Nicole I Wolf1, Adeline Vanderver2, Rosalina M L van Spaendonk2, Raphael Schiffmann2, Bernard Brais2, Marianna Bugiani2, Erik Sistermans2, Coriene Catsman-Berrevoets2, Johan M Kros2, Pedro Soares Pinto2, Daniela Pohl2, Sandya Tirupathi2, Petter Strømme2, Ton de Grauw2, Sébastien Fribourg2, Michelle Demos2, Amy Pizzino2, Sakkubai Naidu2, Kether Guerrero2, Marjo S van der Knaap2, Geneviève Bernard2. 1. From the Departments of Child Neurology (N.I.F., M.B., M.S.v.d.K.), Clinical Genetics (R.M.L.v.S., E.S.), and Pathology (M.B.), Neuroscience Campus (N.I.F., M.B., M.S.v.d.K.), and the Department of Functional Genomics, Center for Neurogenomics and Cognitive Research (M.S.v.d.K.), VU University Medical Center, Amsterdam, the Netherlands; the Center for Genetic Medicine Research, Department of Neurology (A.V., A.P.), Children's National Medical Center, Washington, DC; the Institute of Metabolic Disease (R.S.), Baylor Research Institute, Dallas, TX; the Departments of Neurology and Neurosurgery and Human Genetics (B.B.), Montreal Neurological Institute, Canada; the Department of Paediatric Neurology (C.C.-B.), Erasmus University Hospital-Sophia Children's Hospital; the Department of Pathology (J.M.K.), Erasmus Medical Center, Rotterdam, the Netherlands; the Neuroradiology Department (P.S.P.), Centro Hospitalar do Porto, Portugal; the Division of Neurology (D.P.), Children's Hospital of Eastern Ontario, University of Ottawa, Canada; the Department of Paediatric Neurology (S.T.), Royal Belfast Hospital for Sick Children, UK; the Department of Clinical Neurosciences for Children (P.S.), Oslo University Hospital, Ullevål; University of Oslo (P.S.), Norway; the Department of Neurology (T.d.G.), Cincinnati School of Medicine and Cincinnati Children's Hospital Medical Center, OH; INSERM-IECB (S.F.), Pessac, France; the Department of Pediatric Neurology (M.D.), University of British Columbia and British Columbia Children's Hospital, Vancouver, Canada; Kennedy Krieger Institute/Johns Hopkins Medical Institutions (S.N.), Baltimore, MD; and the Departments of Pediatrics, Neurology, and Neurosurgery, Division of Pediatric Neurology (K.G., G.B.), Montreal Children's Hospital, McGill University Health Center, Montreal, Canada. n.wolf@vumc.nl. 2. From the Departments of Child Neurology (N.I.F., M.B., M.S.v.d.K.), Clinical Genetics (R.M.L.v.S., E.S.), and Pathology (M.B.), Neuroscience Campus (N.I.F., M.B., M.S.v.d.K.), and the Department of Functional Genomics, Center for Neurogenomics and Cognitive Research (M.S.v.d.K.), VU University Medical Center, Amsterdam, the Netherlands; the Center for Genetic Medicine Research, Department of Neurology (A.V., A.P.), Children's National Medical Center, Washington, DC; the Institute of Metabolic Disease (R.S.), Baylor Research Institute, Dallas, TX; the Departments of Neurology and Neurosurgery and Human Genetics (B.B.), Montreal Neurological Institute, Canada; the Department of Paediatric Neurology (C.C.-B.), Erasmus University Hospital-Sophia Children's Hospital; the Department of Pathology (J.M.K.), Erasmus Medical Center, Rotterdam, the Netherlands; the Neuroradiology Department (P.S.P.), Centro Hospitalar do Porto, Portugal; the Division of Neurology (D.P.), Children's Hospital of Eastern Ontario, University of Ottawa, Canada; the Department of Paediatric Neurology (S.T.), Royal Belfast Hospital for Sick Children, UK; the Department of Clinical Neurosciences for Children (P.S.), Oslo University Hospital, Ullevål; University of Oslo (P.S.), Norway; the Department of Neurology (T.d.G.), Cincinnati School of Medicine and Cincinnati Children's Hospital Medical Center, OH; INSERM-IECB (S.F.), Pessac, France; the Department of Pediatric Neurology (M.D.), University of British Columbia and British Columbia Children's Hospital, Vancouver, Canada; Kennedy Krieger Institute/Johns Hopkins Medical Institutions (S.N.), Baltimore, MD; and the Departments of Pediatrics, Neurology, and Neurosurgery, Division of Pediatric Neurology (K.G., G.B.), Montreal Children's Hospital, McGill University Health Center, Montreal, Canada.
