Article
Genetics & Heredity
Chiara Kloeckner, Heinrich Sticht, Pia Zacher, Bernt Popp, Holly E. Babcock, Dewi P. Bakker, Katy Barwick, Michaela Bonfert, Carsten G. Bonnemann, Eva H. Brilstra, Wendy K. Chung, Angus J. Clarke, Patrick Devine, Sandra Donkervoort, Jamie L. Fraser, Jennifer Friedman, Alyssa Gates, Jamal Ghoumid, Emma Hobson, Gabriella Horvath, Jennifer Keller-Ramey, Boris Keren, Manju A. Kurian, Virgina Lee, Kathleen A. Leppig, Johan Lundgren, Marie T. McDonald, Amy McTague, Heather C. Mefford, Cyril Mignot, Mohamad A. Mikati, Caroline Nava, F. Lucy Raymond, Julian R. Sampson, Alba Sanchis-Juan, Vandana Shashi, Joseph T. C. Shieh, Marwan Shinawi, Anne Slavotinek, Tommy Stodberg, Nicholas Stong, Jennifer A. Sullivan, Ashley C. Taylor, Tomi L. Toler, Marie-Jose van den Boogaard, Saskia N. van der Crabben, Koen L. van Gassen, Richard H. van Jaarsveld, Jessica Van Ziffle, Alexandrea F. Wadley, Matias Wagner, Kristen Wigby, Saskia B. Wortmann, Yuri A. Zarate, Rikke S. Moller, Johannes R. Lemke, Konrad Platzer
Summary: This study provides a comprehensive description of SNAP25 developmental and epileptic encephalopathy (SNAP25-DEE) with intellectual disability and early-onset epilepsy as core symptoms, mostly presenting before the age of two. The findings suggest an overlap with other genes encoding components of the SNARE complex, advancing the concept of SNAREopathies as a group of neurodevelopmental disorders.
GENETICS IN MEDICINE
(2021)
Article
Multidisciplinary Sciences
Satoko Miyatake, Mitsuhiro Kato, Takuma Kumamoto, Tomonori Hirose, Eriko Koshimizu, Takaaki Matsui, Hideyuki Takeuchi, Hiroshi Doi, Keisuke Hamada, Mitsuko Nakashima, Kazunori Sasaki, Akio Yamashita, Atsushi Takata, Kohei Hamanaka, Mai Satoh, Takabumi Miyama, Yuri Sonoda, Momoko Sasazuki, Hiroyuki Torisu, Toshiro Hara, Yasunari Sakai, Yushi Noguchi, Mazumi Miura, Yoko Nishimura, Kazuyuki Nakamura, Hideyuki Asai, Nodoka Hinokuma, Fuyuki Miya, Tatsuhiko Tsunoda, Masami Togawa, Yukihiro Ikeda, Nobusuke Kimura, Kaoru Amemiya, Asako Horino, Masataka Fukuoka, Hiroko Ikeda, Goni Merhav, Nina Ekhilevitch, Masaki Miura, Takeshi Mizuguchi, Noriko Miyake, Atsushi Suzuki, Shouichi Ohga, Hirotomo Saitsu, Hidehisa Takahashi, Fumiaki Tanaka, Kazuhiro Ogata, Chiaki Ohtaka-Maruyama, Naomichi Matsumoto
Summary: The study identified de novo ATP1A3 variants causing a severe form of polymicrogyria with epilepsy and developmental delay, distinct from traditional clinical features of AHC, RDP, or CAPOS. This suggests a previously unidentified category of polymicrogyria associated with ATP1A3 abnormalities.
Article
Neurosciences
Xi Zhang, Neng Xiao, Yang Cao, Ying Peng, Aojie Lian, Yuanlu Chen, Pengchao Wang, Weiyue Gu, Bo Xiao, Jing Yu, Hua Wang, Li Shu
Summary: This study aimed to demonstrate the association between de novo variants in the MAST4 gene and neurodevelopmental disorders (NDD) characterized by developmental delay (DD) and infantile spasm (IS), as well as determine genotype-phenotype correlations. Trio-based exome sequencing was performed on four families, and clinical data, MRI, and EEG were collected and reviewed. Bioinformatics analysis and integration of published data were also conducted. Results identified three de novo missense variants in the MAST4 gene, suggesting its potential role in NDD. The variants were predicted to be damaging and affected amino acids that were highly conserved across species.
