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Duyen H Pham, Chuan Tan, Claire C Homan, Kristy Kolc, Mark Corbett, Dale McAninch, Archa Fox, Paul Thomas, Raman Kumar, Jozef Gecz
De novo and inherited mutations of X-chromosome cell adhesion molecule protocadherin 19 (PCDH19) cause frequent, highly variable epilepsy, autism, cognitive decline and behavioural problems syndrome. Intriguingly, hemizygous null males are not affected while heterozygous females are, contradicting established X-chromosome inheritance. The disease mechanism is not known. Cellular mosaicism is the likely driver. We have identified p54nrb/NONO, a multifunctional nuclear paraspeckle protein with known roles in nuclear hormone receptor gene regulation, as a PCDH19 protein interacting partner...
March 17, 2017: Human Molecular Genetics
Piero Perucca, Ingrid E Scheffer, A Simon Harvey, Paul A James, Sebastian Lunke, Natalie Thorne, Clara Gaff, Brigid M Regan, John A Damiano, Michael S Hildebrand, Samuel F Berkovic, Terence J O'Brien, Patrick Kwan
OBJECTIVE: Driven by advances in genomic technology and reduction in costs, next-generation sequencing (NGS) is venturing into routine clinical care. The 'real-world' clinical utility of NGS remains to be determined in focal epilepsies, which account for 60% of all epilepsies and for which the importance of genetic factors is just beginning to emerge. We investigated the diagnostic yield and management implications of whole exome sequencing (WES)-based screening of selected genes in the routine care of common focal epilepsies suspected to have a genetic basis...
March 2017: Epilepsy Research
Joseph D Symonds, Shelagh Joss, Kay A Metcalfe, Suresh Somarathi, Jamie Cruden, Anita M Devlin, Alan Donaldson, Nataliya DiDonato, David Fitzpatrick, Frank J Kaiser, Anne K Lampe, Melissa M Lees, Ailsa McLellan, Tara Montgomery, Vivek Mundada, Lesley Nairn, Ajoy Sarkar, Jens Schallner, Jelena Pozojevic, Ilaria Parenti, Jeen Tan, Peter Turnpenny, William P Whitehouse, Sameer M Zuberi
OBJECTIVE: The phenotype of seizure clustering with febrile illnesses in infancy/early childhood is well recognized. To date the only genetic epilepsy consistently associated with this phenotype is PCDH19, an X-linked disorder restricted to females, and males with mosaicism. The SMC1A gene, which encodes a structural component of the cohesin complex is also located on the X chromosome. Missense variants and small in-frame deletions of SMC1A cause approximately 5% of Cornelia de Lange Syndrome (CdLS)...
April 2017: Epilepsia
Sharon R Cooper, James D Jontes, Marcos Sotomayor
Non-clustered δ-protocadherins are homophilic cell adhesion molecules essential for the development of the vertebrate nervous system, as several are closely linked to neurodevelopmental disorders. Mutations in protocadherin-19 (PCDH19) result in a female-limited, infant-onset form of epilepsy (PCDH19-FE). Over 100 mutations in PCDH19 have been identified in patients with PCDH19-FE, about half of which are missense mutations in the adhesive extracellular domain. Neither the mechanism of homophilic adhesion by PCDH19, nor the biochemical effects of missense mutations are understood...
October 26, 2016: ELife
Ingo Helbig, Abou Ahmad N Tayoun
Epileptic encephalopathies are severe often intractable seizure disorders where epileptiform abnormalities contribute to a progressive disturbance in brain function. Often, epileptic encephalopathies start in childhood and are accompanied by developmental delay and various neurological and non-neurological comorbidities. In recent years, this concept has become virtually synonymous with a group of severe childhood epilepsies including West syndrome, Lennox-Gastaut syndrome, Dravet syndrome, and several other severe childhood epilepsies for which genetic factors are increasingly recognized...
