January 29, 2013; 80 (5) Article
Pontocerebellar hypoplasia type 1
Clinical spectrum and relevance of EXOSC3 mutations
Sabine Rudnik-Schöneborn, Jan Senderek, Joanna C. Jen, Gunnar Houge, Pavel Seeman, Alena Puchmajerová, Luitgard Graul-Neumann, Ulrich Seidel, Rudolf Korinthenberg, Janbernd Kirschner, Jürgen Seeger, Monique M. Ryan, Francesco Muntoni, Maja Steinlin, Laszlo Sztriha, Jaume Colomer, Christoph Hübner, Knut Brockmann, Lionel Van Maldergem, Manuel Schiff, Andreas Holzinger, Peter Barth, William Reardon, Michael Yourshaw, Stanley F. Nelson, Thomas Eggermann, Klaus Zerres
First published January 2, 2013, DOI: https://doi.org/10.1212/WNL.0b013e31827f0f66
Sabine Rudnik-Schöneborn
From the Institute of Human Genetics (S.R.-S., J. Senderek, T.E., K.Z.), Medical Faculty, University Hospital Aachen, Germany; Departments of Neurology (J.C.J.), Human Genetics (M.Y., S.F.N.), Pathology & Laboratory Medicine (S.F.N.), and Psychiatry (S.F.N.), University of California, Los Angeles; Center for Medical Genetics and Molecular Medicine (G.H.), Haukeland University Hospital, Bergen, Norway; Department of Child Neurology (P.S.), 2nd Faculty of Medicine, Charles University Prague and University Hospital, Prague; Institute of Biology and Medical Genetics (A.P.), University Hospital Motol, Prague, Czech Republic; Institute of Medical and Human Genetics (L.G.-N.), Department of Pediatrics (U.S.), and Department of Neuropediatrics (C.H.), Charité Universitätsmedizin Berlin, Berlin; Department of Pediatrics (R.K., J.K.), University Medical Center Freiburg, Freiburg; German Clinic for Diagnostics (J. Seeger), Wiesbaden, Germany; Royal Children's Hospital (M.M.R.), Murdoch Childrens Research Institute, University of Melbourne, Australia; UCL Institute of Child Health & Great Ormond Street Hospital for Children (F.M.), London, UK; Department of Neuropediatrics (M. Steinlin), University Children's Hospital Bern, Bern, Switzerland; Department of Pediatrics (L.S.), University of Szeged, Hungary; Unitat de Patologia Neuromuscular (J.C.), Servei de Neurologica, Hospital Sant Joan de Déu, Barcelona, Spain; Department of Pediatrics and Pediatric Neurology (K.B.), Faculty of Medicine, University of Göttingen, Göttingen, Germany; Centre for Human Genetics (L.V.M.), Université de Franche-Comté, Besanςon; Department of Child Neurology and Metabolic Diseases (M. Schiff), Hospital Robert Debré, Paris, France; Department of Pediatrics, Dr. von Haunersches Kinderspital (A.H.), Friedrich-Baur-Institut (J. Senderek), Ludwig-Maximilian-Universität München, Munich, Germany; Division of Pediatric Neurology (P.B.), Emma Children's Hospital/Academic Medical Center, University Hospital Amsterdam, the Netherlands; and Our Lady's Hospital for Sick Children (W.R.), Crumlin, Dublin, Ireland.
MDJan Senderek
From the Institute of Human Genetics (S.R.-S., J. Senderek, T.E., K.Z.), Medical Faculty, University Hospital Aachen, Germany; Departments of Neurology (J.C.J.), Human Genetics (M.Y., S.F.N.), Pathology & Laboratory Medicine (S.F.N.), and Psychiatry (S.F.N.), University of California, Los Angeles; Center for Medical Genetics and Molecular Medicine (G.H.), Haukeland University Hospital, Bergen, Norway; Department of Child Neurology (P.S.), 2nd Faculty of Medicine, Charles University Prague and University Hospital, Prague; Institute of Biology and Medical Genetics (A.P.), University Hospital Motol, Prague, Czech Republic; Institute of Medical and Human Genetics (L.G.-N.), Department of Pediatrics (U.S.), and Department of Neuropediatrics (C.H.), Charité Universitätsmedizin Berlin, Berlin; Department of Pediatrics (R.K., J.K.), University Medical Center Freiburg, Freiburg; German Clinic for Diagnostics (J. Seeger), Wiesbaden, Germany; Royal Children's Hospital (M.M.R.), Murdoch Childrens Research Institute, University of Melbourne, Australia; UCL Institute of Child Health & Great Ormond Street Hospital for Children (F.M.), London, UK; Department of Neuropediatrics (M. Steinlin), University Children's Hospital Bern, Bern, Switzerland; Department of Pediatrics (L.S.), University of Szeged, Hungary; Unitat de Patologia Neuromuscular (J.C.), Servei de Neurologica, Hospital Sant Joan de Déu, Barcelona, Spain; Department of Pediatrics and Pediatric Neurology (K.B.), Faculty of Medicine, University of Göttingen, Göttingen, Germany; Centre for Human Genetics (L.V.M.), Université de Franche-Comté, Besanςon; Department of Child Neurology and Metabolic Diseases (M. Schiff), Hospital Robert Debré, Paris, France; Department of Pediatrics, Dr. von Haunersches Kinderspital (A.H.), Friedrich-Baur-Institut (J. Senderek), Ludwig-Maximilian-Universität München, Munich, Germany; Division of Pediatric Neurology (P.B.), Emma Children's Hospital/Academic Medical Center, University Hospital Amsterdam, the Netherlands; and Our Lady's Hospital for Sick Children (W.R.), Crumlin, Dublin, Ireland.
MDJoanna C. Jen
From the Institute of Human Genetics (S.R.-S., J. Senderek, T.E., K.Z.), Medical Faculty, University Hospital Aachen, Germany; Departments of Neurology (J.C.J.), Human Genetics (M.Y., S.F.N.), Pathology & Laboratory Medicine (S.F.N.), and Psychiatry (S.F.N.), University of California, Los Angeles; Center for Medical Genetics and Molecular Medicine (G.H.), Haukeland University Hospital, Bergen, Norway; Department of Child Neurology (P.S.), 2nd Faculty of Medicine, Charles University Prague and University Hospital, Prague; Institute of Biology and Medical Genetics (A.P.), University Hospital Motol, Prague, Czech Republic; Institute of Medical and Human Genetics (L.G.-N.), Department of Pediatrics (U.S.), and Department of Neuropediatrics (C.H.), Charité Universitätsmedizin Berlin, Berlin; Department of Pediatrics (R.K., J.K.), University Medical Center Freiburg, Freiburg; German Clinic for Diagnostics (J. Seeger), Wiesbaden, Germany; Royal Children's Hospital (M.M.R.), Murdoch Childrens Research Institute, University of Melbourne, Australia; UCL Institute of Child Health & Great Ormond Street Hospital for Children (F.M.), London, UK; Department of Neuropediatrics (M. Steinlin), University Children's Hospital Bern, Bern, Switzerland; Department of Pediatrics (L.S.), University of Szeged, Hungary; Unitat de Patologia Neuromuscular (J.C.), Servei de Neurologica, Hospital Sant Joan de Déu, Barcelona, Spain; Department of Pediatrics and Pediatric Neurology (K.B.), Faculty of Medicine, University of Göttingen, Göttingen, Germany; Centre for Human Genetics (L.V.M.), Université de Franche-Comté, Besanςon; Department of Child Neurology and Metabolic Diseases (M. Schiff), Hospital Robert Debré, Paris, France; Department of Pediatrics, Dr. von Haunersches Kinderspital (A.H.), Friedrich-Baur-Institut (J. Senderek), Ludwig-Maximilian-Universität München, Munich, Germany; Division of Pediatric Neurology (P.B.), Emma Children's Hospital/Academic Medical Center, University Hospital Amsterdam, the Netherlands; and Our Lady's Hospital for Sick Children (W.R.), Crumlin, Dublin, Ireland.