FRONTIERS IN MOLECULAR NEUROSCIENCE
(2023)
Article
Clinical Neurology
Sathiya N. Manivannan, Jolien Roovers, Noor Smal, Candace T. Myers, Dilsad Turkdogan, Filip Roelens, Oguz Kanca, Hyung-Lok Chung, Tasja Scholz, Katharina Hermann, Tatjana Bierhals, Hande S. Caglayan, Hannah Stamberger, Heather Mefford, Peter de Jonghe, Shinya Yamamoto, Sarah Weckhuysen, Hugo J. Bellen
Summary: This study identified new de novo missense variants in the FZR1 gene associated with developmental and epileptic encephalopathies. Functional studies in a Drosophila model supported the loss-of-function effect of the variants. The clinical phenotypes of patients were consistent with heterozygous loss-of-function of FZR1, including seizure, intellectual disability, and ataxia.
Article
Genetics & Heredity
Lydia von Wintzingerode, Bruria Ben-Zeev, Claudia Cesario, Katie M. Chan, Christel Depienne, Orly Elpeleg, Maria Iascone, Whitley V. Kelley, Marie-Cecile Nassogne, Marcello Niceta, Lidia Pezzani, Nils Rahner, Nicole Revencu, Mir Reza Bekheirnia, Teresa Santiago-Sim, Marco Tartaglia, Michelle L. Thompson, Marina Trivisano, Julia Hentschel, Heinrich Sticht, Rami Abou Jamra, Henry Oppermann
Summary: The study aimed to characterize the neurodevelopmental disorder associated with heterozygous de novo variants in CNOT9 both clinically and molecularly. Variants were identified using exome or genome sequencing and evaluated using in silico predictions. The study suggests CNOT9 as a novel gene for neurodevelopmental disorder and epilepsy.
GENETICS IN MEDICINE
(2023)
Editorial Material
Clinical Neurology
Maike F. Dohrn, Adriana P. Rebelo, Siddharth Srivastava, Gerarda Cappuccio, Robert Smigiel, Alka Malhotra, Donald Basel, Ingrid van de Laar, Rinze Frederik Neuteboom, Coranne Aarts-Tesselaar, Sonal Mahida, Nicola Brunetti-Pierri, Ryan J. Taft, Stephan Zuchner
Summary: This study identified five unrelated children with intellectual disability, spasticity, and peripheral neuropathy carrying heterozygous ATP1A1 variants. The variants led to loss of ATPase function and were associated with additional symptoms such as sensory loss, sleep disturbances, and seizures. These de novo variants had high pathogenicity prediction scores and replicated the haploinsufficiency mechanism of disease.
Review
Pharmacology & Pharmacy
Kenneth A. Myers, Ingrid E. Scheffer
Summary: Epilepsy is a genetically heterogeneous condition, with genetic factors playing a role in most patients. Over 50% of patients with infantile-onset developmental and epileptic encephalopathy (DEE) now have a genetic diagnosis. Precision medicine approaches have the potential to significantly improve the quality of life for these children and their families.
ANNUAL REVIEW OF PHARMACOLOGY AND TOXICOLOGY
(2022)
Article
Clinical Neurology
Haipo Yang, Pan Gong, Xianru Jiao, Yue Niu, Qiujun Zhou, Yuehua Zhang, Zhixian Yang
Summary: The study identified DYNC1H1 gene variants in Chinese patients with infantile spasms, showing a correlation between the variants and IS phenotype, along with brain MRI abnormalities and drug-refractory epilepsy in some patients.
FRONTIERS IN NEUROLOGY
(2021)
Article
Genetics & Heredity
Djurdja Djordjevic, Maxime Pinard, Marie-Soleil Gauthier, Constance Smith-Hicks, Trevor L. Hoffman, Nicole Wolf, Renske Oegema, Ellen van Binsbergen, Berivan Baskin, Genevieve Bernard, Sebastien Fribourg, Benoit Coulombe, Grace Yoon
Summary: POLR3B encodes the second-largest catalytic subunit of RNA polymerase III and its bi-allelic pathogenic variants are associated with hypomyelinating leukodystrophy. New research found de novo missense variants in POLR3B are related to a clinical presentation distinct from POLR3-related disorders, including sensory ataxia, spasticity, intellectual disability, and epilepsy. Protein modeling revealed a unique pathogenic mechanism caused by these variants.
