Gina L O'Grady1, Corien Verschuuren1, Michaela Yuen1, Richard Webster1, Manoj Menezes1, Johanna M Fock1, Natalie Pride1, Heather A Best1, Tatiana Benavides Damm1, Christian Turner1, Monkol Lek1, Andrew G Engel1, Kathryn N North1, Nigel F Clarke1, Daniel G MacArthur1, Erik-Jan Kamsteeg1, Sandra T Cooper2. 1. From the Institute for Neuroscience and Muscle Research (G.L.O., M.Y., N.P., H.A.B., T.B.D., K.N.N., N.F.C., S.T.C.), Kids Research Institute, T.Y. Department of Neurology (M.M., R.W.), and Heart Centre for Children (C.T.), Children's Hospital at Westmead, Sydney; Discipline of Paediatrics and Child Health (G.L.O., M.M., H.A.B., K.N.N., N.F.C., S.T.C.), Faculty of Medicine, University of Sydney, Australia; Departments of Genetics (C.V.) and Child Neurology (J.M.F.), University of Groningen University Medical Center Groningen, the Netherlands; Analytic and Translational Genetics Unit (M.L., D.G.M.), Massachusetts General Hospital, Boston; Broad Institute of Harvard and Massachusetts Institute of Technology (M.L., D.G.M.), Cambridge; Department of Neurology (A.G.E.), Mayo Clinic, Rochester, MN; Murdoch Children's Research Institute (K.N.N.), Royal Children's Hospital, Victoria, Australia; and Department of Human Genetics (E.-J.K.), Radboud University Medical Center, Nijmegen, the Netherlands. 2. From the Institute for Neuroscience and Muscle Research (G.L.O., M.Y., N.P., H.A.B., T.B.D., K.N.N., N.F.C., S.T.C.), Kids Research Institute, T.Y. Department of Neurology (M.M., R.W.), and Heart Centre for Children (C.T.), Children's Hospital at Westmead, Sydney; Discipline of Paediatrics and Child Health (G.L.O., M.M., H.A.B., K.N.N., N.F.C., S.T.C.), Faculty of Medicine, University of Sydney, Australia; Departments of Genetics (C.V.) and Child Neurology (J.M.F.), University of Groningen University Medical Center Groningen, the Netherlands; Analytic and Translational Genetics Unit (M.L., D.G.M.), Massachusetts General Hospital, Boston; Broad Institute of Harvard and Massachusetts Institute of Technology (M.L., D.G.M.), Cambridge; Department of Neurology (A.G.E.), Mayo Clinic, Rochester, MN; Murdoch Children's Research Institute (K.N.N.), Royal Children's Hospital, Victoria, Australia; and Department of Human Genetics (E.-J.K.), Radboud University Medical Center, Nijmegen, the Netherlands. Sandra.cooper@sydney.edu.au.
Abstract
OBJECTIVE: To describe the clinical and genetic characteristics of presynaptic congenital myasthenic syndrome secondary to biallelic variants in SLC18A3. METHODS: Individuals from 2 families were identified with biallelic variants in SLC18A3, the gene encoding the vesicular acetylcholine transporter (VAChT), through whole-exome sequencing. RESULTS: The patients demonstrated features seen in presynaptic congenital myasthenic syndrome, including ptosis, ophthalmoplegia, fatigable weakness, apneic crises, and deterioration of symptoms in cold water for patient 1. Both patients demonstrated moderate clinical improvement on pyridostigmine. Patient 1 had a broader phenotype, including learning difficulties and left ventricular dysfunction. Electrophysiologic studies were typical for a presynaptic defect. Both patients showed profound electrodecrement on low-frequency repetitive stimulation followed by a prolonged period of postactivation exhaustion. In patient 1, this was unmasked only after isometric contraction, a recognized feature of presynaptic disease, emphasizing the importance of activation procedures. CONCLUSIONS: VAChT is responsible for uptake of acetylcholine into presynaptic vesicles. The clinical and electrographic characteristics of the patients described are consistent with previously reported mouse models of VAChT deficiency. These findings make it very likely that defects in VAChT due to variants in SLC18A3 are a cause of congenital myasthenic syndrome in humans.
OBJECTIVE: To describe the clinical and genetic characteristics of presynaptic congenital myasthenic syndrome secondary to biallelic variants in SLC18A3. METHODS: Individuals from 2 families were identified with biallelic variants in SLC18A3, the gene encoding the vesicular acetylcholine transporter (VAChT), through whole-exome sequencing. RESULTS: The patients demonstrated features seen in presynaptic congenital myasthenic syndrome, including ptosis, ophthalmoplegia, fatigable weakness, apneic crises, and deterioration of symptoms in cold water for patient 1. Both patients demonstrated moderate clinical improvement on pyridostigmine. Patient 1 had a broader phenotype, including learning difficulties and left ventricular dysfunction. Electrophysiologic studies were typical for a presynaptic defect. Both patients showed profound electrodecrement on low-frequency repetitive stimulation followed by a prolonged period of postactivation exhaustion. In patient 1, this was unmasked only after isometric contraction, a recognized feature of presynaptic disease, emphasizing the importance of activation procedures. CONCLUSIONS: VAChT is responsible for uptake of acetylcholine into presynaptic vesicles. The clinical and electrographic characteristics of the patients described are consistent with previously reported mouse models of VAChT deficiency. These findings make it very likely that defects in VAChT due to variants in SLC18A3 are a cause of congenital myasthenic syndrome in humans.