September 2016: Molecular Syndromology
Sarenur Gokben, Huseyin Onay, Sanem Yilmaz, Tahir Atik, Gul Serdaroglu, Hande Tekin, Ferda Ozkinay
We investigated the genetic background of early-onset epileptic encephalopathy (EE) using targeted next generation sequencing analysis. Thirty sporadic or familial cases associated with early-onset EE were included. An early-onset EE gene panel including sixteen genes (ARX, CDKL5, CNTNAP2, FOLR1, FOXG1, LAMC3, MBD5, MECP2, NTNG1, PCDH19, PNKP, SCN1A, SCN1B, SCN2A, STXBP1, KCNQ2) was constituted. Nine definite and three potential causal mutations in 30 cases (40 %) were identified. All mutations presented heterozygously except one...
March 2017: Acta Neurologica Belgica
Eric Segal, Helio Pedro, Karen Valdez-Gonzalez, Sarah Parisotto, Felicia Gliksman, Stephen Thompson, Jomard Sabri, Evan Fertig
BACKGROUND: When no chromosomal variations are identified, patients with suspected genetic etiologies can be tested using next-generation sequencing utilizing epilepsy panels. The primary objective of this study was to analyze the diagnostic yield of next-generation sequencing epilepsy panels in medication-resistant epilepsy subjects with non-clinically significant comparative genomic hybridization microarray results. METHODS: We completed a single-center retrospective review of the diagnostic yield of next-generation sequencing epilepsy panels in medication-resistant epilepsy subjects aged 18 years or less who had non-clinically significant comparative genomic hybridization microarray results from January 2011 to December 2014...
November 2016: Pediatric Neurology
A Liu, X Xu, X Yang, Y Jiang, Z Yang, X Liu, Y Wu, X Wu, L Wei, Y Zhang
Mutations in PCDH19, which encodes protocadherin 19, have been identified in epilepsy, mainly in affected females. We summarized the clinical spectrum of female epilepsy patients with PCDH19 mutations in a Chinese population. We screened for PCDH19 mutations in 75 girls diagnosed with Dravet syndrome (DS) without a SCN1A mutation and 29 girls with fever-sensitive and cluster seizures. We identified 11 novel and 7 reported mutations in 21 of 104 probands (20.2%), including 6 (6/75, 8%) DS girls and 15 (15/29, 51...
January 2017: Clinical Genetics
Brian Appavu, Lisa Vanatta, John Condie, John F Kerrigan, Randa Jarrar
PURPOSE: We aimed to study whether ketogenic diet (KD) therapy leads to resolution of super-refractory status epilepticus in pediatric patients without significant harm. METHOD: A retrospective review was performed at Phoenix Children's Hospital on patients with super-refractory status epilepticus undergoing ketogenic diet therapy from 2011 to 2015. RESULTS: Ten children with super-refractory status epilepticus, ages 2-16 years, were identified...
October 2016: Seizure: the Journal of the British Epilepsy Association
M Fujitani, S Zhang, R Fujiki, Y Fujihara, T Yamashita
Chromosome 16p13.11 microduplication is a risk factor associated with various neurodevelopmental disorders such as attention-deficit/hyperactivity disorder, intellectual disabilities, developmental delay and autistic spectrum disorder. The underlying molecular mechanism of this genetic variation remained unknown, but its core genetic locus-conserved across mice and humans-contains seven genes. Here, we generated bacterial artificial chromosome-transgenic mice carrying a human 16p13.11 locus, and these mice showed the behavioral hyperactivity phenotype...
March 2017: Molecular Psychiatry
Marina Trivisano, Nicola Pietrafusa, Vincenzo di Ciommo, Simona Cappelletti, Luca de Palma, Alessandra Terracciano, Enrico Bertini, Federico Vigevano, Nicola Specchio
Aim of this study is to compare PCDH19-related epilepsy and Dravet Syndrome (DS) in order to find out differences between these two infantile epilepsies with fever sensitivity. We retrospectively reviewed the medical records of 15 patients with PCDH19-related epilepsy and 19 with DS. Comparisons were performed with Fisher's exact test or Student's t-test. Females prevailed in PCDH19-related epilepsy. Epilepsy onset was earlier in DS (5.0+2.1 vs 11.2+7.0months; p<0.05). The second seizure/cluster occurred after a longer latency in PCDH19-related epilepsy rather than in DS (10...