MDGunnar Houge
From the Institute of Human Genetics (S.R.-S., J. Senderek, T.E., K.Z.), Medical Faculty, University Hospital Aachen, Germany; Departments of Neurology (J.C.J.), Human Genetics (M.Y., S.F.N.), Pathology & Laboratory Medicine (S.F.N.), and Psychiatry (S.F.N.), University of California, Los Angeles; Center for Medical Genetics and Molecular Medicine (G.H.), Haukeland University Hospital, Bergen, Norway; Department of Child Neurology (P.S.), 2nd Faculty of Medicine, Charles University Prague and University Hospital, Prague; Institute of Biology and Medical Genetics (A.P.), University Hospital Motol, Prague, Czech Republic; Institute of Medical and Human Genetics (L.G.-N.), Department of Pediatrics (U.S.), and Department of Neuropediatrics (C.H.), Charité Universitätsmedizin Berlin, Berlin; Department of Pediatrics (R.K., J.K.), University Medical Center Freiburg, Freiburg; German Clinic for Diagnostics (J. Seeger), Wiesbaden, Germany; Royal Children's Hospital (M.M.R.), Murdoch Childrens Research Institute, University of Melbourne, Australia; UCL Institute of Child Health & Great Ormond Street Hospital for Children (F.M.), London, UK; Department of Neuropediatrics (M. Steinlin), University Children's Hospital Bern, Bern, Switzerland; Department of Pediatrics (L.S.), University of Szeged, Hungary; Unitat de Patologia Neuromuscular (J.C.), Servei de Neurologica, Hospital Sant Joan de Déu, Barcelona, Spain; Department of Pediatrics and Pediatric Neurology (K.B.), Faculty of Medicine, University of Göttingen, Göttingen, Germany; Centre for Human Genetics (L.V.M.), Université de Franche-Comté, Besanςon; Department of Child Neurology and Metabolic Diseases (M. Schiff), Hospital Robert Debré, Paris, France; Department of Pediatrics, Dr. von Haunersches Kinderspital (A.H.), Friedrich-Baur-Institut (J. Senderek), Ludwig-Maximilian-Universität München, Munich, Germany; Division of Pediatric Neurology (P.B.), Emma Children's Hospital/Academic Medical Center, University Hospital Amsterdam, the Netherlands; and Our Lady's Hospital for Sick Children (W.R.), Crumlin, Dublin, Ireland.
MDPavel Seeman
From the Institute of Human Genetics (S.R.-S., J. Senderek, T.E., K.Z.), Medical Faculty, University Hospital Aachen, Germany; Departments of Neurology (J.C.J.), Human Genetics (M.Y., S.F.N.), Pathology & Laboratory Medicine (S.F.N.), and Psychiatry (S.F.N.), University of California, Los Angeles; Center for Medical Genetics and Molecular Medicine (G.H.), Haukeland University Hospital, Bergen, Norway; Department of Child Neurology (P.S.), 2nd Faculty of Medicine, Charles University Prague and University Hospital, Prague; Institute of Biology and Medical Genetics (A.P.), University Hospital Motol, Prague, Czech Republic; Institute of Medical and Human Genetics (L.G.-N.), Department of Pediatrics (U.S.), and Department of Neuropediatrics (C.H.), Charité Universitätsmedizin Berlin, Berlin; Department of Pediatrics (R.K., J.K.), University Medical Center Freiburg, Freiburg; German Clinic for Diagnostics (J. Seeger), Wiesbaden, Germany; Royal Children's Hospital (M.M.R.), Murdoch Childrens Research Institute, University of Melbourne, Australia; UCL Institute of Child Health & Great Ormond Street Hospital for Children (F.M.), London, UK; Department of Neuropediatrics (M. Steinlin), University Children's Hospital Bern, Bern, Switzerland; Department of Pediatrics (L.S.), University of Szeged, Hungary; Unitat de Patologia Neuromuscular (J.C.), Servei de Neurologica, Hospital Sant Joan de Déu, Barcelona, Spain; Department of Pediatrics and Pediatric Neurology (K.B.), Faculty of Medicine, University of Göttingen, Göttingen, Germany; Centre for Human Genetics (L.V.M.), Université de Franche-Comté, Besanςon; Department of Child Neurology and Metabolic Diseases (M. Schiff), Hospital Robert Debré, Paris, France; Department of Pediatrics, Dr. von Haunersches Kinderspital (A.H.), Friedrich-Baur-Institut (J. Senderek), Ludwig-Maximilian-Universität München, Munich, Germany; Division of Pediatric Neurology (P.B.), Emma Children's Hospital/Academic Medical Center, University Hospital Amsterdam, the Netherlands; and Our Lady's Hospital for Sick Children (W.R.), Crumlin, Dublin, Ireland.
MDAlena Puchmajerová
From the Institute of Human Genetics (S.R.-S., J. Senderek, T.E., K.Z.), Medical Faculty, University Hospital Aachen, Germany; Departments of Neurology (J.C.J.), Human Genetics (M.Y., S.F.N.), Pathology & Laboratory Medicine (S.F.N.), and Psychiatry (S.F.N.), University of California, Los Angeles; Center for Medical Genetics and Molecular Medicine (G.H.), Haukeland University Hospital, Bergen, Norway; Department of Child Neurology (P.S.), 2nd Faculty of Medicine, Charles University Prague and University Hospital, Prague; Institute of Biology and Medical Genetics (A.P.), University Hospital Motol, Prague, Czech Republic; Institute of Medical and Human Genetics (L.G.-N.), Department of Pediatrics (U.S.), and Department of Neuropediatrics (C.H.), Charité Universitätsmedizin Berlin, Berlin; Department of Pediatrics (R.K., J.K.), University Medical Center Freiburg, Freiburg; German Clinic for Diagnostics (J. Seeger), Wiesbaden, Germany; Royal Children's Hospital (M.M.R.), Murdoch Childrens Research Institute, University of Melbourne, Australia; UCL Institute of Child Health & Great Ormond Street Hospital for Children (F.M.), London, UK; Department of Neuropediatrics (M. Steinlin), University Children's Hospital Bern, Bern, Switzerland; Department of Pediatrics (L.S.), University of Szeged, Hungary; Unitat de Patologia Neuromuscular (J.C.), Servei de Neurologica, Hospital Sant Joan de Déu, Barcelona, Spain; Department of Pediatrics and Pediatric Neurology (K.B.), Faculty of Medicine, University of Göttingen, Göttingen, Germany; Centre for Human Genetics (L.V.M.), Université de Franche-Comté, Besanςon; Department of Child Neurology and Metabolic Diseases (M. Schiff), Hospital Robert Debré, Paris, France; Department of Pediatrics, Dr. von Haunersches Kinderspital (A.H.), Friedrich-Baur-Institut (J. Senderek), Ludwig-Maximilian-Universität München, Munich, Germany; Division of Pediatric Neurology (P.B.), Emma Children's Hospital/Academic Medical Center, University Hospital Amsterdam, the Netherlands; and Our Lady's Hospital for Sick Children (W.R.), Crumlin, Dublin, Ireland.
MDLuitgard Graul-Neumann
From the Institute of Human Genetics (S.R.-S., J. Senderek, T.E., K.Z.), Medical Faculty, University Hospital Aachen, Germany; Departments of Neurology (J.C.J.), Human Genetics (M.Y., S.F.N.), Pathology & Laboratory Medicine (S.F.N.), and Psychiatry (S.F.N.), University of California, Los Angeles; Center for Medical Genetics and Molecular Medicine (G.H.), Haukeland University Hospital, Bergen, Norway; Department of Child Neurology (P.S.), 2nd Faculty of Medicine, Charles University Prague and University Hospital, Prague; Institute of Biology and Medical Genetics (A.P.), University Hospital Motol, Prague, Czech Republic; Institute of Medical and Human Genetics (L.G.-N.), Department of Pediatrics (U.S.), and Department of Neuropediatrics (C.H.), Charité Universitätsmedizin Berlin, Berlin; Department of Pediatrics (R.K., J.K.), University Medical Center Freiburg, Freiburg; German Clinic for Diagnostics (J. Seeger), Wiesbaden, Germany; Royal Children's Hospital (M.M.R.), Murdoch Childrens Research Institute, University of Melbourne, Australia; UCL Institute of Child Health & Great Ormond Street Hospital for Children (F.M.), London, UK; Department of Neuropediatrics (M. Steinlin), University Children's Hospital Bern, Bern, Switzerland; Department of Pediatrics (L.S.), University of Szeged, Hungary; Unitat de Patologia Neuromuscular (J.C.), Servei de Neurologica, Hospital Sant Joan de Déu, Barcelona, Spain; Department of Pediatrics and Pediatric Neurology (K.B.), Faculty of Medicine, University of Göttingen, Göttingen, Germany; Centre for Human Genetics (L.V.M.), Université de Franche-Comté, Besanςon; Department of Child Neurology and Metabolic Diseases (M. Schiff), Hospital Robert Debré, Paris, France; Department of Pediatrics, Dr. von Haunersches Kinderspital (A.H.), Friedrich-Baur-Institut (J. Senderek), Ludwig-Maximilian-Universität München, Munich, Germany; Division of Pediatric Neurology (P.B.), Emma Children's Hospital/Academic Medical Center, University Hospital Amsterdam, the Netherlands; and Our Lady's Hospital for Sick Children (W.R.), Crumlin, Dublin, Ireland.