Authors: Paweł Stankiewicz; Shashikant Kulkarni; Avinash V Dharmadhikari; Srirangan Sampath; Samarth S Bhatt; Tamim H Shaikh; Zhilian Xia; Amber N Pursley; M Lance Cooper; Marwan Shinawi; Alex R Paciorkowski; Dorothy K Grange; Michael J Noetzel; Scott Saunders; Paul Simons; Marshall Summar; Brendan Lee; Fernando Scaglia; Florence Fellmann; Danielle Martinet; Jacques S Beckmann; Alexander Asamoah; Kathryn Platky; Susan Sparks; Ann S Martin; Suneeta Madan-Khetarpal; Jacqueline Hoover; Livija Medne; Carsten G Bonnemann; John B Moeschler; Stephanie E Vallee; Sumit Parikh; Polly Irwin; Victoria P Dalzell; Wendy E Smith; Valerie C Banks; David B Flannery; Carolyn M Lovell; Gary A Bellus; Kathryn Golden-Grant; Jerome L Gorski; Jennifer L Kussmann; Tracy L McGregor; Rizwan Hamid; Jean Pfotenhauer; Blake C Ballif; Chad A Shaw; Sung-Hae L Kang; Carlos A Bacino; Ankita Patel; Jill A Rosenfeld; Sau Wai Cheung; Lisa G Shaffer Journal: Hum Mutat Date: 2011-11-02 Impact factor: 4.878
Authors: Kornelia Neveling; Ilse Feenstra; Christian Gilissen; Lies H Hoefsloot; Erik-Jan Kamsteeg; Arjen R Mensenkamp; Richard J T Rodenburg; Helger G Yntema; Liesbeth Spruijt; Sascha Vermeer; Tuula Rinne; Koen L van Gassen; Danielle Bodmer; Dorien Lugtenberg; Rick de Reuver; Wendy Buijsman; Ronny C Derks; Nienke Wieskamp; Bert van den Heuvel; Marjolijn J L Ligtenberg; Hannie Kremer; David A Koolen; Bart P C van de Warrenburg; Frans P M Cremers; Carlo L M Marcelis; Jan A M Smeitink; Saskia B Wortmann; Wendy A G van Zelst-Stams; Joris A Veltman; Han G Brunner; Hans Scheffer; Marcel R Nelen Journal: Hum Mutat Date: 2013-10-18 Impact factor: 4.878
Authors: Aline Lara; Denis D Damasceno; Rita Pires; Robert Gros; Enéas R Gomes; Mariana Gavioli; Ricardo F Lima; Diogo Guimarães; Patricia Lima; Carlos Roberto Bueno; Anilton Vasconcelos; Danilo Roman-Campos; Cristiane A S Menezes; Raquel A Sirvente; Vera M Salemi; Charles Mady; Marc G Caron; Anderson J Ferreira; Patricia C Brum; Rodrigo R Resende; Jader S Cruz; Marcus Vinicius Gomez; Vania F Prado; Alvair P de Almeida; Marco A M Prado; Silvia Guatimosim Journal: Mol Cell Biol Date: 2010-02-01 Impact factor: 4.272
Authors: Eugene P Brandon; Tiffany Mellott; Donald P Pizzo; Nicole Coufal; Kevin A D'Amour; Kevin Gobeske; Mark Lortie; Ignacio López-Coviella; Brygida Berse; Leon J Thal; Fred H Gage; Jan Krzysztof Blusztajn Journal: J Neurosci Date: 2004-06-16 Impact factor: 6.167
Authors: Manoj P Menezes; Leigh Waddell; Guy M Lenk; Simranpreet Kaur; Daniel G MacArthur; Miriam H Meisler; Nigel F Clarke Journal: Neuromuscul Disord Date: 2014-05-04 Impact factor: 4.296
Authors: Hermann A Rodrigues; Matheus de C Fonseca; Wallace L Camargo; Patrícia M A Lima; Patrícia M Martinelli; Lígia A Naves; Vânia F Prado; Marco A M Prado; Cristina Guatimosim Journal: PLoS One Date: 2013-11-08 Impact factor: 3.240
Authors: Matheus P S Magalhães-Gomes; Daisy Motta-Santos; Luana P L Schetino; Jéssica N Andrade; Cristiane P Bastos; Diogo A S Guimarães; Sydney K Vaughan; Patrícia M Martinelli; Silvia Guatimosim; Grace S Pereira; Candido C Coimbra; Vânia F Prado; Marco A M Prado; Gregorio Valdez; Cristina Guatimosim Journal: Neurochem Int Date: 2018-07-09 Impact factor: 3.921
Authors: Adi Aran; Reeval Segel; Kota Kaneshige; Suleyman Gulsuner; Paul Renbaum; Scott Oliphant; Tomer Meirson; Ariella Weinberg-Shukron; Yair Hershkovitz; Sharon Zeligson; Ming K Lee; Abraham O Samson; Stanley M Parsons; Mary-Claire King; Ephrat Levy-Lahad; Tom Walsh Journal: Neurology Date: 2017-02-10 Impact factor: 9.910
Authors: Xin-Ming Shen; Rosana H Scola; Paulo J Lorenzoni; Cláudia S K Kay; Lineu C Werneck; Joan Brengman; Duygu Selcen; Andrew G Engel Journal: Ann Clin Transl Neurol Date: 2017-01-16 Impact factor: 4.511