von Murtadha L. Al-Saady ; Charlotte S. Kaiser ; Felipe Wakasuqui ; Christoph Korenke ; Quinten Waisfisz ; Abeltje Polstra ; Petra J. W. Pouwels ; Marianna Bugiani ; Marjo S. van der Knaap ; Roelineke J. Lunsing ; Eva Liebau ; Nicole Wolf
von Jan-Henje Döring ; Julian Schröter ; Jerome Jüngling ; Saskia Biskup ; Kerstin A. Klotz ; Thomas Bast ; Tobias Dietel ; Christoph Korenke ; Sophie Christoph ; Heiko Brennenstuhl ; Guido Rubboli ; Rikke S. Møller ; Gaetan Lesca ; Yves Chaix ; Stefan Kölker ; Georg F. Hoffmann ; Johannes R. Lemke ; Steffen Syrbe
Pathogenic variants in KCNA2, encoding for the voltage-gated potassium channel Kv1.2, have been identified as the cause for an evolving spectrum of neurological disorders. Affected individuals show early-onset developmental and epileptic encephalopathy, intellectual disability, and movement disorders resulting from cerebellar dysfunction. In addition, individuals with a milder course of epilepsy, complicated hereditary spastic paraplegia, and episodic ataxia have been reported. By analyzing phenotypic, functional, and genetic data from published reports and novel cases, we refine and further delineate phenotypic as well as functional subgroups of KCNA2-associated disorders. Carriers of variants, leading to complex and mixed channel dysfunction that are associated with a gain- and loss-of-potassium conductance, more often show early developmental abnormalities and an earlier onset of epilepsy compared to individuals with variants resulting in loss- or gain-of-function. We describe seven additional individuals harboring three known and the novel KCNA2 variants p.(Pro407Ala) and p.(Tyr417Cys). The location of variants reported here highlights the importance of the proline(405)-valine(406)-proline(407) (PVP) motif in transmembrane domain S6 as a mutational hotspot. A novel case of self-limited infantile seizures suggests a continuous clinical spectrum of KCNA2-related disorders. Our study provides further insights into the clinical spectrum, genotype-phenotype correlation, variability, and predicted functional impact of KCNA2 variants.
International journal of molecular sciences Basel : Molecular Diversity Preservation International, 2000 22(2021), 6, Artikel-ID 2824, Seite 1-16 Online-Ressource
von Elodie M. Richard ; Somayeh Bakhtiari ; Ashley P. L. Marsh ; Rauan Kaiyrzhanov ; Matias Wagner ; Sheetal Shetty ; Alex Pagnozzi ; Sandra M. Nordlie ; Brandon S. Guida ; Patricia Cornejo ; Helen Magee ; James Liu ; Bethany Y. Norton ; Richard I. Webster ; Lisa Worgan ; Hakon Hakonarson ; Jiankang Li ; Yiran Guo ; Mahim Jain ; Alyssa Blesson ; Lance H. Rodan ; Mary-Alice Abbott ; Anne Comi ; Julie S. Cohen ; Bader Alhaddad ; Thomas Meitinger ; Dominic Lenz ; Andreas Ziegler ; Urania Kotzaeridou ; Theresa Brunet ; Anna Chassevent ; Constance Smith-Hicks ; Joseph Ekstein ; Tzvi Weiden ; Andreas Hahn ; Nazira Zharkinbekova ; Peter Turnpenny ; Arianna Tucci ; Melissa Yelton ; Rita Horvath ; Serdal Gungor ; Semra Hiz ; Yavuz Oktay ; Hanns Lochmuller ; Marcella Zollino ; Manuela Morleo ; Giuseppe Marangi ; Vincenzo Nigro ; Annalaura Torella ; Michele Pinelli ; Simona Amenta ; Ralf A. Husain ; Benita Grossmann ; Marion Rapp ; Claudia Steen ; Iris Marquardt ; Mona Grimmel ; Ute Grasshoff ; Christoph Korenke ; Marta Owczarek-Lipska ; John Neidhardt ; Francesca Clementina