MDUlrich Seidel
From the Institute of Human Genetics (S.R.-S., J. Senderek, T.E., K.Z.), Medical Faculty, University Hospital Aachen, Germany; Departments of Neurology (J.C.J.), Human Genetics (M.Y., S.F.N.), Pathology & Laboratory Medicine (S.F.N.), and Psychiatry (S.F.N.), University of California, Los Angeles; Center for Medical Genetics and Molecular Medicine (G.H.), Haukeland University Hospital, Bergen, Norway; Department of Child Neurology (P.S.), 2nd Faculty of Medicine, Charles University Prague and University Hospital, Prague; Institute of Biology and Medical Genetics (A.P.), University Hospital Motol, Prague, Czech Republic; Institute of Medical and Human Genetics (L.G.-N.), Department of Pediatrics (U.S.), and Department of Neuropediatrics (C.H.), Charité Universitätsmedizin Berlin, Berlin; Department of Pediatrics (R.K., J.K.), University Medical Center Freiburg, Freiburg; German Clinic for Diagnostics (J. Seeger), Wiesbaden, Germany; Royal Children's Hospital (M.M.R.), Murdoch Childrens Research Institute, University of Melbourne, Australia; UCL Institute of Child Health & Great Ormond Street Hospital for Children (F.M.), London, UK; Department of Neuropediatrics (M. Steinlin), University Children's Hospital Bern, Bern, Switzerland; Department of Pediatrics (L.S.), University of Szeged, Hungary; Unitat de Patologia Neuromuscular (J.C.), Servei de Neurologica, Hospital Sant Joan de Déu, Barcelona, Spain; Department of Pediatrics and Pediatric Neurology (K.B.), Faculty of Medicine, University of Göttingen, Göttingen, Germany; Centre for Human Genetics (L.V.M.), Université de Franche-Comté, Besanςon; Department of Child Neurology and Metabolic Diseases (M. Schiff), Hospital Robert Debré, Paris, France; Department of Pediatrics, Dr. von Haunersches Kinderspital (A.H.), Friedrich-Baur-Institut (J. Senderek), Ludwig-Maximilian-Universität München, Munich, Germany; Division of Pediatric Neurology (P.B.), Emma Children's Hospital/Academic Medical Center, University Hospital Amsterdam, the Netherlands; and Our Lady's Hospital for Sick Children (W.R.), Crumlin, Dublin, Ireland.
MDRudolf Korinthenberg
From the Institute of Human Genetics (S.R.-S., J. Senderek, T.E., K.Z.), Medical Faculty, University Hospital Aachen, Germany; Departments of Neurology (J.C.J.), Human Genetics (M.Y., S.F.N.), Pathology & Laboratory Medicine (S.F.N.), and Psychiatry (S.F.N.), University of California, Los Angeles; Center for Medical Genetics and Molecular Medicine (G.H.), Haukeland University Hospital, Bergen, Norway; Department of Child Neurology (P.S.), 2nd Faculty of Medicine, Charles University Prague and University Hospital, Prague; Institute of Biology and Medical Genetics (A.P.), University Hospital Motol, Prague, Czech Republic; Institute of Medical and Human Genetics (L.G.-N.), Department of Pediatrics (U.S.), and Department of Neuropediatrics (C.H.), Charité Universitätsmedizin Berlin, Berlin; Department of Pediatrics (R.K., J.K.), University Medical Center Freiburg, Freiburg; German Clinic for Diagnostics (J. Seeger), Wiesbaden, Germany; Royal Children's Hospital (M.M.R.), Murdoch Childrens Research Institute, University of Melbourne, Australia; UCL Institute of Child Health & Great Ormond Street Hospital for Children (F.M.), London, UK; Department of Neuropediatrics (M. Steinlin), University Children's Hospital Bern, Bern, Switzerland; Department of Pediatrics (L.S.), University of Szeged, Hungary; Unitat de Patologia Neuromuscular (J.C.), Servei de Neurologica, Hospital Sant Joan de Déu, Barcelona, Spain; Department of Pediatrics and Pediatric Neurology (K.B.), Faculty of Medicine, University of Göttingen, Göttingen, Germany; Centre for Human Genetics (L.V.M.), Université de Franche-Comté, Besanςon; Department of Child Neurology and Metabolic Diseases (M. Schiff), Hospital Robert Debré, Paris, France; Department of Pediatrics, Dr. von Haunersches Kinderspital (A.H.), Friedrich-Baur-Institut (J. Senderek), Ludwig-Maximilian-Universität München, Munich, Germany; Division of Pediatric Neurology (P.B.), Emma Children's Hospital/Academic Medical Center, University Hospital Amsterdam, the Netherlands; and Our Lady's Hospital for Sick Children (W.R.), Crumlin, Dublin, Ireland.
MDJanbernd Kirschner
From the Institute of Human Genetics (S.R.-S., J. Senderek, T.E., K.Z.), Medical Faculty, University Hospital Aachen, Germany; Departments of Neurology (J.C.J.), Human Genetics (M.Y., S.F.N.), Pathology & Laboratory Medicine (S.F.N.), and Psychiatry (S.F.N.), University of California, Los Angeles; Center for Medical Genetics and Molecular Medicine (G.H.), Haukeland University Hospital, Bergen, Norway; Department of Child Neurology (P.S.), 2nd Faculty of Medicine, Charles University Prague and University Hospital, Prague; Institute of Biology and Medical Genetics (A.P.), University Hospital Motol, Prague, Czech Republic; Institute of Medical and Human Genetics (L.G.-N.), Department of Pediatrics (U.S.), and Department of Neuropediatrics (C.H.), Charité Universitätsmedizin Berlin, Berlin; Department of Pediatrics (R.K., J.K.), University Medical Center Freiburg, Freiburg; German Clinic for Diagnostics (J. Seeger), Wiesbaden, Germany; Royal Children's Hospital (M.M.R.), Murdoch Childrens Research Institute, University of Melbourne, Australia; UCL Institute of Child Health & Great Ormond Street Hospital for Children (F.M.), London, UK; Department of Neuropediatrics (M. Steinlin), University Children's Hospital Bern, Bern, Switzerland; Department of Pediatrics (L.S.), University of Szeged, Hungary; Unitat de Patologia Neuromuscular (J.C.), Servei de Neurologica, Hospital Sant Joan de Déu, Barcelona, Spain; Department of Pediatrics and Pediatric Neurology (K.B.), Faculty of Medicine, University of Göttingen, Göttingen, Germany; Centre for Human Genetics (L.V.M.), Université de Franche-Comté, Besanςon; Department of Child Neurology and Metabolic Diseases (M. Schiff), Hospital Robert Debré, Paris, France; Department of Pediatrics, Dr. von Haunersches Kinderspital (A.H.), Friedrich-Baur-Institut (J. Senderek), Ludwig-Maximilian-Universität München, Munich, Germany; Division of Pediatric Neurology (P.B.), Emma Children's Hospital/Academic Medical Center, University Hospital Amsterdam, the Netherlands; and Our Lady's Hospital for Sick Children (W.R.), Crumlin, Dublin, Ireland.