September 2016: Epilepsy Research
Daniel T Pederick, Claire C Homan, Emily J Jaehne, Sandra G Piltz, Bryan P Haines, Bernhard T Baune, Lachlan A Jolly, James N Hughes, Jozef Gecz, Paul Q Thomas
Protocadherin 19 (Pcdh19) is an X-linked gene belonging to the protocadherin superfamily, whose members are predominantly expressed in the central nervous system and have been implicated in cell-cell adhesion, axon guidance and dendrite self-avoidance. Heterozygous loss-of-function mutations in humans result in the childhood epilepsy disorder PCDH19 Girls Clustering Epilepsy (PCDH19 GCE) indicating that PCDH19 is required for brain development. However, understanding PCDH19 function in vivo has proven challenging and has not been studied in mammalian models...
2016: Scientific Reports
Jiao Xue, Hui Li, Yuehua Zhang, Zhixian Yang
OBJECTIVE: Hyperphosphatasia mental retardation syndrome (Mabry syndrome) is an autosomal recessive disorder. We aim to analyze two Chinese patients diagnosed as Mabry syndrome. METHODS: The clinical manifestations, diagnosis and treatment were observed in two patients. Genetic analysis including PIGV and PIGO was examined. RESULTS: Two patients were diagnosed as Mabry syndrome clinically and genetically. Developmental delay, hyperphosphatasia and seizures were presented in both of them...
October 2016: Brain & Development
A J Liu, Y H Zhang, X J Xu, X L Yang, Z X Yang, Y Wu, X Y Liu, Y W Jiang, X R Wu
OBJECTIVE: To explore the genotype and phenotype of female Dravet syndrome (DS) patients with PCDH19 mutations. METHOD: Clinical data of all DS patients seen at Pediatric Department of Peking University First Hospital from February 2005 to May 2015 were prospectively collected. Genomic DNAs were extracted from the patients and their family members. Female DS patients without SCN1A mutation were enrolled. PCR and Sanger sequencing were performed to identify PCDH19 mutations...
May 2016: Zhonghua Er Ke za Zhi. Chinese Journal of Pediatrics
Michael S Hildebrand, Candace T Myers, Gemma L Carvill, Brigid M Regan, John A Damiano, Saul A Mullen, Mark R Newton, Umesh Nair, Elena V Gazina, Carol J Milligan, Christopher A Reid, Steven Petrou, Ingrid E Scheffer, Samuel F Berkovic, Heather C Mefford
OBJECTIVES: We report development of a targeted resequencing gene panel for focal epilepsy, the most prevalent phenotypic group of the epilepsies. METHODS: The targeted resequencing gene panel was designed using molecular inversion probe (MIP) capture technology and sequenced using massively parallel Illumina sequencing. RESULTS: We demonstrated proof of principle that mutations can be detected in 4 previously genotyped focal epilepsy cases...
April 26, 2016: Neurology
Isabelle Thiffault, Emily Farrow, Laurie Smith, Jennifer Lowry, Lee Zellmer, Benjamin Black, Ahmed Abdelmoity, Neil Miller, Sarah Soden, Carol Saunders
Variants in the X-linked gene PCDH19 are associated with early infantile epileptic encephalopathy-9. This unusual condition spares hemizygous males except for psychiatric and behavioral abnormalities, and for this reason is also known as female limited epilepsy. Some cases are due to de novo PCDH19 variants, but may also be paternally inherited. Our patient is a 6-year-old male with epileptic encephalopathy. Exome sequencing revealed apparent heterozygosity in PCDH19 for a novel nonsense variant, c.605C>A (p...
