Annegret Quade1, Anne Thiel2, Ingo Kurth3, Manuel Holtgrewe4, Miriam Elbracht3, Dieter Beule4, Katja Eggermann3, Ute I Scholl5, Martin Häusler6. 1. Division of Neuropediatrics and Social Pediatrics, Dept. of Pediatrics, University Hospital RWTH Aachen, Germany. Electronic address: aquade@ukaachen.de. 2. Department of Nephrology, Medical School, Heinrich Heine University Düsseldorf, 40225, Düsseldorf, Germany. 3. Institute of Human Genetics, Medical Faculty, RWTH Aachen University, Aachen, Germany. 4. Core Unit Bioinformatics, Berlin Institute of Health, Max Delbrück Center for Molecular Medicine in the Helmholtz Association and Charité - Universitätsmedizin Berlin, Germany. 5. Department of Nephrology, Medical School, Heinrich Heine University Düsseldorf, 40225, Düsseldorf, Germany; Department of Nephrology and Medical Intensive Care, BCRT, Charité - Universitätsmedizin Berlin and Berlin Institute of Health, Berlin, Germany. 6. Division of Neuropediatrics and Social Pediatrics, Dept. of Pediatrics, University Hospital RWTH Aachen, Germany.
Abstract
BACKGROUND: Paroxysmal tonic upgaze (PTU), defined as an involuntary upward movement of the eyes, has been considered as a benign phenomenon but may also be associated with ataxia and developmental delay. METHODS: We report eight children with PTU; six of them also exhibiting symptoms of ataxia and/or developmental delay. Treatment with carbonic anhydrase inhibition was offered to children with persisting and/or severe forms. RESULTS: Whole-exome sequencing and genome-wide array analysis (n = 7) did not reveal mutations in the three known genes associated with PTU (CACNA1A, GRID2, SEPSECS), whereas by MLPA a heterozygous deletion of exon 31 of the CACNA1A gene could be detected in one patient, her mother and two further family members. Further exome and array analysis showed no recurrent variants in potentially novel PTU-related genes in more than one patient. A de novo variant at a highly conserved position in the SIM1 gene was detected in one patient, for which a pathogenic effect could be speculated. Carbonic anhydrase inhibition was started in five children and proved at least partially effective in all of them. CONCLUSION: Irrespective of the clinical background and the molecular basic mechanism of PTU, therapeutic carbonic anhydrase inhibition was effective in all five children (acetazolamide, n = 3; sultiame, n = 2) who received this treatment.
BACKGROUND: Paroxysmal tonic upgaze (PTU), defined as an involuntary upward movement of the eyes, has been considered as a benign phenomenon but may also be associated with ataxia and developmental delay. METHODS: We report eight children with PTU; six of them also exhibiting symptoms of ataxia and/or developmental delay. Treatment with carbonic anhydrase inhibition was offered to children with persisting and/or severe forms. RESULTS: Whole-exome sequencing and genome-wide array analysis (n = 7) did not reveal mutations in the three known genes associated with PTU (CACNA1A, GRID2, SEPSECS), whereas by MLPA a heterozygous deletion of exon 31 of the CACNA1A gene could be detected in one patient, her mother and two further family members. Further exome and array analysis showed no recurrent variants in potentially novel PTU-related genes in more than one patient. A de novo variant at a highly conserved position in the SIM1 gene was detected in one patient, for which a pathogenic effect could be speculated. Carbonic anhydrase inhibition was started in five children and proved at least partially effective in all of them. CONCLUSION: Irrespective of the clinical background and the molecular basic mechanism of PTU, therapeutic carbonic anhydrase inhibition was effective in all five children (acetazolamide, n = 3; sultiame, n = 2) who received this treatment.
Authors: Marina P Hommersom; Teije H van Prooije; Maartje Pennings; Meyke I Schouten; Hans van Bokhoven; Erik-Jan Kamsteeg; Bart P C van de Warrenburg Journal: J Neurol Date: 2021-11-22 Impact factor: 6.682
Authors: Bryn D Webb; Anthony Evans; Thomas P Naidich; Lynne M Bird; Sumit Parikh; Meilin Fernandez Garcia; Lindsay B Henderson; Francisca Millan; Yue Si; Kristen J Brennand; Peter Hung; Janet C Rucker; Patricia G Wheeler; Eric E Schadt Journal: Hum Mutat Date: 2021-04-15 Impact factor: 4.700