MDJürgen Seeger
From the Institute of Human Genetics (S.R.-S., J. Senderek, T.E., K.Z.), Medical Faculty, University Hospital Aachen, Germany; Departments of Neurology (J.C.J.), Human Genetics (M.Y., S.F.N.), Pathology & Laboratory Medicine (S.F.N.), and Psychiatry (S.F.N.), University of California, Los Angeles; Center for Medical Genetics and Molecular Medicine (G.H.), Haukeland University Hospital, Bergen, Norway; Department of Child Neurology (P.S.), 2nd Faculty of Medicine, Charles University Prague and University Hospital, Prague; Institute of Biology and Medical Genetics (A.P.), University Hospital Motol, Prague, Czech Republic; Institute of Medical and Human Genetics (L.G.-N.), Department of Pediatrics (U.S.), and Department of Neuropediatrics (C.H.), Charité Universitätsmedizin Berlin, Berlin; Department of Pediatrics (R.K., J.K.), University Medical Center Freiburg, Freiburg; German Clinic for Diagnostics (J. Seeger), Wiesbaden, Germany; Royal Children's Hospital (M.M.R.), Murdoch Childrens Research Institute, University of Melbourne, Australia; UCL Institute of Child Health & Great Ormond Street Hospital for Children (F.M.), London, UK; Department of Neuropediatrics (M. Steinlin), University Children's Hospital Bern, Bern, Switzerland; Department of Pediatrics (L.S.), University of Szeged, Hungary; Unitat de Patologia Neuromuscular (J.C.), Servei de Neurologica, Hospital Sant Joan de Déu, Barcelona, Spain; Department of Pediatrics and Pediatric Neurology (K.B.), Faculty of Medicine, University of Göttingen, Göttingen, Germany; Centre for Human Genetics (L.V.M.), Université de Franche-Comté, Besanςon; Department of Child Neurology and Metabolic Diseases (M. Schiff), Hospital Robert Debré, Paris, France; Department of Pediatrics, Dr. von Haunersches Kinderspital (A.H.), Friedrich-Baur-Institut (J. Senderek), Ludwig-Maximilian-Universität München, Munich, Germany; Division of Pediatric Neurology (P.B.), Emma Children's Hospital/Academic Medical Center, University Hospital Amsterdam, the Netherlands; and Our Lady's Hospital for Sick Children (W.R.), Crumlin, Dublin, Ireland.
MDMonique M. Ryan
From the Institute of Human Genetics (S.R.-S., J. Senderek, T.E., K.Z.), Medical Faculty, University Hospital Aachen, Germany; Departments of Neurology (J.C.J.), Human Genetics (M.Y., S.F.N.), Pathology & Laboratory Medicine (S.F.N.), and Psychiatry (S.F.N.), University of California, Los Angeles; Center for Medical Genetics and Molecular Medicine (G.H.), Haukeland University Hospital, Bergen, Norway; Department of Child Neurology (P.S.), 2nd Faculty of Medicine, Charles University Prague and University Hospital, Prague; Institute of Biology and Medical Genetics (A.P.), University Hospital Motol, Prague, Czech Republic; Institute of Medical and Human Genetics (L.G.-N.), Department of Pediatrics (U.S.), and Department of Neuropediatrics (C.H.), Charité Universitätsmedizin Berlin, Berlin; Department of Pediatrics (R.K., J.K.), University Medical Center Freiburg, Freiburg; German Clinic for Diagnostics (J. Seeger), Wiesbaden, Germany; Royal Children's Hospital (M.M.R.), Murdoch Childrens Research Institute, University of Melbourne, Australia; UCL Institute of Child Health & Great Ormond Street Hospital for Children (F.M.), London, UK; Department of Neuropediatrics (M. Steinlin), University Children's Hospital Bern, Bern, Switzerland; Department of Pediatrics (L.S.), University of Szeged, Hungary; Unitat de Patologia Neuromuscular (J.C.), Servei de Neurologica, Hospital Sant Joan de Déu, Barcelona, Spain; Department of Pediatrics and Pediatric Neurology (K.B.), Faculty of Medicine, University of Göttingen, Göttingen, Germany; Centre for Human Genetics (L.V.M.), Université de Franche-Comté, Besanςon; Department of Child Neurology and Metabolic Diseases (M. Schiff), Hospital Robert Debré, Paris, France; Department of Pediatrics, Dr. von Haunersches Kinderspital (A.H.), Friedrich-Baur-Institut (J. Senderek), Ludwig-Maximilian-Universität München, Munich, Germany; Division of Pediatric Neurology (P.B.), Emma Children's Hospital/Academic Medical Center, University Hospital Amsterdam, the Netherlands; and Our Lady's Hospital for Sick Children (W.R.), Crumlin, Dublin, Ireland.
MDFrancesco Muntoni
From the Institute of Human Genetics (S.R.-S., J. Senderek, T.E., K.Z.), Medical Faculty, University Hospital Aachen, Germany; Departments of Neurology (J.C.J.), Human Genetics (M.Y., S.F.N.), Pathology & Laboratory Medicine (S.F.N.), and Psychiatry (S.F.N.), University of California, Los Angeles; Center for Medical Genetics and Molecular Medicine (G.H.), Haukeland University Hospital, Bergen, Norway; Department of Child Neurology (P.S.), 2nd Faculty of Medicine, Charles University Prague and University Hospital, Prague; Institute of Biology and Medical Genetics (A.P.), University Hospital Motol, Prague, Czech Republic; Institute of Medical and Human Genetics (L.G.-N.), Department of Pediatrics (U.S.), and Department of Neuropediatrics (C.H.), Charité Universitätsmedizin Berlin, Berlin; Department of Pediatrics (R.K., J.K.), University Medical Center Freiburg, Freiburg; German Clinic for Diagnostics (J. Seeger), Wiesbaden, Germany; Royal Children's Hospital (M.M.R.), Murdoch Childrens Research Institute, University of Melbourne, Australia; UCL Institute of Child Health & Great Ormond Street Hospital for Children (F.M.), London, UK; Department of Neuropediatrics (M. Steinlin), University Children's Hospital Bern, Bern, Switzerland; Department of Pediatrics (L.S.), University of Szeged, Hungary; Unitat de Patologia Neuromuscular (J.C.), Servei de Neurologica, Hospital Sant Joan de Déu, Barcelona, Spain; Department of Pediatrics and Pediatric Neurology (K.B.), Faculty of Medicine, University of Göttingen, Göttingen, Germany; Centre for Human Genetics (L.V.M.), Université de Franche-Comté, Besanςon; Department of Child Neurology and Metabolic Diseases (M. Schiff), Hospital Robert Debré, Paris, France; Department of Pediatrics, Dr. von Haunersches Kinderspital (A.H.), Friedrich-Baur-Institut (J. Senderek), Ludwig-Maximilian-Universität München, Munich, Germany; Division of Pediatric Neurology (P.B.), Emma Children's Hospital/Academic Medical Center, University Hospital Amsterdam, the Netherlands; and Our Lady's Hospital for Sick Children (W.R.), Crumlin, Dublin, Ireland.
MDMaja Steinlin
From the Institute of Human Genetics (S.R.-S., J. Senderek, T.E., K.Z.), Medical Faculty, University Hospital Aachen, Germany; Departments of Neurology (J.C.J.), Human Genetics (M.Y., S.F.N.), Pathology & Laboratory Medicine (S.F.N.), and Psychiatry (S.F.N.), University of California, Los Angeles; Center for Medical Genetics and Molecular Medicine (G.H.), Haukeland University Hospital, Bergen, Norway; Department of Child Neurology (P.S.), 2nd Faculty of Medicine, Charles University Prague and University Hospital, Prague; Institute of Biology and Medical Genetics (A.P.), University Hospital Motol, Prague, Czech Republic; Institute of Medical and Human Genetics (L.G.-N.), Department of Pediatrics (U.S.), and Department of Neuropediatrics (C.H.), Charité Universitätsmedizin Berlin, Berlin; Department of Pediatrics (R.K., J.K.), University Medical Center Freiburg, Freiburg; German Clinic for Diagnostics (J. Seeger), Wiesbaden, Germany; Royal Children's Hospital (M.M.R.), Murdoch Childrens Research Institute, University of Melbourne, Australia; UCL Institute of Child Health & Great Ormond Street Hospital for Children (F.M.), London, UK; Department of Neuropediatrics (M. Steinlin), University Children's Hospital Bern, Bern, Switzerland; Department of Pediatrics (L.S.), University of Szeged, Hungary; Unitat de Patologia Neuromuscular (J.C.), Servei de Neurologica, Hospital Sant Joan de Déu, Barcelona, Spain; Department of Pediatrics and Pediatric Neurology (K.B.), Faculty of Medicine, University of Göttingen, Göttingen, Germany; Centre for Human Genetics (L.V.M.), Université de Franche-Comté, Besanςon; Department of Child Neurology and Metabolic Diseases (M. Schiff), Hospital Robert Debré, Paris, France; Department of Pediatrics, Dr. von Haunersches Kinderspital (A.H.), Friedrich-Baur-Institut (J. Senderek), Ludwig-Maximilian-Universität München, Munich, Germany; Division of Pediatric Neurology (P.B.), Emma Children's Hospital/Academic Medical Center, University Hospital Amsterdam, the Netherlands; and Our Lady's Hospital for Sick Children (W.R.), Crumlin, Dublin, Ireland.
