Sabine Illsinger1, G Christoph Korenke2, Sylvia Boesch3, Michael Nocker3, Daniela Karall4, Jean M Nuoffer5, Lucia Laugwitz6, Johannes A Mayr7, Sabine Scholl-Bürgi4, Peter Freisinger8, Tobias Kowald9, Stefan Kölker10, Holger Prokisch11, Tobias B Haack12. 1. University Children's Hospital Oldenburg, Department of Neuropaediatric and Metabolic Diseases, Oldenburg, Germany. Electronic address: sabine.illsinger@gmx.de. 2. University Children's Hospital Oldenburg, Department of Neuropaediatric and Metabolic Diseases, Oldenburg, Germany. 3. Department of Neurology, Medical University Innsbruck, Innsbruck, Austria. 4. Department of Paediatrics I, Inherited Metabolic Disorders, Medical University of Innsbruck, Innsbruck, Austria. 5. University Institute of Clinical Chemistry, Bern University Hospital, Bern, Switzerland; Pediatric Endocrinology, Diabetology and Metabolism, University Children's Hospital Bern, Switzerland. 6. Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany; Department of Neuropediatrics, Developmental Neurology and Social Pediatrics, University of Tübingen, 72076, Tübingen, Germany. 7. Department of Pediatrics, University Hospital Salzburg, Paracelsus Medical University, Salzburg, Austria. 8. Department of Pediatrics, Klinikum Reutlingen, Reutlingen, Germany. 9. Institute for Diagnostic and Interventional Radiology, Klinikum Oldenburg, Oldenburg, Germany. 10. Division of Child Neurology and Metabolic Medicine, Centre for Child and Adolescent Medicine, University Hospital Heidelberg, Germany. 11. Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany; Institute of Human Genetics, Technische Universität München, Munich, Germany. 12. Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany; Institute of Human Genetics, Technische Universität München, Munich, Germany; Centre for Rare Diseases, University of Tuebingen, Tübingen, Germany.
Abstract
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.
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.
Authors: J A Mayr; R G Feichtinger; M T Achleitner; K Brugger; K Kutsam; J Spenger; J Koch; P Hofbauer; F B Lagler; W Sperl; D Weghuber; S B Wortmann Journal: Monatsschr Kinderheilkd Date: 2021-07-29 Impact factor: 0.323
Authors: Heidi Zweers; Annemiek M J van Wegberg; Mirian C H Janssen; Saskia B Wortmann Journal: Orphanet J Rare Dis Date: 2021-07-03 Impact factor: 4.123