June 2016: American Journal of Medical Genetics. Part A
Natalie Trump, Amy McTague, Helen Brittain, Apostolos Papandreou, Esther Meyer, Adeline Ngoh, Rodger Palmer, Deborah Morrogh, Christopher Boustred, Jane A Hurst, Lucy Jenkins, Manju A Kurian, Richard H Scott
BACKGROUND: We sought to investigate the diagnostic yield and mutation spectrum in previously reported genes for early-onset epilepsy and disorders of severe developmental delay. METHODS: In 400 patients with these disorders with no known underlying aetiology and no major structural brain anomaly, we analysed 46 genes using a combination of targeted sequencing on an Illumina MiSeq platform and targeted, exon-level microarray copy number analysis. RESULTS: We identified causative mutations in 71/400 patients (18%)...
May 2016: Journal of Medical Genetics
Hiroko Ikeda, Katsumi Imai, Hitoshi Ikeda, Hideo Shigematsu, Yukitoshi Takahashi, Yushi Inoue, Norimichi Higurashi, Shinichi Hirose
PCDH19-related epilepsy is a genetic disorder that was first described in 1971, then referred to as "epilepsy and mental retardation limited to females". PCDH19 has recently been identified as the responsible gene, but a detailed characterization of the seizure manifestation based on video-EEG recording is still limited. The purpose of this study was to elucidate features of the seizure semiology in children with PCDH19-related epilepsy. To do this, ictal video-EEG recordings of 26 convulsive seizures in three girls with PCDH19-related epilepsy were analysed...
March 2016: Epileptic Disorders: International Epilepsy Journal with Videotape
Jan Lotte, Thomas Bast, Peter Borusiak, Antonietta Coppola, J Helen Cross, Petia Dimova, Andras Fogarasi, Irene Graneß, Renzo Guerrini, Helle Hjalgrim, Reinhard Keimer, Christian M Korff, Gerhard Kurlemann, Steffen Leiz, Michaela Linder-Lucht, Tobias Loddenkemper, Christine Makowski, Christian Mühe, Joost Nicolai, Marina Nikanorova, Simona Pellacani, Sunny Philip, Susanne Ruf, Iván Sánchez Fernández, Kurt Schlachter, Pasquale Striano, Biayna Sukhudyan, Deyana Valcheva, R Jeroen Vermeulen, Tanja Weisbrod, Bernd Wilken, Philipp Wolf, Gerhard Kluger
PURPOSE: PCDH19 mutations cause epilepsy and mental retardation limited to females (EFMR) or Dravet-like syndromes. Especially in the first years of life, epilepsy is known to be highly pharmacoresistant. The aim of our study was to evaluate the effectiveness of antiepileptic therapy in patients with PCDH19 mutations. METHODS: We report a retrospective multicenter study of antiepileptic therapy in 58 female patients with PCDH19 mutations and epilepsy aged 2-27 years (mean age 10...
February 2016: Seizure: the Journal of the British Epilepsy Association
Zaid Afawi, Karen L Oliver, Sara Kivity, Aziz Mazarib, Ilan Blatt, Miriam Y Neufeld, Katherine L Helbig, Hadassa Goldberg-Stern, Adel J Misk, Rachel Straussberg, Simri Walid, Muhammad Mahajnah, Tally Lerman-Sagie, Bruria Ben-Zeev, Esther Kahana, Rafik Masalha, Uri Kramer, Dana Ekstein, Zamir Shorer, Robyn H Wallace, Marie Mangelsdorf, James N MacPherson, Gemma L Carvill, Heather C Mefford, Graeme D Jackson, Ingrid E Scheffer, Melanie Bahlo, Jozef Gecz, Sarah E Heron, Mark Corbett, John C Mulley, Leanne M Dibbens, Amos D Korczyn, Samuel F Berkovic
OBJECTIVE: To analyze the clinical syndromes and inheritance patterns of multiplex families with epilepsy toward the ultimate aim of uncovering the underlying molecular genetic basis. METHODS: Following the referral of families with 2 or more relatives with epilepsy, individuals were classified into epilepsy syndromes. Families were classified into syndromes where at least 2 family members had a specific diagnosis. Pedigrees were analyzed and molecular genetic studies were performed as appropriate...
February 23, 2016: Neurology
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