MDLaszlo Sztriha
From the Institute of Human Genetics (S.R.-S., J. Senderek, T.E., K.Z.), Medical Faculty, University Hospital Aachen, Germany; Departments of Neurology (J.C.J.), Human Genetics (M.Y., S.F.N.), Pathology & Laboratory Medicine (S.F.N.), and Psychiatry (S.F.N.), University of California, Los Angeles; Center for Medical Genetics and Molecular Medicine (G.H.), Haukeland University Hospital, Bergen, Norway; Department of Child Neurology (P.S.), 2nd Faculty of Medicine, Charles University Prague and University Hospital, Prague; Institute of Biology and Medical Genetics (A.P.), University Hospital Motol, Prague, Czech Republic; Institute of Medical and Human Genetics (L.G.-N.), Department of Pediatrics (U.S.), and Department of Neuropediatrics (C.H.), Charité Universitätsmedizin Berlin, Berlin; Department of Pediatrics (R.K., J.K.), University Medical Center Freiburg, Freiburg; German Clinic for Diagnostics (J. Seeger), Wiesbaden, Germany; Royal Children's Hospital (M.M.R.), Murdoch Childrens Research Institute, University of Melbourne, Australia; UCL Institute of Child Health & Great Ormond Street Hospital for Children (F.M.), London, UK; Department of Neuropediatrics (M. Steinlin), University Children's Hospital Bern, Bern, Switzerland; Department of Pediatrics (L.S.), University of Szeged, Hungary; Unitat de Patologia Neuromuscular (J.C.), Servei de Neurologica, Hospital Sant Joan de Déu, Barcelona, Spain; Department of Pediatrics and Pediatric Neurology (K.B.), Faculty of Medicine, University of Göttingen, Göttingen, Germany; Centre for Human Genetics (L.V.M.), Université de Franche-Comté, Besanςon; Department of Child Neurology and Metabolic Diseases (M. Schiff), Hospital Robert Debré, Paris, France; Department of Pediatrics, Dr. von Haunersches Kinderspital (A.H.), Friedrich-Baur-Institut (J. Senderek), Ludwig-Maximilian-Universität München, Munich, Germany; Division of Pediatric Neurology (P.B.), Emma Children's Hospital/Academic Medical Center, University Hospital Amsterdam, the Netherlands; and Our Lady's Hospital for Sick Children (W.R.), Crumlin, Dublin, Ireland.
MDJaume Colomer
From the Institute of Human Genetics (S.R.-S., J. Senderek, T.E., K.Z.), Medical Faculty, University Hospital Aachen, Germany; Departments of Neurology (J.C.J.), Human Genetics (M.Y., S.F.N.), Pathology & Laboratory Medicine (S.F.N.), and Psychiatry (S.F.N.), University of California, Los Angeles; Center for Medical Genetics and Molecular Medicine (G.H.), Haukeland University Hospital, Bergen, Norway; Department of Child Neurology (P.S.), 2nd Faculty of Medicine, Charles University Prague and University Hospital, Prague; Institute of Biology and Medical Genetics (A.P.), University Hospital Motol, Prague, Czech Republic; Institute of Medical and Human Genetics (L.G.-N.), Department of Pediatrics (U.S.), and Department of Neuropediatrics (C.H.), Charité Universitätsmedizin Berlin, Berlin; Department of Pediatrics (R.K., J.K.), University Medical Center Freiburg, Freiburg; German Clinic for Diagnostics (J. Seeger), Wiesbaden, Germany; Royal Children's Hospital (M.M.R.), Murdoch Childrens Research Institute, University of Melbourne, Australia; UCL Institute of Child Health & Great Ormond Street Hospital for Children (F.M.), London, UK; Department of Neuropediatrics (M. Steinlin), University Children's Hospital Bern, Bern, Switzerland; Department of Pediatrics (L.S.), University of Szeged, Hungary; Unitat de Patologia Neuromuscular (J.C.), Servei de Neurologica, Hospital Sant Joan de Déu, Barcelona, Spain; Department of Pediatrics and Pediatric Neurology (K.B.), Faculty of Medicine, University of Göttingen, Göttingen, Germany; Centre for Human Genetics (L.V.M.), Université de Franche-Comté, Besanςon; Department of Child Neurology and Metabolic Diseases (M. Schiff), Hospital Robert Debré, Paris, France; Department of Pediatrics, Dr. von Haunersches Kinderspital (A.H.), Friedrich-Baur-Institut (J. Senderek), Ludwig-Maximilian-Universität München, Munich, Germany; Division of Pediatric Neurology (P.B.), Emma Children's Hospital/Academic Medical Center, University Hospital Amsterdam, the Netherlands; and Our Lady's Hospital for Sick Children (W.R.), Crumlin, Dublin, Ireland.
MDChristoph Hübner
From the Institute of Human Genetics (S.R.-S., J. Senderek, T.E., K.Z.), Medical Faculty, University Hospital Aachen, Germany; Departments of Neurology (J.C.J.), Human Genetics (M.Y., S.F.N.), Pathology & Laboratory Medicine (S.F.N.), and Psychiatry (S.F.N.), University of California, Los Angeles; Center for Medical Genetics and Molecular Medicine (G.H.), Haukeland University Hospital, Bergen, Norway; Department of Child Neurology (P.S.), 2nd Faculty of Medicine, Charles University Prague and University Hospital, Prague; Institute of Biology and Medical Genetics (A.P.), University Hospital Motol, Prague, Czech Republic; Institute of Medical and Human Genetics (L.G.-N.), Department of Pediatrics (U.S.), and Department of Neuropediatrics (C.H.), Charité Universitätsmedizin Berlin, Berlin; Department of Pediatrics (R.K., J.K.), University Medical Center Freiburg, Freiburg; German Clinic for Diagnostics (J. Seeger), Wiesbaden, Germany; Royal Children's Hospital (M.M.R.), Murdoch Childrens Research Institute, University of Melbourne, Australia; UCL Institute of Child Health & Great Ormond Street Hospital for Children (F.M.), London, UK; Department of Neuropediatrics (M. Steinlin), University Children's Hospital Bern, Bern, Switzerland; Department of Pediatrics (L.S.), University of Szeged, Hungary; Unitat de Patologia Neuromuscular (J.C.), Servei de Neurologica, Hospital Sant Joan de Déu, Barcelona, Spain; Department of Pediatrics and Pediatric Neurology (K.B.), Faculty of Medicine, University of Göttingen, Göttingen, Germany; Centre for Human Genetics (L.V.M.), Université de Franche-Comté, Besanςon; Department of Child Neurology and Metabolic Diseases (M. Schiff), Hospital Robert Debré, Paris, France; Department of Pediatrics, Dr. von Haunersches Kinderspital (A.H.), Friedrich-Baur-Institut (J. Senderek), Ludwig-Maximilian-Universität München, Munich, Germany; Division of Pediatric Neurology (P.B.), Emma Children's Hospital/Academic Medical Center, University Hospital Amsterdam, the Netherlands; and Our Lady's Hospital for Sick Children (W.R.), Crumlin, Dublin, Ireland.
MDKnut Brockmann
From the Institute of Human Genetics (S.R.-S., J. Senderek, T.E., K.Z.), Medical Faculty, University Hospital Aachen, Germany; Departments of Neurology (J.C.J.), Human Genetics (M.Y., S.F.N.), Pathology & Laboratory Medicine (S.F.N.), and Psychiatry (S.F.N.), University of California, Los Angeles; Center for Medical Genetics and Molecular Medicine (G.H.), Haukeland University Hospital, Bergen, Norway; Department of Child Neurology (P.S.), 2nd Faculty of Medicine, Charles University Prague and University Hospital, Prague; Institute of Biology and Medical Genetics (A.P.), University Hospital Motol, Prague, Czech Republic; Institute of Medical and Human Genetics (L.G.-N.), Department of Pediatrics (U.S.), and Department of Neuropediatrics (C.H.), Charité Universitätsmedizin Berlin, Berlin; Department of Pediatrics (R.K., J.K.), University Medical Center Freiburg, Freiburg; German Clinic for Diagnostics (J. Seeger), Wiesbaden, Germany; Royal Children's Hospital (M.M.R.), Murdoch Childrens Research Institute, University of Melbourne, Australia; UCL Institute of Child Health & Great Ormond Street Hospital for Children (F.M.), London, UK; Department of Neuropediatrics (M. Steinlin), University Children's Hospital Bern, Bern, Switzerland; Department of Pediatrics (L.S.), University of Szeged, Hungary; Unitat de Patologia Neuromuscular (J.C.), Servei de Neurologica, Hospital Sant Joan de Déu, Barcelona, Spain; Department of Pediatrics and Pediatric Neurology (K.B.), Faculty of Medicine, University of Göttingen, Göttingen, Germany; Centre for Human Genetics (L.V.M.), Université de Franche-Comté, Besanςon; Department of Child Neurology and Metabolic Diseases (M. Schiff), Hospital Robert Debré, Paris, France; Department of Pediatrics, Dr. von Haunersches Kinderspital (A.H.), Friedrich-Baur-Institut (J. Senderek), Ludwig-Maximilian-Universität München, Munich, Germany; Division of Pediatric Neurology (P.B.), Emma Children's Hospital/Academic Medical Center, University Hospital Amsterdam, the Netherlands; and Our Lady's Hospital for Sick Children (W.R.), Crumlin, Dublin, Ireland.