Abstract
OBJECTIVE: To study the clinical and radiologic spectrum and genotype-phenotype correlation of 4H (hypomyelination, hypodontia, hypogonadotropic hypogonadism) leukodystrophy caused by mutations in POLR3A or POLR3B. METHODS: We performed a multinational cross-sectional observational study of the clinical, radiologic, and molecular characteristics of 105 mutation-proven cases. RESULTS: The majority of patients presented before 6 years with gross motor delay or regression. Ten percent had an onset beyond 10 years. The disease course was milder in patients with POLR3B than in patients with POLR3A mutations. Other than the typical neurologic, dental, and endocrine features, myopia was seen in almost all and short stature in 50%. Dental and hormonal findings were not invariably present. Mutations in POLR3A and POLR3B were distributed throughout the genes. Except for French Canadian patients, patients from European backgrounds were more likely to have POLR3B mutations than other populations. Most patients carried the common c.1568T>A POLR3B mutation on one allele, homozygosity for which causes a mild phenotype. Systematic MRI review revealed that the combination of hypomyelination with relative T2 hypointensity of the ventrolateral thalamus, optic radiation, globus pallidus, and dentate nucleus, cerebellar atrophy, and thinning of the corpus callosum suggests the diagnosis. CONCLUSIONS: 4H is a well-recognizable clinical entity if all features are present. Mutations in POLR3A are associated with a more severe clinical course. MRI characteristics are helpful in addressing the diagnosis, especially if patients lack the cardinal non-neurologic features.
OBJECTIVE: To study the clinical and radiologic spectrum and genotype-phenotype correlation of 4H (hypomyelination, hypodontia, hypogonadotropic hypogonadism) leukodystrophy caused by mutations in POLR3A or POLR3B. METHODS: We performed a multinational cross-sectional observational study of the clinical, radiologic, and molecular characteristics of 105 mutation-proven cases. RESULTS: The majority of patients presented before 6 years with gross motor delay or regression. Ten percent had an onset beyond 10 years. The disease course was milder in patients with POLR3B than in patients with POLR3A mutations. Other than the typical neurologic, dental, and endocrine features, myopia was seen in almost all and short stature in 50%. Dental and hormonal findings were not invariably present. Mutations in POLR3A and POLR3B were distributed throughout the genes. Except for French Canadian patients, patients from European backgrounds were more likely to have POLR3B mutations than other populations. Most patients carried the common c.1568T>A POLR3B mutation on one allele, homozygosity for which causes a mild phenotype. Systematic MRI review revealed that the combination of hypomyelination with relative T2 hypointensity of the ventrolateral thalamus, optic radiation, globus pallidus, and dentate nucleus, cerebellar atrophy, and thinning of the corpus callosum suggests the diagnosis. CONCLUSIONS:4H is a well-recognizable clinical entity if all features are present. Mutations in POLR3A are associated with a more severe clinical course. MRI characteristics are helpful in addressing the diagnosis, especially if patients lack the cardinal non-neurologic features.
