldstein, D B; Guerrini, R; Heinzen, E L; Johnson, M R; Marson, A G; Mefford, H C; O'Brien, T J; Petrou, S; Petrovski, S; Ruzzo, E K; Amrom, D; Andermann, E; Andermann, F; Berkovic, S F; Bluvstein, J; Boro, A; Cascino, G; Consalvo, D; Crumrine, P; Devinsky, O; Dlugos, D; Fountain, N; Freyer, C; Friedman, D; Geller, E; Glynn, S; Haas, K; Haut, S; Joshi, S; Kirsch, H; Knowlton, R; Kossoff, E; Kuzniecky, R; Lowenstein, D H; Motika, P V; Ottman, R; Paolicchi, J M; Parent, J M; Poduri, A; Scheffer, I E; Shellhaas, R A; Sherr, E H; Shih, J J; Shinnar, S; Singh, R K; Sperling, M; Smith, M C; Sullivan, J; Vining, E P G; Von, Allmen G K; Widdess-Walsh, P; Winawer, M R; Bautista, J; Fiol, M; Glauser, T; Hayward, J; Helmers, S; Park, K; Sirven, J; Lin, Thio L; Venkat, A; Weisenberg, J; Kuperman, R; McGuire, S; Novotny, E; Sadleir, L
Objective: We sought to identify novel genes and to establish the contribution of known genes in a large cohort of patients with nonsyndromic sporadic polymicrogyria and epilepsy.
Method(s): We enrolled participants with polymicrogyria and their parents through the Epilepsy Phenome/Genome Project. We performed phenotyping and whole exome sequencing (WES), trio analysis, and gene-level collapsing analysis to identify de novo or inherited variants, including germline or mosaic (postzygotic) single nucleotide variants, small insertion-deletion (indel) variants, and copy number variants present in leukocyte-derived DNA.
Result(s): Across the cohort of 86 individuals with polymicrogyria and epilepsy, we identified seven with pathogenic or likely pathogenic variants in PIK3R2, including four germline and three mosaic variants. PIK3R2 was the only gene harboring more than expected de novo variants across the entire cohort, and likewise the only gene that passed the genome-wide threshold of significance in the gene-level rare variant collapsing analysis. Consistent with previous reports, the PIK3R2 phenotype consisted of bilateral polymicrogyria concentrated in the perisylvian region with macrocephaly. Beyond PIK3R2, we also identified one case each with likely causal de novo variants in CCND2 and DYNC1H1 and biallelic variants in WDR62, all genes previously associated with polymicrogyria. Candidate genetic explanations in this cohort included single nucleotide de novo variants in other epilepsy-associated and neurodevelopmental disease-associated genes (SCN2A in two individuals, GRIA3, CACNA1C) and a 597-kb deletion at 15q25, a neurodevelopmental disease susceptibility locus.
Significance: This study confirms germline and postzygotically acquired de novo variants in PIK3R2 as an important cause of bilateral perisylvian polymicrogyria, notably with macrocephaly. In total, trio-based WES identified a genetic diagnosis in 12% and a candidate diagnosis in 6% of our polymicrogyria cohort. Our results suggest possible roles for SCN2A, GRIA3, CACNA1C, and 15q25 deletion in polymicrogyria, each already associated with epilepsy or other neurodevelopmental conditions without brain malformations. The role of these genes in polymicrogyria will be further understood as more patients with polymicrogyria undergo genetic evaluation.
Copyright
EMBASE:2011063913
ISSN: 0013-9580
CID: 4977942

Ataluren for drug-resistant epilepsy in nonsense variant-mediated Dravet syndrome and CDKL5 deficiency disorder

Devinsky, Orrin; King, LaToya; Bluvstein, Judith; Friedman, Daniel
OBJECTIVE:Ataluren is a compound that reads through premature stop codons and increases protein expression by increasing translation without modifying transcription or mRNA stability. We investigated the safety and efficacy of ataluren in children with nonsense variants causing Dravet Syndrome (DS) and CDKL5 Deficiency Syndrome (CDD). METHODS:This single-center double-blind, placebo-controlled crossover trial randomized subjects to receive ataluren or placebo for 12 weeks (period 1), a 4-week washout, then another 12-week treatment (period 2). The primary outcome was ataluren's safety profile. The secondary outcome measures were (1) changes in convulsive and/or drop seizure frequency and (2) changes in minor seizure types during ataluren treatment compared to placebo. Exploratory objectives assessed changes in cognitive, motor, and behavioral function as well as quality of life during ataluren therapy. RESULTS:We enrolled seven subjects with DS and eight subjects with CDD. Three treatment-related adverse events (AE) occurred during the blinded phases. Two subjects withdrew due to AE. Ataluren was not effective in reducing seizure frequency or improving cognitive, motor, or behavioral function or quality of life in subjects with either DS or CDD due to nonsense variants. Limitations included a small sample size and 12-week treatment phase, possibly too short to identify a disease-modifying effect. SIGNIFICANCE/CONCLUSIONS:There was no difference between ataluren and placebo; ataluren is not an effective therapy for seizures or other disorders in children with DS or CDD due to nonsense variants. There were no drug-related serious AE during the double-blind period, consistent with ataluren's favorable safety profile in larger studies. (Funded by Epilepsy Foundation, Dravet Syndrome Foundation, Finding A Cure for Seizures and Epilepsy and PTC Therapeutics, Inc.; ClinicalTrials.gov number, NCT02758626).
PMID: 33538404
ISSN: 2328-9503
CID: 4776542