AMERICAN JOURNAL OF HUMAN GENETICS
(2021)
Article
Genetics & Heredity
Pan Gong, Xianru Jiao, Dan Yu, Zhixian Yang
Summary: KCNT2 gene mutations have been found to cause developmental and epileptic encephalopathies. This study presented detailed clinical features and genetic analysis of two unrelated patients with de novo variants in KCNT2, along with a review of eight previous cases. The most common phenotypes associated with KCNT2 mutations were infantile spasms and epilepsy of infancy with migrating focal seizures, suggesting potential overlap between gain- and loss-of-function mutations in epilepsy phenotype.
FRONTIERS IN GENETICS
(2021)
Article
Genetics & Heredity
Juan Li, Shiyue Mei, Xiao Mao, Lily Wan, Hua Wang, Bo Xiao, Yanmin Song, Weiyue Gu, Yan Liu, Lili Long
Summary: This study identified de novo loss-of-function variants in the KCNJ3 gene associated with early-onset epilepsy. Genetic testing of KCNJ3 in patients with epilepsy may contribute to precision medicine.
JOURNAL OF MEDICAL GENETICS
(2023)
Article
Clinical Neurology
Serena Galosi, Ban H. Edani, Simone Martinelli, Hana Hansikova, Erik A. Eklund, Caterina Caputi, Laura Masuelli, Nicole Corsten-Janssen, Myriam Srour, Renske Oegema, Danielle G. M. Bosch, Colin A. Ellis, Louise Amlie-Wolf, Andrea Accogli, Isis Atallah, Luisa Averdunk, Kristin W. Baranano, Roberto Bei, Irene Bagnasco, Alfredo Brusco, Scott Demarest, Anne-Sophie Alaix, Carlo Di Bonaventura, Felix Distelmaier, Frances Elmslie, Ziv Gan-Or, Jean-Marc Good, Karen Gripp, Erik-Jan Kamsteeg, Ellen Macnamara, Carlo Marcelis, Noelle Mercier, Joseph Peeden, Simone Pizzi, Luca Pannone, Marwan Shinawi, Camilo Toro, Nienke E. Verbeek, Sunita Venkateswaran, Patricia G. Wheeler, Lucie Zdrazilova, Rong Zhang, Giovanna Zorzi, Renzo Guerrini, William C. Sessa, Dirk Lefeber, Marco Tartaglia, Fadi F. Hamdan, Kariona A. Grabinska, Vincenzo Leuzzi
Summary: This study investigated the variants in the DHDDS gene and found that they are associated with a new neurodegenerative disorder characterized by symptoms such as neurodevelopmental disorders, epilepsy, myoclonus, and cognitive decline. The study also revealed dysfunctional lysosomal enzymatic scavenger machinery.
Article
Pediatrics
Zehong Lin, Jinliang Li, Taoyun Ji, Ye Wu, Kai Gao, Yuwu Jiang
Summary: This study summarized the clinical and genetic features of ATP1A1 de novo mutation-related disorders, with findings suggesting that hypomagnesemia may relate to more severe phenotypes in this disorder. Variations in certain transmembrane regions of ATP1A1 were associated with more severe functional defects.
FRONTIERS IN PEDIATRICS
(2021)
Article
Biochemistry & Molecular Biology
Jiao Xue, Zhenfeng Song, Shuyin Ma, Zhi Yi, Chengqing Yang, Fei Li, Kaixuan Liu, Ying Zhang
Summary: Heterozygous missense mutations in TUBB3 are associated with various neurological disorders, with this study reporting a rare case of an eye muscle disorder patient presenting with seizures but lacking congenital cortical development abnormalities, expanding the spectrum of TUBB3 phenotypes. The findings suggest that the phenotypic range of TUBB3 mutations may exist on a more continuous spectrum.
JOURNAL OF MOLECULAR NEUROSCIENCE
(2022)
Article
Cell Biology
Iris Verbinnen, Sara S. S. Procknow, Lisa Lenaerts, Sara Reynhout, Aujan Mehregan, Chris Ulens, Veerle Janssens, Katherine A. A. King
Summary: PP2A-related (neuro) developmental disorders are genetic diseases caused by genetic alterations in the genes encoding subunits of type 2A protein phosphatases. This study reports a case of PPP2CA-affected individual with a novel de novo missense variant, and evaluates its pathogenicity. Clinically, the patient presented with developmental delay, dysmorphic facial features, seizures, and autistic behaviors. This study reveals a milder manifestation of clinical and molecular spectrum in PPP2CA cases.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2022)