Authors: Marjan E Steenweg; Adeline Vanderver; Susan Blaser; Alberto Bizzi; Tom J de Koning; Grazia M S Mancini; Wessel N van Wieringen; Frederik Barkhof; Nicole I Wolf; Marjo S van der Knaap Journal: Brain Date: 2010-10 Impact factor: 13.501
Authors: Heval M Ozgen; Wouterina C G Overweg-Plandsoen; Janneke Blees-Pelk; Philip P Besselaar; Raoul C M Hennekam Journal: Am J Med Genet A Date: 2005-04-15 Impact factor: 2.802
Authors: N I Wolf; I Harting; E Boltshauser; G Wiegand; M J Koch; T Schmitt-Mechelke; E Martin; J Zschocke; B Uhlenberg; G F Hoffmann; L Weber; F Ebinger; D Rating Journal: Neurology Date: 2005-04-26 Impact factor: 9.910
Authors: M Timmons; M Tsokos; M Abu Asab; S B Seminara; G C Zirzow; C R Kaneski; J D Heiss; M S van der Knaap; M T Vanier; R Schiffmann; K Wong Journal: Neurology Date: 2006-12-12 Impact factor: 9.910
Authors: James Y Garbern; Donald A Yool; Gregory J Moore; Ian B Wilds; Michael W Faulk; Matthias Klugmann; Klaus-Amin Nave; Erik A Sistermans; Marjo S van der Knaap; Thomas D Bird; Michael E Shy; John A Kamholz; Ian R Griffiths Journal: Brain Date: 2002-03 Impact factor: 13.501
Authors: N I Wolf; I Harting; A M Innes; S Patzer; P Zeitler; A Schneider; A Wolff; K Baier; J Zschocke; F Ebinger; E Boltshauser; D Rating Journal: Neuropediatrics Date: 2007-04 Impact factor: 1.947
Authors: Laurence Gauquelin; Martine Tétreault; Isabelle Thiffault; Emily Farrow; Neil Miller; Byunggil Yoo; Eric Bareke; Grace Yoon; Oksana Suchowersky; Nicolas Dupré; Mark Tarnopolsky; Bernard Brais; Nicole I Wolf; Jacek Majewski; Guy A Rouleau; Ziv Gan-Or; Geneviève Bernard Journal: Brain Date: 2018-01-01 Impact factor: 13.501
Authors: Jennifer A Wambach; Daniel J Wegner; Nivedita Patni; Martin Kircher; Marcia C Willing; Dustin Baldridge; Chao Xing; Anil K Agarwal; Samantha A Schrier Vergano; Chirag Patel; Dorothy K Grange; Amy Kenney; Tasnim Najaf; Deborah A Nickerson; Michael J Bamshad; F Sessions Cole; Abhimanyu Garg Journal: Am J Hum Genet Date: 2018-11-07 Impact factor: 11.025
Authors: Paula Camila Alves de Assis Pereira Matos; Maria Thereza Drumond Gama; Márcio Luiz Escórcio Bezerra; Antônio José da Rocha; Orlando G P Barsottini; José Luiz Pedroso Journal: Mov Disord Clin Pract Date: 2020-04-18
Authors: Laura A Adang; Omar Sherbini; Laura Ball; Miriam Bloom; Anil Darbari; Hernan Amartino; Donna DiVito; Florian Eichler; Maria Escolar; Sarah H Evans; Ali Fatemi; Jamie Fraser; Leslie Hollowell; Nicole Jaffe; Christopher Joseph; Mary Karpinski; Stephanie Keller; Ryan Maddock; Edna Mancilla; Bruce McClary; Jana Mertz; Kiley Morgart; Thomas Langan; Richard Leventer; Sumit Parikh; Amy Pizzino; Erin Prange; Deborah L Renaud; William Rizzo; Jay Shapiro; Dean Suhr; Teryn Suhr; Davide Tonduti; Jacque Waggoner; Amy Waldman; Nicole I Wolf; Ayelet Zerem; Joshua L Bonkowsky; Genevieve Bernard; Keith van Haren; Adeline Vanderver Journal: Mol Genet Metab Date: 2017-08-20 Impact factor: 4.797
Authors: Davor Lessel; Ayse Bilge Ozel; Susan E Campbell; Abdelkrim Saadi; Martin F Arlt; Keisha Melodi McSweeney; Vasilica Plaiasu; Katalin Szakszon; Anna Szőllős; Cristina Rusu; Armando J Rojas; Jaime Lopez-Valdez; Holger Thiele; Peter Nürnberg; Deborah A Nickerson; Michael J Bamshad; Jun Z Li; Christian Kubisch; Thomas W Glover; Leslie B Gordon Journal: Hum Genet Date: 2018-11-19 Impact factor: 4.132
Authors: Qing Fang; Akima S George; Michelle L Brinkmeier; Amanda H Mortensen; Peter Gergics; Leonard Y M Cheung; Alexandre Z Daly; Adnan Ajmal; María Ines Pérez Millán; A Bilge Ozel; Jacob O Kitzman; Ryan E Mills; Jun Z Li; Sally A Camper Journal: Endocr Rev Date: 2016-11-09 Impact factor: 19.871
Authors: Roberta La Piana; Ferdy K Cayami; Luan T Tran; Kether Guerrero; Rosalina van Spaendonk; Katrin Õunap; Sander Pajusalu; Tobias Haack; Evangeline Wassmer; Dagmar Timmann; Hanna Mierzewska; Bwee T Poll-Thé; Chirag Patel; Helen Cox; Tahir Atik; Huseyin Onay; Ferda Ozkınay; Adeline Vanderver; Marjo S van der Knaap; Nicole I Wolf; Geneviève Bernard Journal: Neurology Date: 2016-03-30 Impact factor: 9.910