Vigabatrin Toxicity in a Patient with Infantile Spasms Treated with Concomitant Hormonal Therapy

Lotan, Eyal; Bluvstein, Judith; Zan, Elcin
PMID: 33236576
ISSN: 1565-1088
CID: 4680722

Vigabatrin Toxicity in a Patient with Infantile Spasms Treated with Concomitant Hormonal Therapy [Case Report]

Lotan, Eyal; Bluvstein, Judith; Zan, Elcin
PMID: 32692506
ISSN: 1565-1088
CID: 4693232

Reflex micturition defecation epilepsy in Angelman syndrome [Case Report]

Pellinen, Jacob; Hasan, Hunaid; Ortiz, Nidia; Bluvstein, Judith; Miles, Daniel
PMCID:6927446
PMID: 32042494
ISSN: 2163-0402
CID: 4311462

The Epilepsy Genetics Initiative: Systematic reanalysis of diagnostic exomes increases yield

Berkovic, Samuel F.; Goldstein, David B.; Heinzen, Erin L.; Laughlin, Brandon L.; Lowenstein, Daniel H.; Lubbers, Laura; Stewart, Randall; Whittemore, Vicky; Angione, Kaitlin; Bazil, Carl W.; Bier, Louise; Bluvstein, Judith; Brimble, Elise; Campbell, Colleen; Cavalleri, Gianpiero; Chambers, Chelsea; Choi, Hyunmi; Cilio, Maria Roberta; Ciliberto, Michael; Cornes, Susannah; Delanty, Norman; Demarest, Scott; Devinsky, Orrin; Dlugos, Dennis; Dubbs, Holly; Dugan, Patricia; Ernst, Michelle E.; Gibbons, Melissa; Goodkin, Howard P.; Helbig, Ingo; Jansen, Laura; Johnson, Kaleas; Joshi, Charuta; Lippa, Natalie C.; Marsh, Eric; Martinez, Alejandro; Millichap, John; Mulhern, Maureen S.; Numis, Adam; Park, Kristen; Pippucci, Tommaso; Poduri, Annapurna; Porter, Brenda; Regan, Brigid; Sands, Tristan T.; Scheffer, Ingrid E.; Schreiber, John M.; Sheidley, Beth; Singhal, Nilika; Smith, Lacey; Sullivan, Joseph; Taylor, Alan; Tolete, Patricia; Afgani, Tahseen M.; Aggarwal, Vimla; Burgess, Rosemary; Dixon-Salazar, Tracy; Hemati, Parisa; Milder, Julie; Petrovski, Slave; Revah-Politi, Anya; Stong, Nicholas
ISI:000477643000007
ISSN: 0013-9580
CID: 4037902

Quantitative analysis of phenotypic elements augments traditional electroclinical classification of common familial epilepsies

Abou-Khalil, Bassel; Afawi, Zaid; Allen, Andrew S.; Bautista, Jocelyn F.; Bellows, Susannah T.; Berkovic, Samuel F.; Bluvstein, Judith; Burgess, Rosemary; Cascino, Gregory; Cossette, Patrick; Cristofaro, Sabrina; Crompton, Douglas E.; Delanty, Norman; Devinsky, Orrin; Dlugos, Dennis; Ellis, Colin A.; Epstein, Michael P.; Fountain, Nathan B.; Freyer, Catharine; Geller, Eric B.; Glauser, Tracy; Glynn, Simon; Goldberg-Stern, Hadassa; Goldstein, David B.; Gravel, Micheline; Haas, Kevin; Haut, Sheryl; Heinzen, Erin L.; Kirsch, Heidi E.; Kivity, Sara; Knowlton, Robert; Korczyn, Amos D.; Kossoff, Eric; Kuzniecky, Ruben; Loeb, Rebecca; Lowenstein, Daniel H.; Marson, Anthony G.; McCormack, Mark; McKenna, Kevin; Mefford, Heather C.; Motika, Paul; Mullen, Saul A.; O\Brien, Terence J.; Ottman, Ruth; Paolicchi, Juliann; Parent, Jack M.; Paterson, Sarah; Petrou, Steven; Petrovski, Slave; Pickrell, William Owen; Poduri, Annapurna; Rees, Mark I.; Sadleir, Lynette G.; Scheffer, Ingrid E.; Shih, Jerry; Singh, Rani; Sirven, Joseph; Smith, Michael; Smith, Phil E. M.; Thio, Liu Lin; Thomas, Rhys H.; Venkat, Anu; Vining, Eileen; Von Allmen, Gretchen; Weisenberg, Judith; Widdess-Walsh, Peter; Winawer, Melodie R.
ISI:000495227300008
ISSN: 0013-9580
CID: 4193752

Lorcaserin therapy for severe epilepsy of childhood onset: A case series

Tolete, Patricia; Knupp, Kelly; Karlovich, Michael; DeCarlo, Elaine; Bluvstein, Judith; Conway, Erin; Friedman, Daniel; Dugan, Patricia; Devinsky, Orrin
PMID: 30258026
ISSN: 1526-632x
CID: 3314392