Radio ; Cecilia Mancini ; Dianela Judith Claps Sepulveda ; Kirsty McWalter ; Amber Begtrup ; Amy Crunk ; Maria J. Guillen Sacoto ; Richard Person ; Rhonda E. Schnur ; Maria Margherita Mancardi ; Florian Kreuder ; Pasquale Striano ; Federico Zara ; Wendy K. Chung ; Warren A. Marks ; Clare L. van Eyk ; Dani L. Webber ; Mark A. Corbett ; Kelly Harper ; Jesia G. Berry ; Alastair H. MacLennan ; Jozef Gecz ; Marco Tartaglia ; Vincenzo Salpietro ; John Christodoulou ; Jan Kaslin ; Sergio Padilla-Lopez ; Kaya Bilguvar ; Alexander Munchau ; Zubair M. Ahmed ; Robert B. Hufnagel ; Michael C. Fahey ; Reza Maroofian ; Henry Houlden ; Heinrich Sticht ; Shrikant M. Mane ; Aboulfazl Rad ; Barbara Vona ; Sheng Chih Jin ; Tobias B. Haack ; Christine Makowski ; Yoel Hirsch ; Saima Riazuddin ; Michael C. Kruer
Spermatogenesis-associated 5 like 1 (SPATA5L1) represents an orphan gene encoding a protein of unknown function. We report 28 bi-allelic variants in SPATA5L1 associated with sensorineural hearing loss in 47 individuals from 28 (26 unrelated) families. In addition, 25/47 affected individuals (53%) presented with microcephaly, developmental delay/intellectual disability, cerebral palsy, and/or epilepsy. Modeling indicated damaging effect of variants on the protein, largely via destabilizing effects on protein domains. Brain imaging revealed diminished cerebral volume, thin corpus callosum, and periventricular leukomalacia, and quantitative volumetry demonstrated significantly diminished white matter volumes in several individuals. Immunofluorescent imaging in rat hippocampal neurons revealed localization of Spata5l1 in neuronal and glial cell nuclei and more prominent expression in neurons. In the rodent inner ear, Spata5l1 is expressed in the neurosensory hair cells and inner ear supporting cells. Transcriptomic analysis performed with fibroblasts from affected individuals was able to distinguish affected from controls by principal components. Analysis of differentially expressed genes and networks suggested a role for SPATA5L1 in cell surface adhesion receptor function, intracellular focal adhesions, and DNA replication and mitosis. Collectively, our results indicate that bi-allelic SPATA5L1 variants lead to a human disease characterized by sensorineural hearing loss (SNHL) with or without a nonprogressive mixed neurodevelopmental phenotype.
The American journal of human genetics New York, NY [u.a.] : Cell Press, 1949 108(2021), 10, Seite 2006-2016
von Fenja Markus ; Annika Kannengießer ; Patricia Näder ; Paul Atigbire ; Alexander Scholten ; Christine Vössing ; Eva Bültmann ; Christoph Korenke ; Marta Owczarek-Lipska ; John Neidhardt
von Tim Van Damme ; Thatjana Gardeitchik ; Miski Mohamed ; Sergio Guerrero-Castillo ; Peter Freisinger ; Brecht Guillemyn ; Ariana Kariminejad ; Daisy Dalloyaux ; Sannevan Kraaij ; Dirk J. Lefeber ; Delfien Syx ; Wouter Steyaert ; Riet De Rycke ; Alexander Hoischen ; Erik-Jan Kamsteeg ; Sunnie Y. Wong ; Monique van Scherpenzeel ; Payman Jamili ; Ulrich Brandt ; Leo Nijtmans ; Christoph Korenke ; Brian H.Y. Chung ; Christopher C.Y. Mak ; Ingrid Hausser ; Uwe Kornak ; Björn Fischer-Zirnsak ; Tim M. Strom ; Thomas Meitinger ; Yasemin Alanay ; Gulem E. Utine ; Peter K.C. Leung ; Siavash Ghaderi-Sohi ; Paul Coucke ; Sofie Symoens ; Anne De Paepe ; Christian Thiel ; Tobias B. Haack ; Fransiska Malfait ; Eva Morava ; Bert Callewaert ; Ron A. Wevers