MDLionel Van Maldergem
From the Institute of Human Genetics (S.R.-S., J. Senderek, T.E., K.Z.), Medical Faculty, University Hospital Aachen, Germany; Departments of Neurology (J.C.J.), Human Genetics (M.Y., S.F.N.), Pathology & Laboratory Medicine (S.F.N.), and Psychiatry (S.F.N.), University of California, Los Angeles; Center for Medical Genetics and Molecular Medicine (G.H.), Haukeland University Hospital, Bergen, Norway; Department of Child Neurology (P.S.), 2nd Faculty of Medicine, Charles University Prague and University Hospital, Prague; Institute of Biology and Medical Genetics (A.P.), University Hospital Motol, Prague, Czech Republic; Institute of Medical and Human Genetics (L.G.-N.), Department of Pediatrics (U.S.), and Department of Neuropediatrics (C.H.), Charité Universitätsmedizin Berlin, Berlin; Department of Pediatrics (R.K., J.K.), University Medical Center Freiburg, Freiburg; German Clinic for Diagnostics (J. Seeger), Wiesbaden, Germany; Royal Children's Hospital (M.M.R.), Murdoch Childrens Research Institute, University of Melbourne, Australia; UCL Institute of Child Health & Great Ormond Street Hospital for Children (F.M.), London, UK; Department of Neuropediatrics (M. Steinlin), University Children's Hospital Bern, Bern, Switzerland; Department of Pediatrics (L.S.), University of Szeged, Hungary; Unitat de Patologia Neuromuscular (J.C.), Servei de Neurologica, Hospital Sant Joan de Déu, Barcelona, Spain; Department of Pediatrics and Pediatric Neurology (K.B.), Faculty of Medicine, University of Göttingen, Göttingen, Germany; Centre for Human Genetics (L.V.M.), Université de Franche-Comté, Besanςon; Department of Child Neurology and Metabolic Diseases (M. Schiff), Hospital Robert Debré, Paris, France; Department of Pediatrics, Dr. von Haunersches Kinderspital (A.H.), Friedrich-Baur-Institut (J. Senderek), Ludwig-Maximilian-Universität München, Munich, Germany; Division of Pediatric Neurology (P.B.), Emma Children's Hospital/Academic Medical Center, University Hospital Amsterdam, the Netherlands; and Our Lady's Hospital for Sick Children (W.R.), Crumlin, Dublin, Ireland.
MDManuel Schiff
From the Institute of Human Genetics (S.R.-S., J. Senderek, T.E., K.Z.), Medical Faculty, University Hospital Aachen, Germany; Departments of Neurology (J.C.J.), Human Genetics (M.Y., S.F.N.), Pathology & Laboratory Medicine (S.F.N.), and Psychiatry (S.F.N.), University of California, Los Angeles; Center for Medical Genetics and Molecular Medicine (G.H.), Haukeland University Hospital, Bergen, Norway; Department of Child Neurology (P.S.), 2nd Faculty of Medicine, Charles University Prague and University Hospital, Prague; Institute of Biology and Medical Genetics (A.P.), University Hospital Motol, Prague, Czech Republic; Institute of Medical and Human Genetics (L.G.-N.), Department of Pediatrics (U.S.), and Department of Neuropediatrics (C.H.), Charité Universitätsmedizin Berlin, Berlin; Department of Pediatrics (R.K., J.K.), University Medical Center Freiburg, Freiburg; German Clinic for Diagnostics (J. Seeger), Wiesbaden, Germany; Royal Children's Hospital (M.M.R.), Murdoch Childrens Research Institute, University of Melbourne, Australia; UCL Institute of Child Health & Great Ormond Street Hospital for Children (F.M.), London, UK; Department of Neuropediatrics (M. Steinlin), University Children's Hospital Bern, Bern, Switzerland; Department of Pediatrics (L.S.), University of Szeged, Hungary; Unitat de Patologia Neuromuscular (J.C.), Servei de Neurologica, Hospital Sant Joan de Déu, Barcelona, Spain; Department of Pediatrics and Pediatric Neurology (K.B.), Faculty of Medicine, University of Göttingen, Göttingen, Germany; Centre for Human Genetics (L.V.M.), Université de Franche-Comté, Besanςon; Department of Child Neurology and Metabolic Diseases (M. Schiff), Hospital Robert Debré, Paris, France; Department of Pediatrics, Dr. von Haunersches Kinderspital (A.H.), Friedrich-Baur-Institut (J. Senderek), Ludwig-Maximilian-Universität München, Munich, Germany; Division of Pediatric Neurology (P.B.), Emma Children's Hospital/Academic Medical Center, University Hospital Amsterdam, the Netherlands; and Our Lady's Hospital for Sick Children (W.R.), Crumlin, Dublin, Ireland.
MDAndreas Holzinger
From the Institute of Human Genetics (S.R.-S., J. Senderek, T.E., K.Z.), Medical Faculty, University Hospital Aachen, Germany; Departments of Neurology (J.C.J.), Human Genetics (M.Y., S.F.N.), Pathology & Laboratory Medicine (S.F.N.), and Psychiatry (S.F.N.), University of California, Los Angeles; Center for Medical Genetics and Molecular Medicine (G.H.), Haukeland University Hospital, Bergen, Norway; Department of Child Neurology (P.S.), 2nd Faculty of Medicine, Charles University Prague and University Hospital, Prague; Institute of Biology and Medical Genetics (A.P.), University Hospital Motol, Prague, Czech Republic; Institute of Medical and Human Genetics (L.G.-N.), Department of Pediatrics (U.S.), and Department of Neuropediatrics (C.H.), Charité Universitätsmedizin Berlin, Berlin; Department of Pediatrics (R.K., J.K.), University Medical Center Freiburg, Freiburg; German Clinic for Diagnostics (J. Seeger), Wiesbaden, Germany; Royal Children's Hospital (M.M.R.), Murdoch Childrens Research Institute, University of Melbourne, Australia; UCL Institute of Child Health & Great Ormond Street Hospital for Children (F.M.), London, UK; Department of Neuropediatrics (M. Steinlin), University Children's Hospital Bern, Bern, Switzerland; Department of Pediatrics (L.S.), University of Szeged, Hungary; Unitat de Patologia Neuromuscular (J.C.), Servei de Neurologica, Hospital Sant Joan de Déu, Barcelona, Spain; Department of Pediatrics and Pediatric Neurology (K.B.), Faculty of Medicine, University of Göttingen, Göttingen, Germany; Centre for Human Genetics (L.V.M.), Université de Franche-Comté, Besanςon; Department of Child Neurology and Metabolic Diseases (M. Schiff), Hospital Robert Debré, Paris, France; Department of Pediatrics, Dr. von Haunersches Kinderspital (A.H.), Friedrich-Baur-Institut (J. Senderek), Ludwig-Maximilian-Universität München, Munich, Germany; Division of Pediatric Neurology (P.B.), Emma Children's Hospital/Academic Medical Center, University Hospital Amsterdam, the Netherlands; and Our Lady's Hospital for Sick Children (W.R.), Crumlin, Dublin, Ireland.