von Pauline E. Schneeberger ; Fanny Kortüm ; Christoph Korenke ; Malik Alaw ; René Santer ; Mathias Woidy ; Daniela Buhas ; Stephanie Fox ; Jane Juusola ; Majid Alfadhel ; Bryn D. Webb ; Emanuele G. Coci ; Rami Abou Jamra ; Manuela Siekmeyer ; Saskia Biskup ; Corina Heller ; Esther M. Maier ; Poupak Javaher-Haghighi ; Maria F. Bedeschi ; Paola F. Ajmone ; Maria Iascone ; Hilde Peeters ; Katleen Ballon ; Jaak Jaeken ; Aroa Rodriguez Alonso ; Maria Palomares-Bralo ; Fernando Santos-Simarro ; Marije E.C. Meuwissen ; Diane Beysen ; R. Frank Kooy ; Henry Houlden ; David Murphy ; Mohammad Doosti ; Ehsan G. Karimiani ; Majid Mojarrad ; Reza Maroofian ; Lenka Noskova ; Stanislav Kmoch ; Tomas Honzik ; Heidi Cope ; Amarilis Sanchez-Valle ; Bruce D. Gelb ; Ingo Kurth ; Maja Hempel ; Kerstin Kutsche
von Sabine Illsinger ; Christoph Korenke ; Sylvia Boesch ; Michael Nocker ; Daniela Karall ; Jean M. Nuoffer ; Lucia Laugwitz ; Johannes A. Mayr ; Sabine Scholl-Bürgi ; Peter Freisinger ; Tobias Kowald ; Stefan Kölker ; Holger Prokisch ; Tobias B. Haack
Background - ECHS1 encodes the mitochondrial short chain enoyl CoA hydratase 1 (SCEH). Biallelic ECHS1 variants have been associated with Leigh-like presentations and milder phenotypes with paroxysmal exercise-induced dystonia. - Patients/methods - We used exome sequencing to investigate molecular bases of paroxysmal and non-paroxysmal dystonia in three patients and performed functional studies in fibroblasts. Disease presentation and response upon dietary interventions were documented. - Results - We identified compound heterozygous ECHS1 missense variants in all individuals; all of them harbouring an c.518C > T (p.Ala173Val) variant. SCEH activity was impaired in patients’ fibroblasts, respiratory chain-, and pyruvate-dehydrogenase-complex activities were normal in one individual. Patient 1 presented from the age of 2.5 years on with paroxysmal opisthotonic posturing. Patient 2 had a first metabolic crisis at the age 20 months developing recurrent exercise-induced dystonic episodes. Disease history of patient 3 was unremarkable for neurological findings until he first presented at the age of 20 years with persistent dystonia. Ketogenic diet had beneficial effects in patient 1. Neither ketogenic nor low protein diets led to milder symptoms in patient 2. Patient 3 benefits from low protein diet with improvement of his torticollis. - Conclusions - In line with literature, our findings corroborate that the pathogenic ECHS1 variant c.518C > T (p.Ala173Val) is associated with milder phenotypes characterized by paroxysmal and non-paroxysmal dystonia. Because of the potentially treatable defect, especially in milder affected patients, it is important to consider SCEH deficiency not only in patients with Leigh-like syndrome but also in patients with paroxysmal dystonia and normal neurological findings between episodes.
European journal of medical genetics New York, NY [u.a.] : Elsevier, 2005 63(2020,11) Artikel-Nummer 104046, 8 Seiten Online-Ressource
von Fenja Markus ; Chloé Angelini ; Aurelien Trimouille ; Gabrielle Rudolf ; Gaetan Lesca ; Cyril Goizet ; Eulalie Lasseaux ; Benoit Arveiler ; Marjon van Slegtenhorst ; Alice S. Brooks ; Rami Abou Jamra ; Christoph Korenke ; John Neidhardt ; Marta Owczarek-Lipska