MDPeter Barth
From the Institute of Human Genetics (S.R.-S., J. Senderek, T.E., K.Z.), Medical Faculty, University Hospital Aachen, Germany; Departments of Neurology (J.C.J.), Human Genetics (M.Y., S.F.N.), Pathology & Laboratory Medicine (S.F.N.), and Psychiatry (S.F.N.), University of California, Los Angeles; Center for Medical Genetics and Molecular Medicine (G.H.), Haukeland University Hospital, Bergen, Norway; Department of Child Neurology (P.S.), 2nd Faculty of Medicine, Charles University Prague and University Hospital, Prague; Institute of Biology and Medical Genetics (A.P.), University Hospital Motol, Prague, Czech Republic; Institute of Medical and Human Genetics (L.G.-N.), Department of Pediatrics (U.S.), and Department of Neuropediatrics (C.H.), Charité Universitätsmedizin Berlin, Berlin; Department of Pediatrics (R.K., J.K.), University Medical Center Freiburg, Freiburg; German Clinic for Diagnostics (J. Seeger), Wiesbaden, Germany; Royal Children's Hospital (M.M.R.), Murdoch Childrens Research Institute, University of Melbourne, Australia; UCL Institute of Child Health & Great Ormond Street Hospital for Children (F.M.), London, UK; Department of Neuropediatrics (M. Steinlin), University Children's Hospital Bern, Bern, Switzerland; Department of Pediatrics (L.S.), University of Szeged, Hungary; Unitat de Patologia Neuromuscular (J.C.), Servei de Neurologica, Hospital Sant Joan de Déu, Barcelona, Spain; Department of Pediatrics and Pediatric Neurology (K.B.), Faculty of Medicine, University of Göttingen, Göttingen, Germany; Centre for Human Genetics (L.V.M.), Université de Franche-Comté, Besanςon; Department of Child Neurology and Metabolic Diseases (M. Schiff), Hospital Robert Debré, Paris, France; Department of Pediatrics, Dr. von Haunersches Kinderspital (A.H.), Friedrich-Baur-Institut (J. Senderek), Ludwig-Maximilian-Universität München, Munich, Germany; Division of Pediatric Neurology (P.B.), Emma Children's Hospital/Academic Medical Center, University Hospital Amsterdam, the Netherlands; and Our Lady's Hospital for Sick Children (W.R.), Crumlin, Dublin, Ireland.
MDWilliam Reardon
From the Institute of Human Genetics (S.R.-S., J. Senderek, T.E., K.Z.), Medical Faculty, University Hospital Aachen, Germany; Departments of Neurology (J.C.J.), Human Genetics (M.Y., S.F.N.), Pathology & Laboratory Medicine (S.F.N.), and Psychiatry (S.F.N.), University of California, Los Angeles; Center for Medical Genetics and Molecular Medicine (G.H.), Haukeland University Hospital, Bergen, Norway; Department of Child Neurology (P.S.), 2nd Faculty of Medicine, Charles University Prague and University Hospital, Prague; Institute of Biology and Medical Genetics (A.P.), University Hospital Motol, Prague, Czech Republic; Institute of Medical and Human Genetics (L.G.-N.), Department of Pediatrics (U.S.), and Department of Neuropediatrics (C.H.), Charité Universitätsmedizin Berlin, Berlin; Department of Pediatrics (R.K., J.K.), University Medical Center Freiburg, Freiburg; German Clinic for Diagnostics (J. Seeger), Wiesbaden, Germany; Royal Children's Hospital (M.M.R.), Murdoch Childrens Research Institute, University of Melbourne, Australia; UCL Institute of Child Health & Great Ormond Street Hospital for Children (F.M.), London, UK; Department of Neuropediatrics (M. Steinlin), University Children's Hospital Bern, Bern, Switzerland; Department of Pediatrics (L.S.), University of Szeged, Hungary; Unitat de Patologia Neuromuscular (J.C.), Servei de Neurologica, Hospital Sant Joan de Déu, Barcelona, Spain; Department of Pediatrics and Pediatric Neurology (K.B.), Faculty of Medicine, University of Göttingen, Göttingen, Germany; Centre for Human Genetics (L.V.M.), Université de Franche-Comté, Besanςon; Department of Child Neurology and Metabolic Diseases (M. Schiff), Hospital Robert Debré, Paris, France; Department of Pediatrics, Dr. von Haunersches Kinderspital (A.H.), Friedrich-Baur-Institut (J. Senderek), Ludwig-Maximilian-Universität München, Munich, Germany; Division of Pediatric Neurology (P.B.), Emma Children's Hospital/Academic Medical Center, University Hospital Amsterdam, the Netherlands; and Our Lady's Hospital for Sick Children (W.R.), Crumlin, Dublin, Ireland.
MDMichael Yourshaw
From the Institute of Human Genetics (S.R.-S., J. Senderek, T.E., K.Z.), Medical Faculty, University Hospital Aachen, Germany; Departments of Neurology (J.C.J.), Human Genetics (M.Y., S.F.N.), Pathology & Laboratory Medicine (S.F.N.), and Psychiatry (S.F.N.), University of California, Los Angeles; Center for Medical Genetics and Molecular Medicine (G.H.), Haukeland University Hospital, Bergen, Norway; Department of Child Neurology (P.S.), 2nd Faculty of Medicine, Charles University Prague and University Hospital, Prague; Institute of Biology and Medical Genetics (A.P.), University Hospital Motol, Prague, Czech Republic; Institute of Medical and Human Genetics (L.G.-N.), Department of Pediatrics (U.S.), and Department of Neuropediatrics (C.H.), Charité Universitätsmedizin Berlin, Berlin; Department of Pediatrics (R.K., J.K.), University Medical Center Freiburg, Freiburg; German Clinic for Diagnostics (J. Seeger), Wiesbaden, Germany; Royal Children's Hospital (M.M.R.), Murdoch Childrens Research Institute, University of Melbourne, Australia; UCL Institute of Child Health & Great Ormond Street Hospital for Children (F.M.), London, UK; Department of Neuropediatrics (M. Steinlin), University Children's Hospital Bern, Bern, Switzerland; Department of Pediatrics (L.S.), University of Szeged, Hungary; Unitat de Patologia Neuromuscular (J.C.), Servei de Neurologica, Hospital Sant Joan de Déu, Barcelona, Spain; Department of Pediatrics and Pediatric Neurology (K.B.), Faculty of Medicine, University of Göttingen, Göttingen, Germany; Centre for Human Genetics (L.V.M.), Université de Franche-Comté, Besanςon; Department of Child Neurology and Metabolic Diseases (M. Schiff), Hospital Robert Debré, Paris, France; Department of Pediatrics, Dr. von Haunersches Kinderspital (A.H.), Friedrich-Baur-Institut (J. Senderek), Ludwig-Maximilian-Universität München, Munich, Germany; Division of Pediatric Neurology (P.B.), Emma Children's Hospital/Academic Medical Center, University Hospital Amsterdam, the Netherlands; and Our Lady's Hospital for Sick Children (W.R.), Crumlin, Dublin, Ireland.
Stanley F. Nelson
From the Institute of Human Genetics (S.R.-S., J. Senderek, T.E., K.Z.), Medical Faculty, University Hospital Aachen, Germany; Departments of Neurology (J.C.J.), Human Genetics (M.Y., S.F.N.), Pathology & Laboratory Medicine (S.F.N.), and Psychiatry (S.F.N.), University of California, Los Angeles; Center for Medical Genetics and Molecular Medicine (G.H.), Haukeland University Hospital, Bergen, Norway; Department of Child Neurology (P.S.), 2nd Faculty of Medicine, Charles University Prague and University Hospital, Prague; Institute of Biology and Medical Genetics (A.P.), University Hospital Motol, Prague, Czech Republic; Institute of Medical and Human Genetics (L.G.-N.), Department of Pediatrics (U.S.), and Department of Neuropediatrics (C.H.), Charité Universitätsmedizin Berlin, Berlin; Department of Pediatrics (R.K., J.K.), University Medical Center Freiburg, Freiburg; German Clinic for Diagnostics (J. Seeger), Wiesbaden, Germany; Royal Children's Hospital (M.M.R.), Murdoch Childrens Research Institute, University of Melbourne, Australia; UCL Institute of Child Health & Great Ormond Street Hospital for Children (F.M.), London, UK; Department of Neuropediatrics (M. Steinlin), University Children's Hospital Bern, Bern, Switzerland; Department of Pediatrics (L.S.), University of Szeged, Hungary; Unitat de Patologia Neuromuscular (J.C.), Servei de Neurologica, Hospital Sant Joan de Déu, Barcelona, Spain; Department of Pediatrics and Pediatric Neurology (K.B.), Faculty of Medicine, University of Göttingen, Göttingen, Germany; Centre for Human Genetics (L.V.M.), Université de Franche-Comté, Besanςon; Department of Child Neurology and Metabolic Diseases (M. Schiff), Hospital Robert Debré, Paris, France; Department of Pediatrics, Dr. von Haunersches Kinderspital (A.H.), Friedrich-Baur-Institut (J. Senderek), Ludwig-Maximilian-Universität München, Munich, Germany; Division of Pediatric Neurology (P.B.), Emma Children's Hospital/Academic Medical Center, University Hospital Amsterdam, the Netherlands; and Our Lady's Hospital for Sick Children (W.R.), Crumlin, Dublin, Ireland.
MDThomas Eggermann
From the Institute of Human Genetics (S.R.-S., J. Senderek, T.E., K.Z.), Medical Faculty, University Hospital Aachen, Germany; Departments of Neurology (J.C.J.), Human Genetics (M.Y., S.F.N.), Pathology & Laboratory Medicine (S.F.N.), and Psychiatry (S.F.N.), University of California, Los Angeles; Center for Medical Genetics and Molecular Medicine (G.H.), Haukeland University Hospital, Bergen, Norway; Department of Child Neurology (P.S.), 2nd Faculty of Medicine, Charles University Prague and University Hospital, Prague; Institute of Biology and Medical Genetics (A.P.), University Hospital Motol, Prague, Czech Republic; Institute of Medical and Human Genetics (L.G.-N.), Department of Pediatrics (U.S.), and Department of Neuropediatrics (C.H.), Charité Universitätsmedizin Berlin, Berlin; Department of Pediatrics (R.K., J.K.), University Medical Center Freiburg, Freiburg; German Clinic for Diagnostics (J. Seeger), Wiesbaden, Germany; Royal Children's Hospital (M.M.R.), Murdoch Childrens Research Institute, University of Melbourne, Australia; UCL Institute of Child Health & Great Ormond Street Hospital for Children (F.M.), London, UK; Department of Neuropediatrics (M. Steinlin), University Children's Hospital Bern, Bern, Switzerland; Department of Pediatrics (L.S.), University of Szeged, Hungary; Unitat de Patologia Neuromuscular (J.C.), Servei de Neurologica, Hospital Sant Joan de Déu, Barcelona, Spain; Department of Pediatrics and Pediatric Neurology (K.B.), Faculty of Medicine, University of Göttingen, Göttingen, Germany; Centre for Human Genetics (L.V.M.), Université de Franche-Comté, Besanςon; Department of Child Neurology and Metabolic Diseases (M. Schiff), Hospital Robert Debré, Paris, France; Department of Pediatrics, Dr. von Haunersches Kinderspital (A.H.), Friedrich-Baur-Institut (J. Senderek), Ludwig-Maximilian-Universität München, Munich, Germany; Division of Pediatric Neurology (P.B.), Emma Children's Hospital/Academic Medical Center, University Hospital Amsterdam, the Netherlands; and Our Lady's Hospital for Sick Children (W.R.), Crumlin, Dublin, Ireland.
PhDKlaus Zerres
From the Institute of Human Genetics (S.R.-S., J. Senderek, T.E., K.Z.), Medical Faculty, University Hospital Aachen, Germany; Departments of Neurology (J.C.J.), Human Genetics (M.Y., S.F.N.), Pathology & Laboratory Medicine (S.F.N.), and Psychiatry (S.F.N.), University of California, Los Angeles; Center for Medical Genetics and Molecular Medicine (G.H.), Haukeland University Hospital, Bergen, Norway; Department of Child Neurology (P.S.), 2nd Faculty of Medicine, Charles University Prague and University Hospital, Prague; Institute of Biology and Medical Genetics (A.P.), University Hospital Motol, Prague, Czech Republic; Institute of Medical and Human Genetics (L.G.-N.), Department of Pediatrics (U.S.), and Department of Neuropediatrics (C.H.), Charité Universitätsmedizin Berlin, Berlin; Department of Pediatrics (R.K., J.K.), University Medical Center Freiburg, Freiburg; German Clinic for Diagnostics (J. Seeger), Wiesbaden, Germany; Royal Children's Hospital (M.M.R.), Murdoch Childrens Research Institute, University of Melbourne, Australia; UCL Institute of Child Health & Great Ormond Street Hospital for Children (F.M.), London, UK; Department of Neuropediatrics (M. Steinlin), University Children's Hospital Bern, Bern, Switzerland; Department of Pediatrics (L.S.), University of Szeged, Hungary; Unitat de Patologia Neuromuscular (J.C.), Servei de Neurologica, Hospital Sant Joan de Déu, Barcelona, Spain; Department of Pediatrics and Pediatric Neurology (K.B.), Faculty of Medicine, University of Göttingen, Göttingen, Germany; Centre for Human Genetics (L.V.M.), Université de Franche-Comté, Besanςon; Department of Child Neurology and Metabolic Diseases (M. Schiff), Hospital Robert Debré, Paris, France; Department of Pediatrics, Dr. von Haunersches Kinderspital (A.H.), Friedrich-Baur-Institut (J. Senderek), Ludwig-Maximilian-Universität München, Munich, Germany; Division of Pediatric Neurology (P.B.), Emma Children's Hospital/Academic Medical Center, University Hospital Amsterdam, the Netherlands; and Our Lady's Hospital for Sick Children (W.R.), Crumlin, Dublin, Ireland.
MDPontocerebellar hypoplasia type 1
Clinical spectrum and relevance of EXOSC3 mutations
Sabine Rudnik-Schöneborn, Jan Senderek, Joanna C. Jen, Gunnar Houge, Pavel Seeman, Alena Puchmajerová, Luitgard Graul-Neumann, Ulrich Seidel, Rudolf Korinthenberg, Janbernd Kirschner, Jürgen Seeger, Monique M. Ryan, Francesco Muntoni, Maja Steinlin, Laszlo Sztriha, Jaume Colomer, Christoph Hübner, Knut Brockmann, Lionel Van Maldergem, Manuel Schiff, Andreas Holzinger, Peter Barth, William Reardon, Michael Yourshaw, Stanley F. Nelson, Thomas Eggermann, Klaus Zerres
Neurology Jan 2013, 80 (5) 438-446; DOI: 10.1212/WNL.0b013e31827f0f66
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Abstract
Objectives: Pontocerebellar hypoplasia with spinal muscular atrophy, also known as PCH1, is a group of autosomal recessive disorders characterized by generalized muscle weakness and global developmental delay commonly resulting in early death. Gene defects had been discovered only in single patients until the recent identification of EXOSC3 mutations in several families with relatively mild course of PCH1. We aim to genetically stratify subjects in a large and well-defined cohort to define the clinical spectrum and genotype–phenotype correlation.
Methods: We documented clinical, neuroimaging, and morphologic data of 37 subjects from 27 families with PCH1. EXOSC3 gene sequencing was performed in 27 unrelated index patients of mixed ethnicity.
Results: Biallelic mutations in EXOSC3 were detected in 10 of 27 families (37%). The most common mutation among all ethnic groups was c.395A>C, p.D132A, responsible for 11 (55%) of the 20 mutated alleles and ancestral in origin. The mutation-positive subjects typically presented with normal pregnancy, normal birth measurements, and relative preservation of brainstem and cortical structures. Psychomotor retardation was profound in all patients but lifespan was variable, with 3 subjects surviving beyond the late teens. Abnormal oculomotor function was commonly observed in patients surviving beyond the first year. Major clinical features previously reported in PCH1, including intrauterine abnormalities, postnatal hypoventilation and feeding difficulties, joint contractures, and neonatal death, were rarely observed in mutation-positive infants but were typical among the mutation-negative subjects.
Conclusion: EXOSC3 mutations account for 30%–40% of patients with PCH1 with variability in survival and clinical severity that is correlated with the genotype.
GLOSSARY
- EXOSC3=
- exosome component 3;
- PCH=
- pontocerebellar hypoplasia;
- PCH1=
- pontocerebellar hypoplasia with spinal muscular atrophy;
- RRP40=
- ribosomal RNA–processing protein 40;
- SMA=
- spinal muscular atrophy
Footnotes
Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
Supplemental data at www.neurology.org
Editorial, page 426
- Received May 25, 2012.
- Accepted October 5, 2012.
- © 2013 American Academy of Neurology
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